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Sample records for mechanism ii molecular

  1. Molecular biological mechanism II. Molecular mechanisms of cell cycle regulation

    International Nuclear Information System (INIS)

    Jung, T.

    2000-01-01

    The cell cycle in eukaryotes is regulated by central cell cycle controlling protein kinase complexes. These protein kinase complexes consist of a catalytic subunit from the cyclin-dependent protein kinase family (CDK), and a regulatory subunit from the cyclin family. Cyclins are characterised by their periodic cell cycle related synthesis and destruction. Each cell cycle phase is characterised by a specific set of CDKs and cyclins. The activity of CDK/cyclin complexes is mainly regulated on four levels. It is controlled by specific phosphorylation steps, the synthesis and destruction of cyclins, the binding of specific inhibitor proteins, and by active control of their intracellular localisation. At several critical points within the cell cycle, named checkpoints, the integrity of the cellular genome is monitored. If damage to the genome or an unfinished prior cell cycle phase is detected, the cell cycle progression is stopped. These cell cycle blocks are of great importance to secure survival of cells. Their primary importance is to prevent the manifestation and heritable passage of a mutated genome to daughter cells. Damage sensing, DNA repair, cell cycle control and apoptosis are closely linked cellular defence mechanisms to secure genome integrity. Disregulation in one of these defence mechanisms are potentially correlated with an increased cancer risk and therefore in at least some cases with an increased radiation sensitivity. (orig.) [de

  2. Learning and Memory, Part II: Molecular Mechanisms of Synaptic Plasticity

    Science.gov (United States)

    Lombroso, Paul; Ogren, Marilee

    2009-01-01

    The molecular events that are responsible for strengthening synaptic connections and how these are linked to memory and learning are discussed. The laboratory preparations that allow the investigation of these events are also described.

  3. Structure and dynamics of hydrated Fe(II) and Fe(III) ions. Quantum mechanical and molecular mechanical simulations

    International Nuclear Information System (INIS)

    Remsungnen, T.

    2002-11-01

    Classical molecular dynamics (MD) and combined em ab initio quantum mechanical/molecular mechanical molecular dynamics (QM/MM-MD) simulations have been performed to investigate structural, dynamical and energetical properties of Fe(II), and Fe(III) transition metal ions in aqueous solution. In the QM/MM-MD simulations the ion and its first hydration sphere were treated at the Hartree-Fock ab initio quantum mechanical level, while ab initio generated pair plus three-body potentials were employed for the remaining system. For the classical MD simulation the pair plus three-body potential were employed for all ion-water interactions. The coordination number of the first hydration shell is 100 % of 6 in both cases. The number of waters in the second hydration shell obtained from classical simulations are 13.4 and 15.1 for Fe(II) and Fe(III), respectively, while QM/MM-MD gives the values of 12.4 and 13.4 for Fe(II) and Fe(III). The energies of hydration obtained from MD and QM/MM-MD for Fe(II) are 520 and 500 kcal/mol, and for Fe(III) 1160 and 1100 kcal/mol respectively. The mean residence times of water in the second shell obtained from QM/MM-MD are 24 and 48 ps for Fe(II) and Fe(III), respectively. In contrast to the data obtained from classical MD simulation, the QM/MM-MD values are all in good agreement with the experimental data available. These investigations and results clearly indicate that many-body effects are essential for the proper description of all properties of the aqueous solution of both Fe(II) and Fe(III) ions. (author)

  4. Dynamics of ligand exchange mechanism at Cu(II) in water: An ab initio quantum mechanical charge field molecular dynamics study with extended quantum mechanical region

    International Nuclear Information System (INIS)

    Moin, Syed Tarique; Hofer, Thomas S.; Weiss, Alexander K. H.; Rode, Bernd M.

    2013-01-01

    Ab initio quantum mechanical charge field molecular dynamics (QMCF-MD) were successfully applied to Cu(II) embedded in water to elucidate structure and to understand dynamics of ligand exchange mechanism. From the simulation studies, it was found that using an extended large quantum mechanical region including two shells of hydration is required for a better description of the dynamics of exchanging water molecules. The structural features characterized by radial distribution function, angular distribution function and other analytical parameters were consistent with experimental data. The major outcome of this study was the dynamics of exchange mechanism and reactions in the first hydration shell that could not be studied so far. The dynamical data such as mean residence time of the first shell water molecules and other relevant data from the simulations are close to the results determined experimentally. Another major characteristic of hydrated Cu(II) is the Jahn-Teller distortion which was also successfully reproduced, leading to the final conclusion that the dominating aqua complex is a 6-coordinated species. The ab initio QMCF-MD formalism proved again its capabilities of unraveling even ambiguous properties of hydrated species that are far difficult to explore by any conventional quantum mechanics/molecular mechanics (QM/MM) approach or experiment

  5. Dynamics of ligand exchange mechanism at Cu(II) in water: an ab initio quantum mechanical charge field molecular dynamics study with extended quantum mechanical region.

    Science.gov (United States)

    Moin, Syed Tarique; Hofer, Thomas S; Weiss, Alexander K H; Rode, Bernd M

    2013-07-07

    Ab initio quantum mechanical charge field molecular dynamics (QMCF-MD) were successfully applied to Cu(II) embedded in water to elucidate structure and to understand dynamics of ligand exchange mechanism. From the simulation studies, it was found that using an extended large quantum mechanical region including two shells of hydration is required for a better description of the dynamics of exchanging water molecules. The structural features characterized by radial distribution function, angular distribution function and other analytical parameters were consistent with experimental data. The major outcome of this study was the dynamics of exchange mechanism and reactions in the first hydration shell that could not be studied so far. The dynamical data such as mean residence time of the first shell water molecules and other relevant data from the simulations are close to the results determined experimentally. Another major characteristic of hydrated Cu(II) is the Jahn-Teller distortion which was also successfully reproduced, leading to the final conclusion that the dominating aqua complex is a 6-coordinated species. The ab initio QMCF-MD formalism proved again its capabilities of unraveling even ambiguous properties of hydrated species that are far difficult to explore by any conventional quantum mechanics/molecular mechanics (QM/MM) approach or experiment.

  6. Insertion of molecular oxygen into a palladium(II) methyl bond: a radical chain mechanism involving palladium(III) intermediates.

    Science.gov (United States)

    Boisvert, Luc; Denney, Melanie C; Hanson, Susan Kloek; Goldberg, Karen I

    2009-11-04

    The reaction of (bipy)PdMe(2) (1) (bipy = 2,2'-bipyridine) with molecular oxygen results in the formation of the palladium(II) methylperoxide complex (bipy)PdMe(OOMe) (2). The identity of the product 2 has been confirmed by independent synthesis. Results of kinetic studies of this unprecedented oxygen insertion reaction into a palladium alkyl bond support the involvement of a radical chain mechanism. Reproducible rates, attained in the presence of the radical initiator 2,2'-azobis(2-methylpropionitrile) (AIBN), reveal that the reaction is overall first-order (one-half-order in both [1] and [AIBN], and zero-order in [O(2)]). The unusual rate law (half-order in [1]) implies that the reaction proceeds by a mechanism that differs significantly from those for organic autoxidations and for the recently reported examples of insertion of O(2) into Pd(II) hydride bonds. The mechanism for the autoxidation of 1 is more closely related to that found for the autoxidation of main group and early transition metal alkyl complexes. Notably, the chain propagation is proposed to proceed via a stepwise associative homolytic substitution at the Pd center of 1 with formation of a pentacoordinate Pd(III) intermediate.

  7. Quantum mechanics/molecular mechanics simulation of the ligand vibrations of the water-oxidizing Mn4CaO5 cluster in photosystem II.

    Science.gov (United States)

    Nakamura, Shin; Noguchi, Takumi

    2016-10-11

    During photosynthesis, the light-driven oxidation of water performed by photosystem II (PSII) provides electrons necessary to fix CO 2 , in turn supporting life on Earth by liberating molecular oxygen. Recent high-resolution X-ray images of PSII show that the water-oxidizing center (WOC) is composed of an Mn 4 CaO 5 cluster with six carboxylate, one imidazole, and four water ligands. FTIR difference spectroscopy has shown significant structural changes of the WOC during the S-state cycle of water oxidation, especially within carboxylate groups. However, the roles that these carboxylate groups play in water oxidation as well as how they should be properly assigned in spectra are unresolved. In this study, we performed a normal mode analysis of the WOC using the quantum mechanics/molecular mechanics (QM/MM) method to simulate FTIR difference spectra on the S 1 to S 2 transition in the carboxylate stretching region. By evaluating WOC models with different oxidation and protonation states, we determined that models of high-oxidation states, Mn(III) 2 Mn(IV) 2 , satisfactorily reproduced experimental spectra from intact and Ca-depleted PSII compared with low-oxidation models. It is further suggested that the carboxylate groups bridging Ca and Mn ions within this center tune the reactivity of water ligands bound to Ca by shifting charge via their π conjugation.

  8. Insights into Photosystem II from Isomorphous Difference Fourier Maps of Femtosecond X-ray Diffraction Data and Quantum Mechanics/Molecular Mechanics Structural Models.

    Science.gov (United States)

    Wang, Jimin; Askerka, Mikhail; Brudvig, Gary W; Batista, Victor S

    2017-02-10

    Understanding structure-function relations in photosystem II (PSII) is important for the development of biomimetic photocatalytic systems. X-ray crystallography, computational modeling, and spectroscopy have played central roles in elucidating the structure and function of PSII. Recent breakthroughs in femtosecond X-ray crystallography offer the possibility of collecting diffraction data from the X-ray free electron laser (XFEL) before radiation damage of the sample, thereby overcoming the main challenge of conventional X-ray diffraction methods. However, the interpretation of XFEL data from PSII intermediates is challenging because of the issues regarding data-processing, uncertainty on the precise positions of light oxygen atoms next to heavy metal centers, and different kinetics of the S-state transition in microcrystals compared to solution. Here, we summarize recent advances and outstanding challenges in PSII structure-function determination with emphasis on the implementation of quantum mechanics/molecular mechanics techniques combined with isomorphous difference Fourier maps, direct methods, and high-resolution spectroscopy.

  9. Characterization of the Sr(2+)- and Cd(2+)-Substituted Oxygen-Evolving Complex of Photosystem II by Quantum Mechanics/Molecular Mechanics Calculations.

    Science.gov (United States)

    Pitari, Fabio; Bovi, Daniele; Narzi, Daniele; Guidoni, Leonardo

    2015-09-29

    The Mn4CaO5 cluster in the oxygen-evolving complex is the catalytic core of the Photosystem II (PSII) enzyme, responsible for the water splitting reaction in oxygenic photosynthesis. The role of the redox-inactive ion in the cluster has not yet been fully clarified, although several experimental data are available on Ca2+-depleted and Ca2+-substituted PSII complexes, indicating Sr2+-substituted PSII as the only modification that preserves oxygen evolution. In this work, we investigated the structural and electronic properties of the PSII catalytic core with Ca2+ replaced with Sr2+ and Cd2+ in the S2 state of the Kok−Joliot cycle by means of density functional theory and ab initio molecular dynamics based on a quantum mechanics/ molecular mechanics approach. Our calculations do not reveal significant differences between the substituted and wild-type systems in terms of geometries, thermodynamics, and kinetics of two previously identified intermediate states along the S2 to S3 transition, namely, the open cubane S2 A and closed cubane S2 B conformers. Conversely, our calculations show different pKa values for the water molecule bound to the three investigated heterocations. Specifically, for Cd-substituted PSII, the pKa value is 5.3 units smaller than the respective value in wild type Ca-PSII. On the basis of our results, we conclude that, assuming all the cations sharing the same binding site, the induced difference in the acidity of the binding pocket might influence the hydrogen bonding network and the redox levels to prevent the further evolution of the cycle toward the S3 state.

  10. Diagnostics of the molecular component of photon-dominated regions with mechanical heating. II. Line intensities and ratios

    NARCIS (Netherlands)

    Kazandjian, M.; Meijerink, R.; Pelupessy, F.I.; Israel, F.P.; Spaans, M.

    2015-01-01

    CO observations in active galactic nuclei and starbursts reveal high kinetic temperatures. Those environments are thought to be very turbulent due to dynamic phenomena, such as outflows and high supernova rates. We investigate the effect of mechanical heating on atomic fine-structure and molecular

  11. Polarizable molecular mechanics studies of Cu(I)/Zn(II) superoxide dismutase: bimetallic binding site and structured waters.

    Science.gov (United States)

    Gresh, Nohad; El Hage, Krystel; Perahia, David; Piquemal, Jean-Philip; Berthomieu, Catherine; Berthomieu, Dorothée

    2014-11-05

    The existence of a network of structured waters in the vicinity of the bimetallic site of Cu/Zn-superoxide dismutase (SOD) has been inferred from high-resolution X-ray crystallography. Long-duration molecular dynamics (MD) simulations could enable to quantify the lifetimes and possible interchanges of these waters between themselves as well as with a ligand diffusing toward the bimetallic site. The presence of several charged or polar ligands makes it necessary to resort to second-generation polarizable potentials. As a first step toward such simulations, we benchmark in this article the accuracy of one such potential, sum of interactions between fragments Ab initio computed (SIBFA), by comparisons with quantum mechanics (QM) computations. We first consider the bimetallic binding site of a Cu/Zn-SOD, in which three histidines and a water molecule are bound to Cu(I) and three histidines and one aspartate are bound to Zn(II). The comparisons are made for different His6 complexes with either one or both cations, and either with or without Asp and water. The total net charges vary from zero to three. We subsequently perform preliminary short-duration MD simulations of 296 waters solvating Cu/Zn-SOD. Six representative geometries are selected and energy-minimized. Single-point SIBFA and QM computations are then performed in parallel on model binding sites extracted from these six structures, each of which totals 301 atoms including the closest 28 waters from the Cu metal site. The ranking of their relative stabilities as given by SIBFA is identical to the QM one, and the relative energy differences by both approaches are fully consistent. In addition, the lowest-energy structure, from SIBFA and QM, has a close overlap with the crystallographic one. The SIBFA calculations enable to quantify the impact of polarization and charge transfer in the ranking of the six structures. Five structural waters, which connect Arg141 and Glu131, are endowed with very high dipole moments

  12. Molecular mechanics calculations on cobalt phthalocyanine dimers

    NARCIS (Netherlands)

    Heuts, J.P.A.; Schipper, E.T.W.M.; Piet, P.; German, A.L.

    1995-01-01

    In order to obtain insight into the structure of cobalt phthalocyanine dimers, molecular mechanics calculations were performed on dimeric cobalt phthalocyanine species. Molecular mechanics calculations are first presented on monomeric cobalt(II) phthalocyanine. Using the Tripos force field for the

  13. Molecular imaging II

    International Nuclear Information System (INIS)

    Semmler, Wolfhard; Schwaiger, Markus

    2008-01-01

    The aim of this textbook of molecular imaging is to provide an up to date review of this rapidly growing field and to discuss basic methodological aspects necessary for the interpretation of experimental and clinical results. Emphasis is placed on the interplay of imaging technology and probe development, since the physical properties of the imaging approach need to be closely linked with the biologic application of the probe (i.e. nanoparticles and microbubbles). Various chemical strategies are discussed and related to the biologic applications. Reporter-gene imaging is being addressed not only in experimental protocols, but also first clinical applications are discussed. Finally, strategies of imaging to characterize apoptosis and angiogenesis are described and discussed in the context of possible clinical translation. (orig.)

  14. Molecular Mechanisms of Preeclampsia

    Directory of Open Access Journals (Sweden)

    N. Vitoratos

    2012-01-01

    Full Text Available Preeclampsia is one of the leading causes of maternal morbidity/mortality. The pathogenesis of preeclampsia is still under investigation. The aim of this paper is to present the molecular mechanisms implicating in the pathway leading to preeclampsia.

  15. Conformational analysis of vitamin D 3 derivatives by molecular mechanics . Part II. 1α,25-dihydroxyvitamin D 3 and analogues

    Science.gov (United States)

    Mosquera, Ricardo A.; Rios, Miguel A.; Tovar, Clara A.; Maestro, Miguel

    1989-10-01

    The conformational analysis of vitamin D 3 derivatives, including the biologically active form 1α,25-dihydroxyvitamin D 3 (III) and several synthetic analogues: b-deoxy-1α,25-dihydroxyvitamin D 3 (IV), 3-deoxy-3α-methyl-1α,25-dihydroxyvitamin D 3 (V), 3-deoxy-3β-methyl-1α,25-dihydroxyvitamin D 3 (VI), and 3-deoxy-3,3-dimethyl-1α,25-dihydroxyvitamin D 3 (VII), has been carried out employing Allinger's molecular mechanics method. The results obtained for conformational equilibrium populations are found to be in good agreement with those provided by NMR studies. Comparison of the active form of vitamin D 3 (1α,25-dihydroxyvitamin D 3) with the other species reveals no important geometrical differences.

  16. Evolution from S3 to S4 States of the Oxygen-Evolving Complex in Photosystem II Monitored by Quantum Mechanics/Molecular Mechanics (QM/MM) Dynamics.

    Science.gov (United States)

    Narzi, Daniele; Capone, Matteo; Bovi, Daniele; Guidoni, Leonardo

    2018-04-16

    Water oxidation in the early steps of natural photosynthesis is fulfilled by photosystem II, which is a protein complex embedded in the thylakoid membrane inside chloroplasts. The water oxidation reaction occurs in the catalytic core of photosystem II, which consists of a Mn4Ca metal cluster, at which, after the accumulation of four oxidising equivalents through five steps (S0-S4) of the Kok-Joliot cycle, two water molecules are split into electrons, protons, and molecular oxygen. In recent years, by combining experimental and theoretical approaches, new insights have been achieved into the structural and electronic properties of different steps of the catalytic cycle. Nevertheless, the exact catalytic mechanism, especially concerning the final stages of the cycle, remains elusive and greatly debated. Herein, by means of quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulations, from the structural, electronic, and magnetic points of view, the S 3 state before and upon oxidation has been characterised. In contrast with the S 2 state, the oxidation of the S 3 state is not followed by a spontaneous proton-coupled electron-transfer event. Nevertheless, upon modelling the reduction of the tyrosine residue in photosystem II (Tyr Z ) and the protonation of Asp61, spontaneous proton transfer occurs, leading to the deprotonation of an oxygen atom bound to Mn1; thus making it available for O-O bond formation. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Molecular mechanisms and signaling pathways of angiotensin II-induced muscle wasting: potential therapeutic targets for cardiac cachexia

    Science.gov (United States)

    Yoshida, Tadashi; Tabony, A. Michael; Galvez, Sarah; Mitch, William E.; Higashi, Yusuke; Sukhanov, Sergiy; Delafontaine, Patrice

    2013-01-01

    Cachexia is a serious complication of many chronic diseases, such as congestive heart failure (CHF) and chronic kidney disease (CKD). Many factors are involved in the development of cachexia, and there is increasing evidence that angiotensin II (Ang II), the main effector molecule of the renin-angiotensin system (RAS), plays an important role in this process. Patients with advanced CHF or CKD often have increased Ang II levels and cachexia, and angiotensin-converting enzyme (ACE) inhibitor treatment improves weight loss. In rodent models, an increase in systemic Ang II leads to weight loss through increased protein breakdown, reduced protein synthesis in skeletal muscle and decreased appetite. Ang II activates the ubiquitin-proteasome system via generation of reactive oxygen species and via inhibition of the insulin-like growth factor-1 signaling pathway. Furthermore, Ang II inhibits 5′ AMP-activated protein kinase (AMPK) activity and disrupts normal energy balance. Ang II also increases cytokines and circulating hormones such as tumor necrosis factor-α, interleukin-6, serum amyloid-A, glucocorticoids and myostatin, which regulate muscle protein synthesis and degradation. Ang II acts on hypothalamic neurons to regulate orexigenic/anorexigenic neuropeptides, such as neuropeptide-Y, orexin and corticotropin-releasing hormone, leading to reduced appetite. Also, Ang II may regulate skeletal muscle regenerative processes. Several clinical studies have indicated that blockade of Ang II signaling via ACE inhibitors or Ang II type 1 receptor blockers prevents weight loss and improves muscle strength. Thus the RAS is a promising target for the treatment of muscle atrophy in patients with CHF and CKD. PMID:23769949

  18. Understanding molecular structure from molecular mechanics.

    Science.gov (United States)

    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.

  19. Molecular mechanisms in gliomagenesis

    DEFF Research Database (Denmark)

    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...

  20. Calculation of wave-functions with frozen orbitals in mixed quantum mechanics/molecular mechanics methods. II. Application of the local basis equation.

    Science.gov (United States)

    Ferenczy, György G

    2013-04-05

    The application of the local basis equation (Ferenczy and Adams, J. Chem. Phys. 2009, 130, 134108) in mixed quantum mechanics/molecular mechanics (QM/MM) and quantum mechanics/quantum mechanics (QM/QM) methods is investigated. This equation is suitable to derive local basis nonorthogonal orbitals that minimize the energy of the system and it exhibits good convergence properties in a self-consistent field solution. These features make the equation appropriate to be used in mixed QM/MM and QM/QM methods to optimize orbitals in the field of frozen localized orbitals connecting the subsystems. Calculations performed for several properties in divers systems show that the method is robust with various choices of the frozen orbitals and frontier atom properties. With appropriate basis set assignment, it gives results equivalent with those of a related approach [G. G. Ferenczy previous paper in this issue] using the Huzinaga equation. Thus, the local basis equation can be used in mixed QM/MM methods with small size quantum subsystems to calculate properties in good agreement with reference Hartree-Fock-Roothaan results. It is shown that bond charges are not necessary when the local basis equation is applied, although they are required for the self-consistent field solution of the Huzinaga equation based method. Conversely, the deformation of the wave-function near to the boundary is observed without bond charges and this has a significant effect on deprotonation energies but a less pronounced effect when the total charge of the system is conserved. The local basis equation can also be used to define a two layer quantum system with nonorthogonal localized orbitals surrounding the central delocalized quantum subsystem. Copyright © 2013 Wiley Periodicals, Inc.

  1. Molecular mechanisms of cancer

    National Research Council Canada - National Science Library

    Weber, Georg F

    2007-01-01

    ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Section I. General Mechanisms of Transformation 1. Theories of Carcinogenesis...

  2. Molecular Mechanisms of Preeclampsia

    OpenAIRE

    N. Vitoratos; D. Hassiakos; C. Iavazzo

    2012-01-01

    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 ...

  3. Molecular Mechanisms of Preeclampsia.

    Science.gov (United States)

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

    2015-08-20

    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. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

  4. Molecular Mechanisms of Preeclampsia

    Science.gov (United States)

    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

  5. Molecular mechanisms of carcinogenesis

    International Nuclear Information System (INIS)

    Hall, E.J.

    1997-01-01

    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

  6. Quantum mechanics II advanced topics

    CERN Document Server

    Rajasekar, S

    2015-01-01

    Quantum Mechanics II: Advanced Topics uses more than a decade of research and the authors’ own teaching experience to expound on some of the more advanced topics and current research in quantum mechanics. A follow-up to the authors introductory book Quantum Mechanics I: The Fundamentals, this book begins with a chapter on quantum field theory, and goes on to present basic principles, key features, and applications. It outlines recent quantum technologies and phenomena, and introduces growing topics of interest in quantum mechanics. The authors describe promising applications that include ghost imaging, detection of weak amplitude objects, entangled two-photon microscopy, detection of small displacements, lithography, metrology, and teleportation of optical images. They also present worked-out examples and provide numerous problems at the end of each chapter.

  7. STATINS AND MYOPATHY: MOLECULAR MECHANISMS

    Directory of Open Access Journals (Sweden)

    O. M. Drapkina

    2012-01-01

    Full Text Available The safety of statin therapy is considered. In particular the reasons of a complication such as myopathy are discussed in detail. The molecular mechanisms of statin myopathy , as well as its risk factors are presented. The role of coenzyme Q10 in the myopathy development and coenzyme Q10 application for the prevention of this complication are considered. 

  8. Hyperinsulinemic Hypoglycemia ? The Molecular Mechanisms

    OpenAIRE

    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 secretio...

  9. Molecular features of colorectal polyps presenting Kudo’s type II mucosal crypt pattern: are they based on the same mechanism of tumorigenesis?

    Science.gov (United States)

    Shinmura, Kensuke; Konishi, Kazuo; Yamochi, Toshiko; Kubota, Yutaro; Yano, Yuichiro; Katagiri, Atsushi; Muramoto, Takashi; Kihara, Toshihiro; Tojo, Masayuki; Konda, Kenichi; Tagawa, Teppei; Yanagisawa, Fumito; Kogo, Mari; Makino, Reiko; Takimoto, Masafumi; Yoshida, Hitoshi

    2014-01-01

    Background and study aims: The molecular features of serrated polyps (SPs) with hyperplastic crypt pattern, also called Kudo’s type II observed by chromoendoscopy, were evaluated. Methods: The clinicopathological and molecular features of 114 SPs with a hyperplastic pit pattern detected under chromoendoscopy (five dysplastic SPs, 63 sessile serrated adenoma/polyps (SSA/Ps), 36 microvesicular hyperplastic polyps (MVHPs), and 10 goblet cell-rich hyperplastic polyps (GCHPs)) were examined. The frequency of KRAS and BRAF mutations and CpG island methylator phenotype (CIMP) were investigated. Results: Dysplastic SPs and SSA/Ps were frequently located in the proximal colon compared to others (SSA/Ps vs. MVHPs or GCHPs, P GCHP (60 % for dysplastic SPs, 44 % for SSA/Ps, 47 % for MVHPs, and 0 % for GCHPs). The frequency of CIMP was higher in dysplastic SPs or SSA/Ps than in MVHPs or GCHPs (60 % for dysplastic SPs, 56 % for SSA/Ps, 32 % for MVHPs, and 10 % for GCHPs) (SSA/Ps vs. GCHP, P = 0.0068). When serrated neoplasias (SNs) and MVHPs were classified into proximal and distal lesions, the frequency of CIMP was significantly higher in the proximal compared to the distal SNs (64 % vs. 11 %, P = 0.0032). Finally, multivariate analysis showed that proximal location and BRAF mutation were significantly associated with an increased risk of CIMP. Conclusions: Distinct molecular features were observed between proximal and distal SPs with hyperplastic crypt pattern. Proximal MVHPs may develop more frequently through SSA/Ps to CIMP cancers than distal MVHPs. PMID:26134964

  10. Molecular features of colorectal polyps presenting Kudo's type II mucosal crypt pattern: are they based on the same mechanism of tumorigenesis?

    Science.gov (United States)

    Shinmura, Kensuke; Konishi, Kazuo; Yamochi, Toshiko; Kubota, Yutaro; Yano, Yuichiro; Katagiri, Atsushi; Muramoto, Takashi; Kihara, Toshihiro; Tojo, Masayuki; Konda, Kenichi; Tagawa, Teppei; Yanagisawa, Fumito; Kogo, Mari; Makino, Reiko; Takimoto, Masafumi; Yoshida, Hitoshi

    2014-09-01

    The molecular features of serrated polyps (SPs) with hyperplastic crypt pattern, also called Kudo's type II observed by chromoendoscopy, were evaluated. The clinicopathological and molecular features of 114 SPs with a hyperplastic pit pattern detected under chromoendoscopy (five dysplastic SPs, 63 sessile serrated adenoma/polyps (SSA/Ps), 36 microvesicular hyperplastic polyps (MVHPs), and 10 goblet cell-rich hyperplastic polyps (GCHPs)) were examined. The frequency of KRAS and BRAF mutations and CpG island methylator phenotype (CIMP) were investigated. Dysplastic SPs and SSA/Ps were frequently located in the proximal colon compared to others (SSA/Ps vs. MVHPs or GCHPs, P GCHP (60 % for dysplastic SPs, 44 % for SSA/Ps, 47 % for MVHPs, and 0 % for GCHPs). The frequency of CIMP was higher in dysplastic SPs or SSA/Ps than in MVHPs or GCHPs (60 % for dysplastic SPs, 56 % for SSA/Ps, 32 % for MVHPs, and 10 % for GCHPs) (SSA/Ps vs. GCHP, P = 0.0068). When serrated neoplasias (SNs) and MVHPs were classified into proximal and distal lesions, the frequency of CIMP was significantly higher in the proximal compared to the distal SNs (64 % vs. 11 %, P = 0.0032). Finally, multivariate analysis showed that proximal location and BRAF mutation were significantly associated with an increased risk of CIMP. Distinct molecular features were observed between proximal and distal SPs with hyperplastic crypt pattern. Proximal MVHPs may develop more frequently through SSA/Ps to CIMP cancers than distal MVHPs.

  11. Molecular mechanisms of fluoride toxicity.

    Science.gov (United States)

    Barbier, Olivier; Arreola-Mendoza, Laura; Del Razo, Luz María

    2010-11-05

    Halfway through the twentieth century, fluoride piqued the interest of toxicologists due to its deleterious effects at high concentrations in human populations suffering from fluorosis and in in vivo experimental models. Until the 1990s, the toxicity of fluoride was largely ignored due to its "good reputation" for preventing caries via topical application and in dental toothpastes. However, in the last decade, interest in its undesirable effects has resurfaced due to the awareness that this element interacts with cellular systems even at low doses. In recent years, several investigations demonstrated that fluoride can induce oxidative stress and modulate intracellular redox homeostasis, lipid peroxidation and protein carbonyl content, as well as alter gene expression and cause apoptosis. Genes modulated by fluoride include those related to the stress response, metabolic enzymes, the cell cycle, cell-cell communications and signal transduction. The primary purpose of this review is to examine recent findings from our group and others that focus on the molecular mechanisms of the action of inorganic fluoride in several cellular processes with respect to potential physiological and toxicological implications. This review presents an overview of the current research on the molecular aspects of fluoride exposure with emphasis on biological targets and their possible mechanisms of involvement in fluoride cytotoxicity. The goal of this review is to enhance understanding of the mechanisms by which fluoride affects cells, with an emphasis on tissue-specific events in humans. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  12. Molecular mechanisms of renal aging.

    Science.gov (United States)

    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.

  13. Molecular Mechanism of Somite Development

    Directory of Open Access Journals (Sweden)

    Gulfidan Coskun

    2013-06-01

    Full Text Available From third week of gestation, notochord and the neural folds begin to gather at the center of the embryo to form the paraxial mesoderm. Paraxial mesoderm separates into blocks of cells called somitomers at the lateral sides of the neural tube of the head region. At the beginning of the third week somitomeres take ring shapes and form blocks of somites from occipital region to caudal region. Although somites are transient structures, they are extremely important in organizing the segmental pattern of vertebrate embryos. Somites give rise to the cells that form the vertebrae and ribs, the dermis of the dorsal skin, the skeletal muscles of the back, and the skeletal muscles of the body wall and limbs. Somitogenesis are formed by a genetic mechanism that is regulated by cyclical expression of genes in the Notch, Wnt and fibroblast growth factor signaling pathways. The prevailing model of the mechanism governing somitogenesis is the “clock and wave front”. Somitogenesis has components of periodicity, separation, epithelialization and axial specification. According to this model, the clock causes cells to undergo repeated oscillations, with a particular phase of each oscillation defining the competency of cells in the presomitic mesoderm to form a somite. Any disruption in this mechanism can be cause of severe segmentation defects of the vertebrae and congenital anomalies. In this review, we discuss the molecular mechanisms underlying the somitogenesis which is an important part of morphogenesis. [Archives Medical Review Journal 2013; 22(3.000: 362-376

  14. The O2-Evolving Complex of Photosystem II: Recent Insights from Quantum Mechanics/Molecular Mechanics (QM/MM), Extended X-ray Absorption Fine Structure (EXAFS), and Femtosecond X-ray Crystallography Data.

    Science.gov (United States)

    Askerka, Mikhail; Brudvig, Gary W; Batista, Victor S

    2017-01-17

    Efficient photoelectrochemical water oxidation may open a way to produce energy from renewable solar power. In biology, generation of fuel due to water oxidation happens efficiently on an immense scale during the light reactions of photosynthesis. To oxidize water, photosynthetic organisms have evolved a highly conserved protein complex, Photosystem II. Within that complex, water oxidation happens at the CaMn 4 O 5 inorganic catalytic cluster, the so-called oxygen-evolving complex (OEC), which cycles through storage "S" states as it accumulates oxidizing equivalents and produces molecular oxygen. In recent years, there has been significant progress in understanding the OEC as it evolves through the catalytic cycle. Studies have combined conventional and femtosecond X-ray crystallography with extended X-ray absorption fine structure (EXAFS) and quantum mechanics/molecular mechanics (QM/MM) methods and have addressed changes in protonation states of μ-oxo bridges and the coordination of substrate water through the analysis of ammonia binding as a chemical analog of water. These advances are thought to be critical to understanding the catalytic cycle since protonation states regulate the relative stability of different redox states and the geometry of the OEC. Therefore, establishing the mechanism for substrate water binding and the nature of protonation/redox state transitions in the OEC is essential for understanding the catalytic cycle of O 2 evolution. The structure of the dark-stable S 1 state has been a target for X-ray crystallography for the past 15 years. However, traditional X-ray crystallography has been hampered by radiation-induced reduction of the OEC. Very recently, a revolutionary X-ray free electron laser (XFEL) technique was applied to PSII to reveal atomic positions at 1.95 Å without radiation damage, which brought us closer than ever to establishing the ultimate structure of the OEC in the S 1 state. However, the atom positions in this crystal

  15. Molecular Mechanisms of Induced Pluripotency

    Science.gov (United States)

    Muchkaeva, I.A.; Dashinimaev, E.B.; Terskikh, V.V.; Sukhanov, Y.V.; Vasiliev, A.V.

    2012-01-01

    In this review the distinct aspects of somatic cell reprogramming are discussed. The molecular mechanisms of generation of induced pluripotent stem (iPS) cells from somatic cells via the introduction of transcription factors into adult somatic cells are considered. Particular attention is focused on the generation of iPS cells without genome modifications via the introduction of the mRNA of transcription factors or the use of small molecules. Furthermore, the strategy of direct reprogramming of somatic cells omitting the generation of iPS cells is considered. The data concerning the differences between ES and iPS cells and the problem of epigenetic memory are also discussed. In conclusion, the possibility of using iPS cells in regenerative medicine is considered. PMID:22708059

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

    Science.gov (United States)

    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 S N 1-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.

  17. Molecular Mechanisms of Bacterial Pathogenicity

    Science.gov (United States)

    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.

  18. Molecular toxicity mechanism of nanosilver

    Directory of Open Access Journals (Sweden)

    Danielle McShan

    2014-03-01

    Full Text Available 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 O2 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.

  19. Conformation analysis of trehalose. Molecular dynamics simulation and molecular mechanics

    International Nuclear Information System (INIS)

    Donnamaira, M.C.; Howard, E.I.; Grigera, J.R.

    1992-09-01

    Conformational analysis of the disaccharide trehalose is done by molecular dynamics and molecular mechanics. In spite of the different force fields used in each case, comparison between the molecular dynamics trajectories of the torsional angles of glycosidic linkage and energy conformational map shows a good agreement between both methods. By molecular dynamics it is observed a moderate mobility of the glycosidic linkage. The demands of computer time is comparable in both cases. (author). 6 refs, 4 figs

  20. On the distinction of the mechanisms of DNA cleavage by restriction enzymes—The I-, II-, and III-type molecular motors

    Science.gov (United States)

    Pikin, S. A.

    2008-09-01

    A comparative physical description is given for the functioning of various restriction enzymes and for their processes of DNA cleavage. The previously proposed model system of kinetic equations is applied to the I-and III-type enzymes, which use ATP molecules as an energy source, while the II-type enzymes work thanks to catalytic reactions with participation of an electric field. All the enzymes achieved bending and twisting DNA, providing for either the linear motion of the II-type enzyme along the DNA chain or the DNA translocation by the I-and III-type enzymes due to moving chiral kinks. A comparative estimation of the considered linear and angular velocities is performed. The role of stalling forces for enzyme-DNA complexes, which induce the observed cutting of the DNA either inside the enzyme (II) or in some “weak” places outside enzymes I and III, which results in the supercoiling of the DNA, is shown. The role of ionic screening for the described processes is discussed.

  1. Molecular mechanisms of NCAM function

    DEFF Research Database (Denmark)

    Hinsby, Anders M; Berezin, Vladimir; Bock, Elisabeth

    2004-01-01

    receptor that responds to both homophilic and heterophilic cues, as well as a mediator of cell-cell adhesion. This review describes NCAM function at the molecular level. We discuss recent models for extracellular ligand-interactions of NCAM, and the intracellular signaling cascade that follows to define...

  2. Molecular mechanisms of insulin resistance

    African Journals Online (AJOL)

    Review Article. ,. Molecular ... This review discusses recent advances in understanding of the structure and ... insulin action from receptor to the alteration of blood glucose. Hence, in ... the first protein to have its amino acid sequence determined;2 ... an integral membrane glycoprotein composed of two subunits, a and 13 ...

  3. Polarization effects in molecular mechanical force fields

    Energy Technology Data Exchange (ETDEWEB)

    Cieplak, Piotr [Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92120 (United States); Dupradeau, Francois-Yves [UMR CNRS 6219-Faculte de Pharmacie, Universite de Picardie Jules Verne, 1 rue des Louvels, F-80037 Amiens (France); Duan, Yong [Genome Center and Department of Applied Science, University of California, Davis, One Shields Avenue, Davis, CA 95616 (United States); Wang Junmei, E-mail: pcieplak@burnham.or [Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Boulevard, ND9.136, Dallas, TX 75390-9050 (United States)

    2009-08-19

    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. (topical review)

  4. Molecular mechanism of insulin resistance

    Indian Academy of Sciences (India)

    Free fatty acids are known to play a key role in promoting loss of insulin sensitivity, thereby causing insulin resistance and type 2 diabetes. However, the underlying mechanism involved is still unclear. In searching for the cause of the mechanism, it has been found that palmitate inhibits insulin receptor (IR) gene expression, ...

  5. Semiclassical mechanics with molecular applications

    CERN Document Server

    Child, M S

    2014-01-01

    Semiclassical mechanics, which stems from the old quantum theory, has seen a remarkable revival in recent years as a physically intuitive and computationally accurate scheme for the interpretation of modern experiments. The main text concentrates less on the mathematical foundations than on the global influence of the classical phase space structures on the quantum mechanical observables. Further mathematical detail is contained in the appendices. Worked problem sets are included as an aid to the student.

  6. Molecular mechanism of radiosensitization by nitro compounds

    International Nuclear Information System (INIS)

    Kagiya, T.; Wada, T.; Nishimoto, S.I.

    1984-01-01

    In this chapter a molecular mechanism of radiosensitization by electron-affinic nitro compounds is discussed, mainly on the basis of the results of the radiation-induced chemical studies of DNA-related compounds in aqueous solutions. In Section II the general aspects of the radiation chemistry of organic compounds in the absence and presence of oxygen in aqueous solution are shown in order to demonstrate characteristic differences between radiation chemical reactions in hypoxic and oxic cells. The effects of nitro compounds on the radiolysis yields of DNA-related compounds in aqueous solutions are described in Section III. In Section IV the retardation effects of misonidazole on the radiation chemical processes of DNA-related compounds are shown along with the reaction characteristics of misonidazole with hydroxyl radical ( . OH) and hydrated electron (e/sub aq/-bar) produced by the radiolysis of water. The promotion of radiation-induced oxidation of thymine into thymine glycol (TG) by nitro radiosensitizers in deoxygenated solution and the relations between the activity of nitro compound for the thymine glycol formation and the enhancement activity measured in vitro are described in Section V. Finally, the protection against radiation-induced damage of thymine by a sulfhydryl compound of glutathione and the ability of electron-affinic compounds to decompose the intracellular radioprotector are described in Section VI

  7. Molecular mechanisms of crystal growth

    International Nuclear Information System (INIS)

    Pina, C. M.

    2000-01-01

    In this paper I present an example of the research that the Mineral Surface Group of the Munster University is conducting in the field of Crystal Growth. Atomic Force Microscopy (Am) in situ observations of different barite (BaSO4) faces growing from aqueous solutions, in combination with computer simulations of the surface attachment of growth units allows us to test crystal growth models. Our results demonstrate the strong structural control that a crystal can exert on its own growth, revealing also the limitation of the classical crystal growth theories (two dimensional nucleation and spiral growth models) in providing a complete explanation for the growth behaviour at a molecular scale. (Author) 6 refs

  8. Molecular mechanisms of induced pluripotency.

    Science.gov (United States)

    Kulcenty, Katarzyna; Wróblewska, Joanna; Mazurek, Sylwia; Liszewska, Ewa; Jaworski, Jacek

    2015-01-01

    Growing knowledge concerning transcriptional control of cellular pluripotency has led to the discovery that the fate of differentiated cells can be reversed, which has resulted in the generation, by means of genetic manipulation, of induced pluripotent stem cells. Overexpression of just four pluripotency-related transcription factors, namely Oct3/4, Sox2, Klf4, and c-Myc (Yamanaka factors, OKSM), in fibroblasts appears sufficient to produce this new cell type. Currently, we know that these factors induce several changes in genetic program of differentiated cells that can be divided in two general phases: the initial one is stochastic, and the subsequent one is highly hierarchical and organised. This review briefly discusses the molecular events leading to induction of pluripotency in response to forced presence of OKSM factors in somatic cells. We also discuss other reprogramming strategies used thus far as well as the advantages and disadvantages of laboratory approaches towards pluripotency induction in different cell types.

  9. Molecular pathogenesis and mechanisms of thyroid cancer

    Science.gov (United States)

    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

  10. Molecular Mechanisms of Renal Ischemic Conditioning Strategies

    DEFF Research Database (Denmark)

    Kierulf-Lassen, Casper; Nieuwenhuijs-Moeke, Gertrude J; Krogstrup, Nicoline V

    2015-01-01

    summarizes research on the molecular mechanisms underlying both local and remote ischemic pre-, per- and postconditioning of the kidney. The different types of conditioning strategies in the kidney recruit similar powerful pro-survival mechanisms. Likewise, renal ischemic conditioning mobilizes many...

  11. Molecular mechanisms of thyroid tumorigenesis

    International Nuclear Information System (INIS)

    Krause, K.; Fuehrer, D.

    2008-01-01

    Thyroid nodules are the most frequent endocrine disorder and occur in approximately 30% of the German population. Thyroid nodular disease constitutes a very heterogeneous entity. A striking diversity of possible functional and morphological features of a thyroid tumour derived from the same thyroid ancestor cell, is a hallmark of thyroid tumorigenesis and is due to specific genetic alterations. Defects in known candidate genes can be found in up to 70% of differentiated thyroid carcinomas and determine the respective cancer phenotype. Papillary thyroid cancers (PTC) harbour BRAF (or much less frequently RAS) mutations in sporadically occurring tumours, while radiation-induced PTC display chromosomal rearrangements such as RET, TRK, APR9 / BRAF. These genetic events results in constitutive MAPKinase activation. Follicular thyroid cancers (FTC) harbour RAS mutations or PAX8/ PPARγ rearrangements, both of which, however have also been identified in follicular adenoma. In addition, recent studies show, that activation of PI3K/AKT signalling occurs with high frequency in follicular thyroid tumours. Undifferentiated (anaplastic) thyroid cancers (ATC) display genetic features of FTC or PTC, in addition to aberant activation of multiple tyrosinkinase pathways (overexpression or mutations in PI3K and MAPK pathways). This underscores the concept of a sequential evolution of ATC from differentiated thyroid cancer, a process widely conceived to be triggered by p53 inactivation. In contrast, the molecular pathogenesis of benign thyroid tumours, in particular cold thyroid nodules is less known, except for toxic thyroid nodules, which arise from constitutive activation of cAMP signalling, predominantly through TSHR mutations. (orig.)

  12. Molecular Mechanisms of Appetite Regulation

    Directory of Open Access Journals (Sweden)

    Ji Hee Yu

    2012-12-01

    Full Text Available 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.

  13. Molecular Mechanisms Underlying Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Christian Trepo

    2009-11-01

    Full Text Available Hepatocarcinogenesis is a complex process that remains still partly understood. That might be explained by the multiplicity of etiologic factors, the genetic/epigenetic heterogeneity of tumors bulks and the ignorance of the liver cell types that give rise to tumorigenic cells that have stem cell-like properties. The DNA stress induced by hepatocyte turnover, inflammation and maybe early oncogenic pathway activation and sometimes viral factors, leads to DNA damage response which activates the key tumor suppressive checkpoints p53/p21Cip1 and p16INK4a/pRb responsible of cell cycle arrest and cellular senescence as reflected by the cirrhosis stage. Still obscure mechanisms, but maybe involving the Wnt signaling and Twist proteins, would allow pre-senescent hepatocytes to bypass senescence, acquire immortality by telomerase reactivation and get the last genetic/epigenetic hits necessary for cancerous transformation. Among some of the oncogenic pathways that might play key driving roles in hepatocarcinogenesis, c-myc and the Wnt/β-catenin signaling seem of particular interest. Finally, antiproliferative and apoptosis deficiencies involving TGF-β, Akt/PTEN, IGF2 pathways for instance are prerequisite for cancerous transformation. Of evidence, not only the transformed liver cell per se but the facilitating microenvironment is of fundamental importance for tumor bulk growth and metastasis.

  14. Mechanical Behaviour of Materials Volume II Fracture Mechanics and Damage

    CERN Document Server

    François, Dominique; Zaoui, André

    2013-01-01

    Designing new structural materials, extending lifetimes and guarding against fracture in service are among the preoccupations of engineers, and to deal with these they need to have command of the mechanics of material behaviour. This ought to reflect in the training of students. In this respect, the first volume of this work deals with elastic, elastoplastic, elastoviscoplastic and viscoelastic behaviours; this second volume continues with fracture mechanics and damage, and with contact mechanics, friction and wear. As in Volume I, the treatment links the active mechanisms on the microscopic scale and the laws of macroscopic behaviour. Chapter I is an introduction to the various damage phenomena. Chapter II gives the essential of fracture mechanics. Chapter III is devoted to brittle fracture, chapter IV to ductile fracture and chapter V to the brittle-ductile transition. Chapter VI is a survey of fatigue damage. Chapter VII is devoted to hydogen embrittlement and to environment assisted cracking, chapter VIII...

  15. Molecular mechanisms of DNA photodamage

    Energy Technology Data Exchange (ETDEWEB)

    Starrs, S.M

    2000-05-01

    Photodamage in DNA, caused by ultraviolet (UV) light, can occur by direct excitation of the nucleobases or indirectly via the action of photosensitisers. Such, DNA photodamage can be potentially mutagenic or lethal. Among the methods available for detecting UV-induced DNA damage, gel sequencing protocols, utilising synthetic oligodeoxyribonucleotides as targets for UV radiation, allow photolesions to be mapped at nucleotide resolution. This approach has been applied to investigate both DNA damage mechanisms. Following a general overview of DNA photoreactivity, and a description of the main experimental procedures, Chapter 3 identifies the origin of an anomalous mobility shift observed in purine chemical sequence ladders that can confuse the interpretation of DNA cleavage results; measures to abolish this shift are also described. Chapters 4 and 5 examine the alkali-labile DNA damage photosensitised by representative nonsteroidal antiinflammatory drugs (NSAIDs) and the fluoroquinolone antibiotics. Suprofen was the most photoactive NSAID studied, producing different patterns of guanine-specific damage in single-stranded and duplex DNA. Uniform modification of guanine bases, typifying attack by singlet oxygen, was observed in single-stranded oligodeoxyribonucleotides. In duplex molecules, modification was limited to the 5'-G of GG doublets, which is indicative of an electron transfer. The effect of quenchers and photoproduct analysis substantiated these findings. The quinolone, nalidixic acid, behaves similarly. The random base cleavage photosensitised by the fluoroquinolones, has been attributed to free radicals produced during their photodecomposition. Chapter 6 addresses the photoreactivity of purines within unusual DNA structures formed by the repeat sequences (GGA){sub n} and (GA){sub n}, and a minihairpin. There was no definitive evidence for enhanced purine reactivity caused by direct excitation. Finally, Chapter 7 investigates the mutagenic potential of a

  16. Molecular mechanisms of DNA photodamage

    International Nuclear Information System (INIS)

    Starrs, S.M.

    2000-05-01

    Photodamage in DNA, caused by ultraviolet (UV) light, can occur by direct excitation of the nucleobases or indirectly via the action of photosensitisers. Such, DNA photodamage can be potentially mutagenic or lethal. Among the methods available for detecting UV-induced DNA damage, gel sequencing protocols, utilising synthetic oligodeoxyribonucleotides as targets for UV radiation, allow photolesions to be mapped at nucleotide resolution. This approach has been applied to investigate both DNA damage mechanisms. Following a general overview of DNA photoreactivity, and a description of the main experimental procedures, Chapter 3 identifies the origin of an anomalous mobility shift observed in purine chemical sequence ladders that can confuse the interpretation of DNA cleavage results; measures to abolish this shift are also described. Chapters 4 and 5 examine the alkali-labile DNA damage photosensitised by representative nonsteroidal antiinflammatory drugs (NSAIDs) and the fluoroquinolone antibiotics. Suprofen was the most photoactive NSAID studied, producing different patterns of guanine-specific damage in single-stranded and duplex DNA. Uniform modification of guanine bases, typifying attack by singlet oxygen, was observed in single-stranded oligodeoxyribonucleotides. In duplex molecules, modification was limited to the 5'-G of GG doublets, which is indicative of an electron transfer. The effect of quenchers and photoproduct analysis substantiated these findings. The quinolone, nalidixic acid, behaves similarly. The random base cleavage photosensitised by the fluoroquinolones, has been attributed to free radicals produced during their photodecomposition. Chapter 6 addresses the photoreactivity of purines within unusual DNA structures formed by the repeat sequences (GGA) n and (GA) n , and a minihairpin. There was no definitive evidence for enhanced purine reactivity caused by direct excitation. Finally, Chapter 7 investigates the mutagenic potential of a dimeric

  17. Quantum Mechanics/Molecular Mechanics Modeling of Drug Metabolism

    DEFF Research Database (Denmark)

    Lonsdale, Richard; Fort, Rachel M; Rydberg, Patrik

    2016-01-01

    )-mexiletine in CYP1A2 with hybrid quantum mechanics/molecular mechanics (QM/MM) methods, providing a more detailed and realistic model. Multiple reaction barriers have been calculated at the QM(B3LYP-D)/MM(CHARMM27) level for the direct N-oxidation and H-abstraction/rebound mechanisms. Our calculated barriers......The mechanism of cytochrome P450(CYP)-catalyzed hydroxylation of primary amines is currently unclear and is relevant to drug metabolism; previous small model calculations have suggested two possible mechanisms: direct N-oxidation and H-abstraction/rebound. We have modeled the N-hydroxylation of (R...... indicate that the direct N-oxidation mechanism is preferred and proceeds via the doublet spin state of Compound I. Molecular dynamics simulations indicate that the presence of an ordered water molecule in the active site assists in the binding of mexiletine in the active site...

  18. Molecular machines with bio-inspired mechanisms.

    Science.gov (United States)

    Zhang, Liang; Marcos, Vanesa; Leigh, David A

    2018-02-26

    The widespread use of molecular-level motion in key natural processes suggests that great rewards could come from bridging the gap between the present generation of synthetic molecular machines-which by and large function as switches-and the machines of the macroscopic world, which utilize the synchronized behavior of integrated components to perform more sophisticated tasks than is possible with any individual switch. Should we try to make molecular machines of greater complexity by trying to mimic machines from the macroscopic world or instead apply unfamiliar (and no doubt have to discover or invent currently unknown) mechanisms utilized by biological machines? Here we try to answer that question by exploring some of the advances made to date using bio-inspired machine mechanisms.

  19. Molecular mechanism of Endosulfan action in mammals

    Indian Academy of Sciences (India)

    Keywords. DNA damage; double-strand break; genomic instability; infertility; MMEJ; NHEJ; pesticides. Abstract. Endosulfan is a broad-spectrum organochlorine pesticide, speculated to be detrimental to human health in areas ofactive exposure. However, the molecular insights to its mechanism of action remain poorly ...

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

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

    2016-09-13

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

  2. Molecular Mechanisms Behind the Chemopreventive Effects of Anthocyanidins

    Directory of Open Access Journals (Sweden)

    De-Xing Hou

    2004-01-01

    Full Text Available Anthocyanins are polyphenolic ring-based flavonoids, and are widespread in fruits and vegetables of red-blue color. Epidemiological investigations and animal experiments have indicated that anthocyanins may contribute to cancer chemoprevention. The studies on the mechanism have been done recently at molecular level. This review summarizes current molecular bases for anthocyanidins on several key steps involved in cancer chemoprevention: (i inhibition of anthocyanidins in cell transformation through targeting mitogen-activated protein kinase (MAPK pathway and activator protein 1 (AP-1 factor; (ii suppression of anthocyanidins in inflammation and carcinogenesis through targeting nuclear factor kappa B (NF-κB pathway and cyclooxygenase 2 (COX-2 gene; (iii apoptotic induction of cancer cells by anthocyanidins through reactive oxygen species (ROS / c-Jun NH2-terminal kinase (JNK-mediated caspase activation. These data provide a first molecular view of anthocyanidins contributing to cancer chemoprevention.

  3. Molecular Mechanisms of Neuroplasticity: An Expanding Universe.

    Science.gov (United States)

    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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Miller, Susan M. [UCSF

    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.

  5. Molecular mechanisms of curcumin action: gene expression.

    Science.gov (United States)

    Shishodia, Shishir

    2013-01-01

    Curcumin derived from the tropical plant Curcuma longa has a long history of use as a dietary agent, food preservative, and in traditional Asian medicine. It has been used for centuries to treat biliary disorders, anorexia, cough, diabetic wounds, hepatic disorders, rheumatism, and sinusitis. The preventive and therapeutic properties of curcumin are associated with its antioxidant, anti-inflammatory, and anticancer properties. Extensive research over several decades has attempted to identify the molecular mechanisms of curcumin action. Curcumin modulates numerous molecular targets by altering their gene expression, signaling pathways, or through direct interaction. Curcumin regulates the expression of inflammatory cytokines (e.g., TNF, IL-1), growth factors (e.g., VEGF, EGF, FGF), growth factor receptors (e.g., EGFR, HER-2, AR), enzymes (e.g., COX-2, LOX, MMP9, MAPK, mTOR, Akt), adhesion molecules (e.g., ELAM-1, ICAM-1, VCAM-1), apoptosis related proteins (e.g., Bcl-2, caspases, DR, Fas), and cell cycle proteins (e.g., cyclin D1). Curcumin modulates the activity of several transcription factors (e.g., NF-κB, AP-1, STAT) and their signaling pathways. Based on its ability to affect multiple targets, curcumin has the potential for the prevention and treatment of various diseases including cancers, arthritis, allergies, atherosclerosis, aging, neurodegenerative disease, hepatic disorders, obesity, diabetes, psoriasis, and autoimmune diseases. This review summarizes the molecular mechanisms of modulation of gene expression by curcumin. Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc.

  6. Molecular mechanisms for protein-encoded inheritance

    Science.gov (United States)

    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

    2013-01-01

    Strains are phenotypic variants, encoded by nucleic acid sequences in chromosomal inheritance and by protein “conformations” in prion inheritance and transmission. But how is a protein “conformation” stable enough to endure transmission between cells or organisms? Here new polymorphic crystal structures of segments of prion and other amyloid proteins offer structural mechanisms for prion strains. In packing polymorphism, prion strains are encoded by alternative packings (polymorphs) of β-sheets formed by the same segment of a protein; in a second mechanism, segmental polymorphism, prion strains are encoded by distinct β-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 information into prion strains share features with the familiar mechanism for transfer of information by nucleic acid inheritance, including sequence specificity and recognition by non-covalent bonds. PMID:19684598

  7. MOLECULAR MECHANISMS OF FEAR LEARNING AND MEMORY

    Science.gov (United States)

    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

  8. Molecular mechanisms of fear learning and memory.

    Science.gov (United States)

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

    2011-10-28

    Pavlovian fear conditioning is a particularly 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. Collectively, this body of 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. Copyright © 2011 Elsevier Inc. All rights reserved.

  9. Prompt mechanism of type II supernovae

    International Nuclear Information System (INIS)

    Burrows, A.; Lattimer, J.M.

    1985-01-01

    We report in this Letter on an extensive set of hydrodynamical simulations of the stellar collapse of the cores of massive stars. A new hydro technique and a series of state-of-the art equations of state were employed. The purpose of this project was to understand in detail core implosion and immediate postbounce behavior (first 25 ms) and to investigate the viability of the hydrodynamic mechanism for Type II supernovae. We find that the bounce-shock always stalls upon encountering the massive infalling outer core for the calculated cores of stars between 8 and 25 M/sub sun/ and the standard input physics. In particular, it is found that Nomoto's 8l8 m/sub sun/ star and Woosley, Weaver, and Taam's 10 M/sub sun/ star do not explode via the prompt mechanism. Our conclusions appear to depend not on the details of the progenitor structure calculated by others but rather on the generic nature of these structures

  10. Molecular Mechanisms in Exercise-Induced Cardioprotection

    Directory of Open Access Journals (Sweden)

    Saeid Golbidi

    2011-01-01

    Full Text Available Physical inactivity is increasingly recognized as modifiable behavioral risk factor for cardiovascular diseases. A partial list of proposed mechanisms for exercise-induced cardioprotection include induction of heat shock proteins, increase in cardiac antioxidant capacity, expression of endoplasmic reticulum stress proteins, anatomical and physiological changes in the coronary arteries, changes in nitric oxide production, adaptational changes in cardiac mitochondria, increased autophagy, and improved function of sarcolemmal and/or mitochondrial ATP-sensitive potassium channels. It is currently unclear which of these protective mechanisms are essential for exercise-induced cardioprotection. However, most investigations focus on sarcolemmal KATP channels, NO production, and mitochondrial changes although it is very likely that other mechanisms may also exist. This paper discusses current information about these aforementioned topics and does not consider potentially important adaptations within blood or the autonomic nervous system. A better understanding of the molecular basis of exercise-induced cardioprotection will help to develop better therapeutic strategies.

  11. Biological Applications of Hybrid Quantum Mechanics/Molecular Mechanics Calculation

    Directory of Open Access Journals (Sweden)

    Jiyoung Kang

    2012-01-01

    Full Text Available Since in most cases biological macromolecular systems including solvent water molecules are remarkably large, the computational costs of performing ab initio calculations for the entire structures are prohibitive. Accordingly, QM calculations that are jointed with MM calculations are crucial to evaluate the long-range electrostatic interactions, which significantly affect the electronic structures of biological macromolecules. A UNIX-shell-based interface program connecting the quantum mechanics (QMs and molecular mechanics (MMs calculation engines, GAMESS and AMBER, was developed in our lab. The system was applied to a metalloenzyme, azurin, and PU.1-DNA complex; thereby, the significance of the environmental effects on the electronic structures of the site of interest was elucidated. Subsequently, hybrid QM/MM molecular dynamics (MD simulation using the calculation system was employed for investigation of mechanisms of hydrolysis (editing reaction in leucyl-tRNA synthetase complexed with the misaminoacylated tRNALeu, and a novel mechanism of the enzymatic reaction was revealed. Thus, our interface program can play a critical role as a powerful tool for state-of-the-art sophisticated hybrid ab initio QM/MM MD simulations of large systems, such as biological macromolecules.

  12. Molecular mechanism of Danshensu on platelet antiaggregation

    Science.gov (United States)

    Yu, Chen; Geng, Feng; Fan, Hua-Ying; Luan, Hai-Yun; Liu, Yue; Ji, Kai; Fu, Feng-Hua

    2018-04-01

    In this study, we detected the effect of Danshensu on PARs-PLCβsignaling pathway to elucidate molecular mechanism of Danshensu on platelet anti-aggregation. Our results demonstrate that Danshensu is able to decrease the levels of IP3, Ca2+ and AA secretion, which indicate that Danshensu may involve in PARs-PLCβ signaling pathways. Molecular docking study shows that Danshesu has similar polar interactions with PAR1 receptors as BMS200261 at the same position. The findings from our study enable a better understanding of Danshensu biological properties, which could ultimately lead to the development of multi-target antiplatelet natural medicine for the treatment and/or prevention of some thrombotic diseases.

  13. Measuring the mechanical properties of molecular conformers

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  15. Kinetics of FeII-polyaminocarboxylate oxidation by molecular oxygen

    Science.gov (United States)

    Wilson, Jessica M.; Farley, Kevin J.; Carbonaro, Richard F.

    2018-03-01

    Complexation of iron by naturally-occurring and synthetic organic ligands has a large effect on iron oxidation and reduction rates which in turn affect the aqueous geochemistry of many other chemical constituents. In this study, the kinetics of FeII oxidation in the presence of the polyaminocarboxylate synthetic chelating agents ethylene glycol tetraacetic acid (EGTA) and trimethylenediamine-N,N,N‧,N‧-tetraacetic acid (TMDTA) was investigated over the pH range 5.50-8.53. Batch oxidation experiments in the presence of molecular oxygen were conducted using a 2:1 M concentration ratio of polyaminocarboxylate (ligand, L) to FeII. The experimental data resembled first order kinetics for the oxidation of FeII-L to FeIII-L and observed rate constants at pH 6.0 were comparable to rate constants for the oxidation of inorganic FeII. Similar to other structurally-similar FeII-polyaminocarboxylate complexes, oxidation rates of FeII-EGTA and FeII-TMDTA decrease with increasing pH, which is the opposite trend for the oxidation of FeII complexed with inorganic ligands. However, the oxidation rates of FeII complexed with EGTA and TMDTA were considerably lower (4-5 orders of magnitude) than FeII complexed to ethylenediaminetetraacetic acid (EDTA). The distinguishing feature of the slower-reacting complexes is that they have a longer backbone between diamine functional groups. An analytical equilibrium model was developed to determine the contributions of the species FeIIL2- and FeII(H)L- to the overall oxidation rate of FeII-L. Application of this model indicated that the protonated FeII(H)L species are more than three orders of magnitude more reactive than FeIIL2-. These rate constants were used in a coupled kinetic equilibrium numerical model where the ligand to iron ratio (TOTL:TOTFe) and pH were varied to evaluate the effect on the FeII oxidation rate. Overall, increasing TOTL:TOTFe for EGTA and TMDTA enhances FeII oxidation rates at lower pH and inhibits FeII oxidation

  16. Mechanically controllable break junctions for molecular electronics.

    Science.gov (United States)

    Xiang, Dong; Jeong, Hyunhak; Lee, Takhee; Mayer, Dirk

    2013-09-20

    A mechanically controllable break junction (MCBJ) represents a fundamental technique for the investigation of molecular electronic junctions, especially for the study of the electronic properties of single molecules. With unique advantages, the MCBJ technique has provided substantial insight into charge transport processes in molecules. In this review, the techniques for sample fabrication, operation and the various applications of MCBJs are introduced and the history, challenges and future of MCBJs are discussed. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Molecular mechanisms of action of bacterial exotoxins.

    Science.gov (United States)

    Balfanz, J; Rautenberg, P; Ullmann, U

    1996-07-01

    Toxins are one of the inventive strategies that bacteria have developed in order to survive. As virulence factors, they play a major role in the pathogenesis of infectious diseases. Recent discoveries have once more highlighted the effectiveness of these precisely adjusted bacterial weapons. Furthermore, toxins have become an invaluable tool in the investigation of fundamental cell processes, including regulation of cellular functions by various G proteins, cytoskeletal dynamics and neural transmission. In this review, the bacterial toxins are presented in a rational classification based on the molecular mechanisms of action.

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

    Science.gov (United States)

    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. Copyright © 2011 Wiley Periodicals, Inc.

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

    Science.gov (United States)

    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.

  20. Molecular mechanisms in radiation damage to DNA

    International Nuclear Information System (INIS)

    Osman, R.

    1991-01-01

    The objectives of this work are to elucidate the molecular mechanisms that are responsible for radiation-induced DNA damage. The overall goal is to understand the relationship between the chemical and structural changes produced by ionizing radiation in DNA and the resulting impairment of biological function expressed as carcinogenesis or cell death. The studies are based on theoretical explorations of possible mechanisms that link initial radiation damage in the form of base and sugar damage to conformational changes in DNA. These mechanistic explorations should lead to the formulation of testable hypothesis regarding the processes of impairment of regulation of gene expression, alternation in DNA repair, and damage to DNA structure involved in cell death or cancer

  1. Molecular mechanisms of glucocorticoid receptor signaling

    Directory of Open Access Journals (Sweden)

    Marta Labeur

    2010-10-01

    Full Text Available 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 glucocorticoid 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.

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

    Science.gov (United States)

    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.

  3. Programmed necrosis and necroptosis – molecular mechanisms

    Directory of Open Access Journals (Sweden)

    Agata Giżycka

    2015-12-01

    Full Text Available Programmed necrosis has been proven vital for organism development and homeostasis maintenance. Its regulatory effects on functional activity of the immune system, as well as on pathways regulating the death mechanisms in cells with diminished apoptotic activity, including malignant cells, have been confirmed. There is also increasing evidence indicating necrosis involvement in many human pathologies. Contrary to previous beliefs, necrosis is not only a passive, pathological, gene-independent process. However, the current knowledge regarding molecular regulation of programmed necrosis is scarce. In part this is due to the multiplicity and complexity of signaling pathways involved in programmed necrosis, as well as the absence of specific cellular markers identifying this process, but also the ambiguous and imprecise international terminology. This review presents the current state of the art on molecular mechanisms of programmed necrosis. In particular, its specific and frequent form, necroptosis, is discussed. The role of RIP1 and RIP3 kinases in this process is presented, as well as the diverse pathways induced by ligation of tumor necrosis factor α, to its receptor, TNFR1, i.e. cell survival, apoptosis or necroptosis.

  4. Understanding the molecular mechanisms of reprogramming

    Energy Technology Data Exchange (ETDEWEB)

    Krause, Marie N. [Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla 92037, CA (United States); University Hospital of Würzburg, Department of Pediatrics, 2 Josef-Schneiderstrasse, 97080 Würzburg (Germany); Sancho-Martinez, Ignacio [Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla 92037, CA (United States); Centre for Stem Cells and Regenerative Medicine, King' s College London, 28th Floor, Tower Wing, Guy' s Hospital, Great Maze Pond, London (United Kingdom); Izpisua Belmonte, Juan Carlos, E-mail: belmonte@salk.edu [Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla 92037, CA (United States)

    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.

  5. Small Galactic H II regions. II. The molecular clouds and star formation

    International Nuclear Information System (INIS)

    Hunter, D.A.; Thronson, H.A. Jr.; Wilton, C.

    1990-01-01

    CO maps of molecular clouds associated with 11 small Galactic H II regions are presented and compared with IR images obtained by IRAS. The molecular masses of the clouds are computed and compared with the masses of the stellar content. The mapped clouds have masses of 1000-60,000 solar and are typical of the more numerous, smaller Galactic molecular clouds. All of the clouds have recently made massive OB stars, and many have complex spatial and kinematic structures. The coincidence of IRAS sources and CO peaks suggests that many of the clouds have sites of star formation other than the optically visible H II region. Star-formation efficiencies are uncertain, with values for the clouds ranging from 0.02 to 0.6 with an average value of 0.2. There is no trend of the upper stellar mass limit with Galactic radius and with molecular cloud mass. 53 refs

  6. Molecular analysis of carnitine palmitoyltransferase II deficiency with hepatocardiomuscular expression

    Energy Technology Data Exchange (ETDEWEB)

    Bonnefont, J.P.; Cepanec, C.; Leroux, J.P. [Unite INSERM, Paris (France)] [and others

    1996-05-01

    Carnitine palmitoyltransferase (CPT) II deficiency, an inherited disorder of mitochondrial long-chain fatty-acid (LCFA) oxidation, results in two distinct clinical act phenotypes, namely, an adult (muscular) form and an infantile (hepatocardiomuscular) form. The rationale of this phenotypic heterogeneity is poorly understood. The adult form of the disease is commonly ascribed to the Ser-113-Leu substitution in CPT II. Only few data are available regarding the molecular basis of the infantile form of the disease. We report herein a homozygous A-2399-C transversion predicting a Tyr-628-Ser substitution in a CPT II-deficient infant. In vitro expression of mutant cDNA in COS-1 cells demonstrated the responsibility of this mutation for the disease. Metabolic consequences of the Ser-113-Leu and Tyr-628-Ser substitutions were studied in fibroblasts. The Tyr-628-Ser substitution (infantile form) resulted in a 10% CPT II residual activity, markedly impairing LCFA oxidation, whereas the Ser-113-Leu substitution (adult form) resulted in a 20% CPT II residual activity, without consequence on LCFA oxidation. These data show that CPT II activity has to be reduced below a critical threshold in order for LCFA oxidation in fibroblasts to be impaired. The hypothesis that this critical threshold differs among tissues could provide a basis to explain phenotypic heterogeneity of CPT II deficiency. 32 refs., 5 figs.

  7. High Molecular Weight Forms of Mammalian Respiratory Chain Complex II

    Czech Academy of Sciences Publication Activity Database

    Kovářová, Nikola; Mráček, Tomáš; Nůsková, Hana; Holzerová, Eliška; Vrbacký, Marek; Pecina, Petr; Hejzlarová, Kateřina; Klučková, Katarína; Rohlena, Jakub; Neužil, Jiří; Houštěk, Josef

    2013-01-01

    Roč. 8, č. 8 (2013), e71869 E-ISSN 1932-6203 R&D Projects: GA ČR(CZ) GPP303/10/P227; GA MŠk(CZ) LL1204; GA MZd(CZ) NT12370; GA ČR(CZ) GAP301/10/1937 Institutional research plan: CEZ:AV0Z50520701 Institutional support: RVO:67985823 Keywords : supercomplexes * high molecular weihgt forms of complex II * native electrophoretic systems Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.534, year: 2013

  8. Molecular Mechanisms of Mouse Skin Tumor Promotion

    International Nuclear Information System (INIS)

    Rundhaug, Joyce E.; Fischer, Susan M.

    2010-01-01

    Multiple molecular mechanisms are involved in the promotion of skin carcinogenesis. Induction of sustained proliferation and epidermal hyperplasia by direct activation of mitotic signaling pathways or indirectly in response to chronic wounding and/or inflammation, or due to a block in terminal differentiation or resistance to apoptosis is necessary to allow clonal expansion of initiated cells with DNA mutations to form skin tumors. The mitotic pathways include activation of epidermal growth factor receptor and Ras/Raf/mitogen-activated protein kinase signaling. Chronic inflammation results in inflammatory cell secretion of growth factors and cytokines such as tumor necrosis factor-α and interleukins, as well as production of reactive oxygen species, all of which can stimulate proliferation. Persistent activation of these pathways leads to tumor promotion

  9. Molecular Mechanisms of Neonatal Brain Injury

    Directory of Open Access Journals (Sweden)

    Claire Thornton

    2012-01-01

    Full Text Available Fetal/neonatal brain injury is an important cause of neurological disability. Hypoxia-ischemia and excitotoxicity are considered important insults, and, in spite of their acute nature, brain injury develops over a protracted time period during the primary, secondary, and tertiary phases. The concept that most of the injury develops with a delay after the insult makes it possible to provide effective neuroprotective treatment after the insult. Indeed, hypothermia applied within 6 hours after birth in neonatal encephalopathy reduces neurological disability in clinical trials. In order to develop the next generation of treatment, we need to know more about the pathophysiological mechanism during the secondary and tertiary phases of injury. We review some of the critical molecular events related to mitochondrial dysfunction and apoptosis during the secondary phase and report some recent evidence that intervention may be feasible also days-weeks after the insult.

  10. Molecular Mechanisms of DNA Replication Checkpoint Activation

    Directory of Open Access Journals (Sweden)

    Bénédicte Recolin

    2014-03-01

    Full Text Available 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.

  11. Molecular mechanism of the Syk activation switch.

    Science.gov (United States)

    Tsang, Emily; Giannetti, Anthony M; Shaw, David; Dinh, Marie; Tse, Joyce K Y; Gandhi, Shaan; Ho, Hoangdung; Wang, Sandra; Papp, Eva; Bradshaw, J Michael

    2008-11-21

    Many immune signaling pathways require activation of the Syk tyrosine kinase to link ligation of surface receptors to changes in gene expression. Despite the central role of Syk in these pathways, the Syk activation process remains poorly understood. In this work we quantitatively characterized the molecular mechanism of Syk activation in vitro using a real time fluorescence kinase assay, mutagenesis, and other biochemical techniques. We found that dephosphorylated full-length Syk demonstrates a low initial rate of substrate phosphorylation that increases during the kinase reaction due to autophosphorylation. The initial rate of Syk activity was strongly increased by either pre-autophosphorylation or binding of phosphorylated immune tyrosine activation motif peptides, and each of these factors independently fully activated Syk. Deletion mutagenesis was used to identify regions of Syk important for regulation, and residues 340-356 of the SH2 kinase linker region were identified to be important for suppression of activity before activation. Comparison of the activation processes of Syk and Zap-70 revealed that Syk is more readily activated by autophosphorylation than Zap-70, although both kinases are rapidly activated by Src family kinases. We also studied Syk activity in B cell lysates and found endogenous Syk is also activated by phosphorylation and immune tyrosine activation motif binding. Together these experiments show that Syk functions as an "OR-gate" type of molecular switch. This mechanism of switch-like activation helps explain how Syk is both rapidly activated after receptor binding but also sustains activity over time to facilitate longer term changes in gene expression.

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

    Science.gov (United States)

    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.

  13. Molecular and cellular mechanisms of aortic stenosis.

    Science.gov (United States)

    Yetkin, Ertan; Waltenberger, Johannes

    2009-06-12

    Calcific aortic stenosis is the most common cause of aortic valve replacement in developed countries, and this condition increases in prevalence with advancing age. The fibrotic thickening and calcification are common eventual endpoint in both non-rheumatic calcific and rheumatic aortic stenoses. New observations in human aortic valves support the hypothesis that degenerative valvular aortic stenosis is the result of active bone formation in the aortic valve, which may be mediated through a process of osteoblast-like differentiation in these tissues. Additionally histopathologic evidence suggests that early lesions in aortic valves are not just a disease process secondary to aging, but an active cellular process that follows the classical "response to injury hypothesis" similar to the situation in atherosclerosis. Although there are similarities with the risk factor and as well as with the process of atherogenesis, not all the patients with coronary artery disease or atherosclerosis have calcific aortic stenosis. This review mainly focuses on the potential vascular and molecular mechanisms involved in the pathogenesis of aortic valve stenosis. Namely extracellular matrix remodeling, angiogenesis, inflammation, and eventually osteoblast-like differentiation resulting in bone formation have been shown to play a role in the pathogenesis of calcific aortic stenosis. Several mediators related to underlying mechanisms, including growth factors especially transforming growth factor-beta1 and vascular endothelial growth factors, angiogenesis, cathepsin enzymes, adhesion molecules, bone regulatory proteins and matrix metalloproteinases have been demonstrated, however the target to be attacked is not defined yet.

  14. Variational principles of continuum mechanics II applications

    CERN Document Server

    Berdichevsky, Victor L

    2009-01-01

    This concise and understandable book about variational principles of continuum mechanics presents the classical models. The book is accessible to applied mathematicians, physicists and engineers who have an interest in continuum mechanics.

  15. Neuroprotective Effects and Mechanisms of Curcumin–Cu(II and –Zn(II Complexes Systems and Their Pharmacological Implications

    Directory of Open Access Journals (Sweden)

    Fa-Shun Yan

    2017-12-01

    Full Text Available Alzheimer’s disease (AD is the main form of dementia and has a steadily increasing prevalence. As both oxidative stress and metal homeostasis are involved in the pathogenesis of AD, it would be interesting to develop a dual function agent, targeting the two factors. Curcumin, a natural compound isolated from the rhizome of Curcuma longa, is an antioxidant and can also chelate metal ions. Whether the complexes of curcumin with metal ions possess neuroprotective effects has not been evaluated. Therefore, the present study was designed to investigate the protective effects of the complexes of curcumin with Cu(II or Zn(II on hydrogen peroxide (H2O2-induced injury and the underlying molecular mechanisms. The use of rat pheochromocytoma (PC12 cells, a widely used neuronal cell model system, was adopted. It was revealed that curcumin–Cu(II complexes systems possessed enhanced O2·–-scavenging activities compared to unchelated curcumin. In comparison with unchelated curcumin, the protective effects of curcumin–Cu(II complexes systems were stronger than curcumin–Zn(II system. Curcumin–Cu(II or –Zn(II complexes systems significantly enhanced the superoxide dismutase, catalase, and glutathione peroxidase activities and attenuated the increase of malondialdehyde levels and caspase-3 and caspase-9 activities, in a dose-dependent manner. The curcumin–Cu(II complex system with a 2:1 ratio exhibited the most significant effect. Further mechanistic study demonstrated that curcumin–Cu(II or –Zn(II complexes systems inhibited cell apoptosis via downregulating the nuclear factor κB (NF-κB pathway and upregulating Bcl-2/Bax pathway. In summary, the present study found that curcumin–Cu(II or –Zn(II complexes systems, especially the former, possess significant neuroprotective effects, which indicates the potential advantage of curcumin as a promising agent against AD and deserves further study.

  16. Neuroprotective Effects and Mechanisms of Curcumin-Cu(II) and -Zn(II) Complexes Systems and Their Pharmacological Implications.

    Science.gov (United States)

    Yan, Fa-Shun; Sun, Jian-Long; Xie, Wen-Hai; Shen, Liang; Ji, Hong-Fang

    2017-12-28

    Alzheimer's disease (AD) is the main form of dementia and has a steadily increasing prevalence. As both oxidative stress and metal homeostasis are involved in the pathogenesis of AD, it would be interesting to develop a dual function agent, targeting the two factors. Curcumin, a natural compound isolated from the rhizome of Curcuma longa , is an antioxidant and can also chelate metal ions. Whether the complexes of curcumin with metal ions possess neuroprotective effects has not been evaluated. Therefore, the present study was designed to investigate the protective effects of the complexes of curcumin with Cu(II) or Zn(II) on hydrogen peroxide (H₂O₂)-induced injury and the underlying molecular mechanisms. The use of rat pheochromocytoma (PC12) cells, a widely used neuronal cell model system, was adopted. It was revealed that curcumin-Cu(II) complexes systems possessed enhanced O₂ ·- -scavenging activities compared to unchelated curcumin. In comparison with unchelated curcumin, the protective effects of curcumin-Cu(II) complexes systems were stronger than curcumin-Zn(II) system. Curcumin-Cu(II) or -Zn(II) complexes systems significantly enhanced the superoxide dismutase, catalase, and glutathione peroxidase activities and attenuated the increase of malondialdehyde levels and caspase-3 and caspase-9 activities, in a dose-dependent manner. The curcumin-Cu(II) complex system with a 2:1 ratio exhibited the most significant effect. Further mechanistic study demonstrated that curcumin-Cu(II) or -Zn(II) complexes systems inhibited cell apoptosis via downregulating the nuclear factor κB (NF-κB) pathway and upregulating Bcl-2/Bax pathway. In summary, the present study found that curcumin-Cu(II) or -Zn(II) complexes systems, especially the former, possess significant neuroprotective effects, which indicates the potential advantage of curcumin as a promising agent against AD and deserves further study.

  17. Molecular Mechanisms of Insulin Resistance Development

    Directory of Open Access Journals (Sweden)

    Vsevolod Arsen'evich Tkachuk

    2014-05-01

    Full Text Available Insulin resistance (IR is a phenomenon associated with an impaired ability of insulin to stimulate glucose uptake by target cells and to reduce the blood glucose level. A response increase in insulin secretion by the pancreas and hyperinsulinemia are compensatory reactions of the body. The development of IR leads to the inability of target cells to respond to insulin that results in developing type 2 diabetes mellitus (T2DM and metabolic syndrome. For this reason, the metabolic syndrome is defined in practice as a combination of IR with one or more pathologies such as T2DM, arterial hypertension, dyslipidemia, abdominal obesity, non-alcoholic fatty liver disease, and some others. However, a combination of high blood glucose and insulin levels always serves as its physiological criterion.IR should be considered as a systemic failure of the endocrine regulation in the body. Physiological causes of IR are diverse. The main ones are nutritional overload and accumulation of certain lipids and their metabolites in cells, low physical activity, chronic inflammation and stress of various nature, including oxidative and endoplasmic reticulum stress (impairment of damaged protein degradation in the cell. Recent studies have demonstrated that these physiological mechanisms likely act through a single intracellular scenario. This is the impairment of signal transduction from the insulin receptor to its targets via the negative feedback mechanism in intracellular insulin-dependent signaling cascades.This review describes the physiological and intracellular mechanisms of insulin action and focuses on their abnormalities upon IR development. Finally, feasible trends in early molecular diagnosis and therapy of IR are discussed.

  18. Multiresolution molecular mechanics: Implementation and efficiency

    Energy Technology Data Exchange (ETDEWEB)

    Biyikli, Emre; To, Albert C., E-mail: albertto@pitt.edu

    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.

  19. Chemical and mechanical efficiencies of molecular motors and implications for motor mechanisms

    International Nuclear Information System (INIS)

    Wang Hongyun

    2005-01-01

    Molecular motors operate in an environment dominated by viscous friction and thermal fluctuations. The chemical reaction in a motor may produce an active force at the reaction site to directly move the motor forward. Alternatively a molecular motor may generate a unidirectional motion by rectifying thermal fluctuations using free energy barriers established in the chemical reaction. The reaction cycle has many occupancy states, each having a different effect on the motor motion. The average effect of the chemical reaction on the motor motion can be characterized by the motor potential profile. The biggest advantage of studying the motor potential profile is that it can be reconstructed from the time series of motor positions measured in single-molecule experiments. In this paper, we use the motor potential profile to express the Stokes efficiency as the product of the chemical efficiency and the mechanical efficiency. We show that both the chemical and mechanical efficiencies are bounded by 100% and, thus, are properly defined efficiencies. We discuss implications of high efficiencies for motor mechanisms: a mechanical efficiency close to 100% implies that the motor potential profile is close to a constant slope; a chemical efficiency close to 100% implies that (i) the chemical transitions are not slower than the mechanical motion and (ii) the equilibrium constant of each chemical transition is close to one

  20. NEWLY IDENTIFIED EXTENDED GREEN OBJECTS (EGOs) FROM THE SPITZER GLIMPSE II SURVEY. II. MOLECULAR CLOUD ENVIRONMENTS

    Energy Technology Data Exchange (ETDEWEB)

    Chen Xi; Gan Conggui; Shen Zhiqiang [Key Laboratory for Research in Galaxies and Cosmology, Shanghai Astronomical Observatory, Chinese Academy of Sciences, Shanghai 200030 (China); Ellingsen, Simon P.; Titmarsh, Anita [School of Mathematics and Physics, University of Tasmania, Hobart, Tasmania (Australia); He Jinhua, E-mail: chenxi@shao.ac.cn [Key Laboratory for the Structure and Evolution of Celestial Objects, Yunnan Astronomical Observatory/National Astronomical Observatory, Chinese Academy of Sciences, P.O. Box 110, Kunming 650011, Yunnan Province (China)

    2013-06-01

    We have undertaken a survey of molecular lines in the 3 mm band toward 57 young stellar objects using the Australia Telescope National Facility Mopra 22 m radio telescope. The target sources were young stellar objects with active outflows (extended green objects (EGOs)) newly identified from the GLIMPSE II survey. We observe a high detection rate (50%) of broad line wing emission in the HNC and CS thermal lines, which combined with the high detection rate of class I methanol masers toward these sources (reported in Paper I) further demonstrates that the GLIMPSE II EGOs are associated with outflows. The physical and kinematic characteristics derived from the 3 mm molecular lines for these newly identified EGOs are consistent with these sources being massive young stellar objects with ongoing outflow activity and rapid accretion. These findings support our previous investigations of the mid-infrared properties of these sources and their association with other star formation tracers (e.g., infrared dark clouds, methanol masers and millimeter dust sources) presented in Paper I. The high detection rate (64%) of the hot core tracer CH{sub 3}CN reveals that the majority of these new EGOs have evolved to the hot molecular core stage. Comparison of the observed molecular column densities with predictions from hot core chemistry models reveals that the newly identified EGOs from the GLIMPSE II survey are members of the youngest hot core population, with an evolutionary time scale of the order of 10{sup 3} yr.

  1. Low Mass Aeroshell Deployment Mechanism, Phase II

    Data.gov (United States)

    National Aeronautics and Space Administration — Cornerstone Research Group Inc. (CRG) will develop new shape memory polymer (SMP) deployment mechanisms for actuating thermal protection system (TPS) panels to...

  2. Molecular mechanism for generation of antibody memory.

    Science.gov (United States)

    Shivarov, Velizar; Shinkura, Reiko; Doi, Tomomitsu; Begum, Nasim A; Nagaoka, Hitoshi; Okazaki, Il-Mi; Ito, Satomi; Nonaka, Taichiro; Kinoshita, Kazuo; Honjo, Tasuku

    2009-03-12

    Activation-induced cytidine deaminase (AID) is the essential enzyme inducing the DNA cleavage required for both somatic hypermutation and class switch recombination (CSR) of the immunoglobulin gene. We originally proposed the RNA-editing model for the mechanism of DNA cleavage by AID. We obtained evidence that fulfils three requirements for CSR by this model, namely (i) AID shuttling between nucleus and cytoplasm, (ii) de novo protein synthesis for CSR, and (iii) AID-RNA complex formation. The alternative hypothesis, designated as the DNA-deamination model, assumes that the in vitro DNA deamination activity of AID is representative of its physiological function in vivo. Furthermore, the resulting dU was removed by uracil DNA glycosylase (UNG) to generate a basic site, followed by phosphodiester bond cleavage by AP endonuclease. We critically examined each of these provisional steps. We identified a cluster of mutants (H48A, L49A, R50A and N51A) that had particularly higher CSR activities than expected from their DNA deamination activities. The most striking was the N51A mutant that had no ability to deaminate DNA in vitro but retained approximately 50 per cent of the wild-type level of CSR activity. We also provide further evidence that UNG plays a non-canonical role in CSR, namely in the repair step of the DNA breaks. Taking these results together, we favour the RNA-editing model for the function of AID in CSR.

  3. Synthesis, molecular structure, biological properties and molecular docking studies on Mn(II), Co(II) and Zn(II) complexes containing bipyridine-azide ligands.

    Science.gov (United States)

    Thamilarasan, Vijayan; Jayamani, Arumugam; Sengottuvelan, Nallathambi

    2015-01-07

    Metal complexes of the type Mn(bpy)2(N3)2 (1), Co(bpy)2(N3)2·3H2O (2) and Zn2(bpy)2(N3)4 (3) (Where bpy = 2,2-bipyridine) have been synthesized and characterized by elemental analysis and spectral (FT-IR, UV-vis) studies. The structure of complexes (1-3) have been determined by single crystal X-ray diffraction studies and the configuration of ligand-coordinated metal(II) ion was well described as distorted octahedral coordination geometry for Mn(II), Co(II) and distorted square pyramidal geometry for Zn(II) complexes. DNA binding interaction of these complexes (1-3) were investigated by UV-vis absorption, fluorescence circular dichroism spectral and molecular docking studies. The intrinsic binding constants Kb of complexes 1, 2 and 3 with CT-DNA obtained from UV-vis absorption studies were 8.37 × 10(4), 2.23 × 10(5) and 5.52 × 10(4) M(-1) respectively. The results indicated that the three complexes are able to bind to DNA with different binding affinity, in the order 2 > 1 > 3. Complexes (1-3) exhibit a good binding propensity to bovine serum albumin (BSA) proteins having relatively high binding constant values. Gel electrophoresis assay demonstrated the ability of the complexes 1-3 promote the cleavage ability of the pBR322 plasmid DNA in the presence of the reducing agent 3-mercaptopropionic acid (MPA) but with different cleavage mechanisms: the complex 3 cleaves DNA via hydrolytic pathway (T4 DNA ligase assay), while the DNA cleavage by complexes 1 and 2 follows oxidative pathway. The chemical nuclease activity follows the order: 2 > 1 > 3. The effects of various activators were also investigated and the nuclease activity efficacy followed the order MPA > GSH > H2O2 > Asc. The cytotoxicity studies of complexes 1-3 were tested in vitro on breast cancer cell line (MCF-7) and they found to be active. Copyright © 2014. Published by Elsevier Masson SAS.

  4. Molecular mechanisms of intrauterine growth restriction.

    Science.gov (United States)

    Gurugubelli Krishna, Rao; Vishnu Bhat, B

    2017-07-10

    Intrauterine growth restriction (IUGR) is a pregnancy specific disease characterized by decreased growth rate of fetus than the normal growth potential at particular gestational age. In the current scenario it is a leading cause of fetal and neonatal morbidity and mortality. In the last decade exhilarating experimental studies from several laboratories have provided fascinating proof for comprehension of molecular basis of IUGR. Atypical expression of enzymes governed by TGFβ causes the placental apoptosis and altered expression of TGFβ due to hyper alimentation causes impairment of lung function. Crosstalk of cAMP with protein kinases plays a prominent role in the regulation of cortisol levels. Increasing levels of NOD1 proteins leads to development of IUGR by increasing the levels of inflammatory mediators. Increase in leptin synthesis in placental trophoblast cells is associated with IUGR. In this review, we emphasize on the regulatory mechanisms of IUGR and its associated diseases. They may help improve the in-utero fetal growth and provide a better therapeutic intervention for prevention and treatment of IUGR.

  5. Molecular and genetic mechanisms of environmental mutagens

    International Nuclear Information System (INIS)

    Kubitschek, H.E.; Derstine, P.L.; Griego, V.M.; Matsushita, T.; Peak, J.G.; Peak, M.J.; Reynolds, P.R.; Webb, R.B.; Williams-Hill, D.

    1981-01-01

    This program is primarily concerned with elucidation of the nature of DNA lesions produced by environmental and energy related mutagens, their mechanisms of action, and their repair. The main focus is on actions of chemical mutagens and electromagnetic radiations. Synergistic interactions between mutagens and the mutational processes that lead to synergism are being investigated. Mutagens are chosen for study on the basis of their potential for analysis of mutation (as genetic probes), for development of procedures for reducing mutational damage, for their potential importance to risk assessment, and for development of improved mutagen testing systems. Bacterial cells are used because of the rapidity and clarity of scientific results that can be obtained, the detailed genetic maps, and the many well-defined mutand strains available. The conventional tools of microbial and molecular genetics are used, along with intercomparison of genetically related strains. Advantage is taken of tcollective dose commitment will result in more attention being paid to potential releases of radionuclides at relatively short times after disposal

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

    Science.gov (United States)

    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.

  7. Type II dehydroquinase: molecular replacement with many copies

    International Nuclear Information System (INIS)

    Stewart, Kirsty Anne; Robinson, David Alexander; Lapthorn, Adrian Jonathan

    2007-01-01

    The type II dehydroquinase enzyme is a symmetrical dodecameric protein which crystallizes in either high-symmetry cubic space groups or low-symmetry crystal systems with multiple copies in the asymmetric unit. Both systems have provided challenging examples for molecular replacement; for example, a triclinic crystal form has 16 dodecamers (192 monomers) in the unit cell. Three difficult examples are discussed and two are used as test cases to compare the performance of four commonly used molecular-replacement packages. Type II dehydroquinase is a small (150-amino-acid) protein which in solution packs together to form a dodecamer with 23 cubic symmetry. In crystals of this protein the symmetry of the biological unit can be coincident with the crystallographic symmetry, giving rise to cubic crystal forms with a single monomer in the asymmetric unit. In crystals where this is not the case, multiple copies of the monomer are present, giving rise to significant and often confusing noncrystallographic symmetry in low-symmetry crystal systems. These different crystal forms pose a variety of challenges for solution by molecular replacement. Three examples of structure solutions, including a highly unusual triclinic crystal form with 16 dodecamers (192 monomers) in the unit cell, are described. Four commonly used molecular-replacement packages are assessed against two of these examples, one of high symmetry and the other of low symmetry; this study highlights how program performance can vary significantly depending on the given problem. In addition, the final refined structure of the 16-dodecamer triclinic crystal form is analysed and shown not to be a superlattice structure, but rather an F-centred cubic crystal with frustrated crystallographic symmetry

  8. Proceedings of II Molecular Imaging Symposium Cuba - Japan

    International Nuclear Information System (INIS)

    2016-01-01

    In the Central Theater, University Hospital 'General Calixto Garcia' took place the II Symposium on Molecular Imaging Cuba Japan in the framework of the Scientific Convention for the 120th anniversary of the hospital. The event was organized by the hospital itself with the support of the Society of Medical Physics (medical physics section), CEADEN, the Embassy of Japan and the Theragnostic Compounds R&D Center Neuroscience Research Institute Gachon University, Incheon Korea. It was attended by 80 national scientific leaders and with the invaluable presence of Dr. Tatsuo IDO, Emeritus professor of Tohoku University (Sendai, Japan) who presented the results of the scientific papers presented this year in national and international events , referring to the new technologies of molecular imaging and the importance of medical physics in its development. During the meeting the importance of the new technologies of molecular imaging, its undisputed diagnosis intake and medical treatment and the value of human capital struggled to deal with the new technologies, the view that these are only used best when it is understood that they are multidisciplinary systems where each specialist and technical personnel plays an indispensable role. The challenge has medical physics to address these new technologies and the need for changes in the theoretical and practical training in the specialty. These analyzes will be given continuity in the next symposia molecular imaging. (author)

  9. Molecular mechanisms in radiation carcinogenesis: introduction

    International Nuclear Information System (INIS)

    Setlow, R.B.

    1975-01-01

    Molecular studies of radiation carcinogenesis are discussed in relation to theories for extrapolating from cellular and animal models to man. Skin cancer is emphasized because of sunlight-induced photochemical damage to DNA. It is emphasized that cellular and animal models are needed as well as molecular theories for quantitative evaluation of hazardous environmental agents. (U.S.)

  10. HYLIFE-II reactor chamber mechanical design

    International Nuclear Information System (INIS)

    House, P.A.

    1992-01-01

    Mechanical design features of the reactor chamber for the HYLIFE-11 inertial confinement fusion power plant are presented. A combination of oscillating and steady, molten salt streams are used for shielding and blast protection. The system is designed for an 8 Hz repetition rate. Beam path clearing, between shots, is accomplished with the oscillating flow. The mechanism for generating the oscillating streams is described. A design configuration of the vessel wall allows adequate cooling and provides extra shielding to reduce thermal stresses to tolerable levels. The bottom portion of the reactor chamber is designed to minimize splash back of the high velocity (20 m/s) salt streams and also recover up to half of the dynamic head

  11. Quantum chemical approaches: semiempirical molecular orbital and hybrid quantum mechanical/molecular mechanical techniques.

    Science.gov (United States)

    Bryce, Richard A; Hillier, Ian H

    2014-01-01

    The use of computational quantum chemical methods to aid drug discovery is surveyed. An overview of the various computational models spanning ab initio, density function theory, semiempirical molecular orbital (MO), and hybrid quantum mechanical (QM)/molecular mechanical (MM) methods is given and their strengths and weaknesses are highlighted, focussing on the challenge of obtaining the accuracy essential for them to make a meaningful contribution to drug discovery. Particular attention is given to hybrid QM/MM and semiempirical MO methods which have the potential to yield the necessary accurate predictions of macromolecular structure and reactivity. These methods are shown to have advanced the study of many aspects of substrate-ligand interactions relevant to drug discovery. Thus, the successful parametrization of semiempirical MO methods and QM/MM methods can be used to model noncovalent substrate-protein interactions, and to lead to improved scoring functions. QM/MM methods can be used in crystal structure refinement and are particularly valuable for modelling covalent protein-ligand interactions and can thus aid the design of transition state analogues. An extensive collection of examples from the areas of metalloenzyme structure, enzyme inhibition, and ligand binding affinities and scoring functions are used to illustrate the power of these techniques.

  12. Molecular Mechanisms of Microbially Facilitated Corrosion

    Science.gov (United States)

    1986-10-23

    destierliaoice Mickels et ill. inl experimne desi 19810c, the efferts ol amipil ’ td grazi gig amiud resoutrce loirtitioli itg gas well dril Ii in i (Morrison...utilized todihlerenti- Gendrean td lakol isms contained all enlarged carliosyl hand tt 1740 cvi 1. This Lijotn co ati osY at group i nch uded Biacillus... Ihq *It mtl’ idi~ o, Chlratvi .44 Alr"It 04’/ ,t44 .4. lh ,,f,, 4 4 l,/. 4 I’m ~ .. 1igI4.ii . -hdC4itS %e.iliti, I I At% S Ir. r,- (Atc-,,n ift 215

  13. Cisplatin in cancer therapy: molecular mechanisms of action.

    Science.gov (United States)

    Dasari, Shaloam; Tchounwou, Paul Bernard

    2014-10-05

    Cisplatin, cisplatinum, or cis-diamminedichloroplatinum (II), is a well-known chemotherapeutic drug. It has been used for treatment of numerous human cancers including bladder, head and neck, lung, ovarian, and testicular cancers. It is effective against various types of cancers, including carcinomas, germ cell tumors, lymphomas, and sarcomas. Its mode of action has been linked to its ability to crosslink with the purine bases on the DNA; interfering with DNA repair mechanisms, causing DNA damage, and subsequently inducing apoptosis in cancer cells. However, because of drug resistance and numerous undesirable side effects such as severe kidney problems, allergic reactions, decrease immunity to infections, gastrointestinal disorders, hemorrhage, and hearing loss especially in younger patients, other platinum-containing anti-cancer drugs such as carboplatin, oxaliplatin and others, have also been used. Furthermore, combination therapies of cisplatin with other drugs have been highly considered to overcome drug-resistance and reduce toxicity. This comprehensive review highlights the physicochemical properties of cisplatin and related platinum-based drugs, and discusses its uses (either alone or in combination with other drugs) for the treatment of various human cancers. A special attention is paid to its molecular mechanisms of action, and its undesirable side effects. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. Cisplatin in cancer therapy: molecular mechanisms of action

    Science.gov (United States)

    Dasari, Shaloam; Tchounwou, Paul Bernard

    2014-01-01

    Cisplatin, cisplatinum, or cis-diamminedichloroplatinum (II), is a well-known chemotherapeutic drug. It has been used for treatment of numerous human cancers including bladder, head and neck, lung, ovarian, and testicular cancers. It is effective against various types of cancers, including carcinomas, germ cell tumors, lymphomas, and sarcomas. Its mode of action has been linked to its ability to crosslink with the purine bases on the DNA; interfering with DNA repair mechanisms, causing DNA damage, and subsequently inducing apoptosis in cancer cells. However, because of drug resistance and numerous undesirable side effects such as severe kidney problems, allergic reactions, decrease immunity to infections, gastrointestinal disorders, hemorrhage, and hearing loss especially in younger patients, other platinum-containing anti-cancer drugs such as carboplatin, oxaliplatin and others, have also been used. Furthermore, combination therapies of cisplatin with other drugs have been highly considered to overcome drug-resistance and reduce toxicity. This comprehensive review highlights the physicochemical properties of cisplatin and related platinum-based drugs, and discusses its uses (either alone or in combination with other drugs) for the treatment of various human cancers. A special attention is given to its molecular mechanisms of action, and its undesirable side effects. PMID:25058905

  15. Ab Initio Ligand Field Molecular Mechanics and the Nature of Metal-Ligand π-Bonding in Fe(II) 2,6-di(pyrazol-1-yl)pyridine Spin Crossover Complexes.

    Science.gov (United States)

    Deeth, Robert J; Halcrow, Malcolm A; Kershaw Cook, Laurence J; Raithby, Paul R

    2018-04-06

    A ligand field molecular mechanics (LFMM) force field has been constructed for the spin states of [Fe(bpp) 2 ] 2+ (bpp=2,6-di(pyrazol-1-yl)pyridine) and related complexes. A new charge scheme is employed which interpolates between partial charges for neutral bpp and protonated [H 3 bpp] 3+ to achieve a target metal charge. The LFMM angular overlap model (AOM) parameters are fitted to fully ab initio d orbital energies. However, several AOM parameter sets are possible. The ambiguity is resolved by calculating the Jahn-Teller distortion mode for high spin, which indicates that in [Fe(bpp) 2 ] 2+ pyridine is a π-acceptor and pyrazole a weak π-donor. The alternative fit, assumed previously, where both ligands act as π-donors leads to an inconsistent distortion. LFMM optimisations in the presence of [BF 4 ] - or [PF 6 ] - anions are in good agreement with experiment and the model also correctly predicts the spin state energetics for 3-pyrazolyl substituents where the interactions are mainly steric. However, for 4-pyridyl or 4-pyrazolyl substituents, LFMM only treats the electrostatic contribution which, for the pyridyl substituents, generates a fair correlation with the spin crossover transition temperatures, T 1/2 , but in the reverse sense to the dominant electronic effect. Thus, LFMM generates its smallest spin state energy difference for the substituent with the highest T 1/2 . One parameter set for all substituted bpp ligands is insufficient and further LFMM development will be required. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. The cognitive life of mechanical molecular models.

    Science.gov (United States)

    Charbonneau, Mathieu

    2013-12-01

    The use of physical models of molecular structures as research tools has been central to the development of biochemistry and molecular biology. Intriguingly, it has received little attention from scholars of science. In this paper, I argue that these physical models are not mere three-dimensional representations but that they are in fact very special research tools: they are cognitive augmentations. Despite the fact that they are external props, these models serve as cognitive tools that augment and extend the modeler's cognitive capacities and performance in molecular modeling tasks. This cognitive enhancement is obtained because of the way the modeler interacts with these models, the models' materiality contributing to the solving of the molecule's structure. Furthermore, I argue that these material models and their component parts were designed, built and used specifically to serve as cognitive facilitators and cognitive augmentations. Copyright © 2013 Elsevier Ltd. All rights reserved.

  17. Quantum mechanics of molecular rate processes

    CERN Document Server

    Levine, Raphael D

    1999-01-01

    This survey of applications of the theory of collisions and rate processes to molecular problems explores collisions of molecules with internal structure, generalized Ehrenfest theorem, theory of reactive collisions, and role of symmetry. It also reviews partitioning technique, equivalent potentials and quasibound states, theory of direct reactions, more. 1969 edition.

  18. Oligodendroglioma: pathology, molecular mechanisms and markers

    NARCIS (Netherlands)

    Wesseling, P.; Bent, M. van den; Perry, A.

    2015-01-01

    For nearly a century, the diagnosis and grading of oligodendrogliomas and oligoastrocytomas has been based on histopathology alone. Roughly 20 years ago, the first glioma-associated molecular signature was found with complete chromosome 1p and 19q codeletion being particularly common in

  19. Statistical ensembles and molecular dynamics studies of anisotropic solids. II

    International Nuclear Information System (INIS)

    Ray, J.R.; Rahman, A.

    1985-01-01

    We have recently discussed how the Parrinello--Rahman theory can be brought into accord with the theory of the elastic and thermodynamic behavior of anisotropic media. This involves the isoenthalpic--isotension ensemble of statistical mechanics. Nose has developed a canonical ensemble form of molecular dynamics. We combine Nose's ideas with the Parrinello--Rahman theory to obtain a canonical form of molecular dynamics appropriate to the study of anisotropic media subjected to arbitrary external stress. We employ this isothermal--isotension ensemble in a study of a fcc→ close-packed structural phase transformation in a Lennard-Jones solid subjected to uniaxial compression. Our interpretation of the Nose theory does not involve a scaling of the time variable. This latter fact leads to simplifications when studying the time dependence of quantities

  20. Molecular Mechanisms of Bacterial Mercury Transformation

    Energy Technology Data Exchange (ETDEWEB)

    Summers, Anne O. [Univ. of Georgia, Athens, GA (United States). Dept. of Microbiology; Smith, Jeremy C. [Univ. of Tennessee, Knoxville, TN (United States). Dept. of Biochemistry and Cellular and Molecular Biology

    2016-04-25

    Hg is of special interest to DOE due to past intensive use in manufacture of nuclear weapons at the Oak Ridge Reservation (ORR). Because of its facile oxidation/reduction [Hg(II)/Hg(0)] chemistry, ability to bond to carbon [as in highly toxic methylmercury: MeHg(I)] and its unique physical properties [e.g., volatility of Hg(0)], Hg has a complex environmental cycle involving soils, sediments, waterways and the atmosphere and including biotic and abiotic chemical and physical transport and transformations. Understanding such processes well enough to design stewardship plans that minimize negative impacts in diverse ecological settings requires rich knowledge of the contributing abiotic and biotic processes. Prokaryotes are major players in the global Hg cycle. Facultative and anaerobic bacteria can form MeHg(I) with consequent intoxication of wildlife and humans. Sustainable stewardship of Hg-contaminated sites requires eliminating not only MeHg(I) but also the Hg(II) substrate for methylation. Fortunately, a variety of mercury resistant (HgR) aerobic and facultative bacteria and archaea can do both things. Prokaryotes harboring narrow or broad Hg resistance (mer) loci detoxify Hg(II) or RHg(I), respectively, to relatively inert, less toxic, volatile Hg(0). HgR microbes are enriched in highly contaminated sites and extensive field data show they depress levels of MeHg >500-fold in such zones. So, enhancing the natural capacity of indigenous HgR microbes to remove Hg(II) and RHg(I) from soils, sediments and waterways is a logical component of a comprehensive plan for clean up and stewardship of contaminated sites.

  1. Molecular mechanisms involved in convergent crop domestication.

    Science.gov (United States)

    Lenser, Teresa; Theißen, Günter

    2013-12-01

    Domestication has helped to understand evolution. We argue that, vice versa, novel insights into evolutionary principles could provide deeper insights into domestication. Molecular analyses have demonstrated that convergent phenotypic evolution is often based on molecular changes in orthologous genes or pathways. Recent studies have revealed that during plant domestication the causal mutations for convergent changes in key traits are likely to be located in particular genes. These insights may contribute to defining candidate genes for genetic improvement during the domestication of new plant species. Such efforts may help to increase the range of arable crops available, thus increasing crop biodiversity and food security to help meet the predicted demands of the continually growing global population under rapidly changing environmental conditions. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Molecular mechanisms of induced-mutations

    International Nuclear Information System (INIS)

    Kato, Takeshi

    1985-01-01

    The outcome of recent studies on mechanisms of induced-mutations is outlined with particular emphasis on the dependence of recA gene function in Escherichia coli. Genes involved in spontaneous mutation and x-ray- and chemical-induced mutation and genes involved in adaptive response are presented. As for SOS mutagenesis, SOS-induced regulation mechanisms and mutagenic routes are described. Furthermore, specificity of mutagens themselves are discussed in relation to mechanisms of base substitution, frameshift, and deletion mutagenesis. (Namekawa, K.)

  3. Molecular Mechanisms of Bacterial Superantigen Function

    National Research Council Canada - National Science Library

    Sadegh-Nasseri, Scheherazade

    2004-01-01

    ...) Vb domains and can result in systemic shock and death. Rational design of strategies for prevention or treatments of such diseases may only be possible if we have insights into the mechanisms of T cell activation by SEs...

  4. Molecular mechanisms of HIV-1 associated neurodegeneration

    Indian Academy of Sciences (India)

    Unknown

    progressive multiple symptoms of motor, cognitive dys- function and behavioural ..... using different types of neurons such as rodent cortical, hippocampal and ..... in the neocortex of rat via a mechanism involving CXCR4 chemokine receptor ...

  5. Mechanically magnified imaging of molecular interferograms

    International Nuclear Information System (INIS)

    Stibor, A.; Stefanov, A.; Goldfarb, F.; Reiger, E.; Arndt, M.

    2005-01-01

    Full text: Imaging of surface adsorbed molecules is presented as a valuable detection method for matter interferometry with fluorescent particles. A mechanical magnification scheme is implemented to circumvent the optical resolution limit. Mechanically magnified fluorescence imaging turns out to be an excellent tool for recording quantum interference patterns with high visibility. A unique advantage of this technique is its scalability: for certain classes of nanosized objects, the detection sensitivity will even increase significantly with increasing size of the particle. (author)

  6. Molecular biological mechanisms I. DNA repair

    International Nuclear Information System (INIS)

    Friedl, A.A.

    2000-01-01

    Cells of all living systems possess a variety of mechanisms that allow to repair spontaneous and exogeneously induced DNA damage. DNA repair deficiencies may invoke enhanced sensitivity towards DNA-damaging agents such as ionizing radiation. They may also enhance the risk of cancer development, both spontaneously or after induction. This article reviews several DNA repair mechanisms, especially those dealing with DNA double-strand breaks, and describes hereditary diseases associated with DNA repair defects. (orig.) [de

  7. The molecular mechanism of gene-radiotherapy of tumor

    International Nuclear Information System (INIS)

    Zhu Xian

    2004-01-01

    Gene-radiotherapy of tumor is a new method which is induced by ionizing radiation. The molecular mechanism is to activate various molecular target by many ways and induce the apoptosis of tumor cell. It is a gene therapy based on the radiation-inducible property of the Egr-1 gene. It has good application prospect in therapy of tumor

  8. Molecular mechanisms of canalization: Hsp90 and beyond

    Indian Academy of Sciences (India)

    Madhu Sudhan

    2007-03-26

    Mar 26, 2007 ... clients are essential nodes in signal transduction pathways and regulatory circuits, accounting for the .... respective contributions of genetics versus epigenetics ... authors succeeded in elucidating the molecular mechanism.

  9. Symposium on molecular and cellular mechanisms of mutagenesis

    International Nuclear Information System (INIS)

    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

  10. What molecular mechanism is adapted by plants during salt stress ...

    African Journals Online (AJOL)

    What molecular mechanism is adapted by plants during salt stress tolerance? ... Salt stress harmfully shocks agricultural yield throughout the world affecting production whether it is for subsistence or economic outcomes. ... from 32 Countries:.

  11. Symposium on molecular and cellular mechanisms of mutagenesis

    Energy Technology Data Exchange (ETDEWEB)

    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)

  12. Molecular Dynamics Simulations with Quantum Mechanics/Molecular Mechanics and Adaptive Neural Networks.

    Science.gov (United States)

    Shen, Lin; Yang, Weitao

    2018-03-13

    Direct molecular dynamics (MD) simulation with ab initio quantum mechanical and molecular mechanical (QM/MM) methods is very powerful for studying the mechanism of chemical reactions in a complex environment but also very time-consuming. The computational cost of QM/MM calculations during MD simulations can be reduced significantly using semiempirical QM/MM methods with lower accuracy. To achieve higher accuracy at the ab initio QM/MM level, a correction on the existing semiempirical QM/MM model is an attractive idea. Recently, we reported a neural network (NN) method as QM/MM-NN to predict the potential energy difference between semiempirical and ab initio QM/MM approaches. The high-level results can be obtained using neural network based on semiempirical QM/MM MD simulations, but the lack of direct MD samplings at the ab initio QM/MM level is still a deficiency that limits the applications of QM/MM-NN. In the present paper, we developed a dynamic scheme of QM/MM-NN for direct MD simulations on the NN-predicted potential energy surface to approximate ab initio QM/MM MD. Since some configurations excluded from the database for NN training were encountered during simulations, which may cause some difficulties on MD samplings, an adaptive procedure inspired by the selection scheme reported by Behler [ Behler Int. J. Quantum Chem. 2015 , 115 , 1032 ; Behler Angew. Chem., Int. Ed. 2017 , 56 , 12828 ] was employed with some adaptions to update NN and carry out MD iteratively. We further applied the adaptive QM/MM-NN MD method to the free energy calculation and transition path optimization on chemical reactions in water. The results at the ab initio QM/MM level can be well reproduced using this method after 2-4 iteration cycles. The saving in computational cost is about 2 orders of magnitude. It demonstrates that the QM/MM-NN with direct MD simulations has great potentials not only for the calculation of thermodynamic properties but also for the characterization of

  13. Insight into the molecular switch mechanism of human Rab5a from molecular dynamics simulations

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jing-Fang, E-mail: jfwang@gordonlifescience.org [Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031 (China); Shanghai Center for Bioinformation Technology, 100 Qinzhou Road, Shanghai 200235 (China); Gordon Life Science Institute, 13784 Torrey Del Mar Drive, San Diego, CA 92130 (United States); Chou, Kuo-Chen [Gordon Life Science Institute, 13784 Torrey Del Mar Drive, San Diego, CA 92130 (United States)

    2009-12-18

    Rab5a is currently a most interesting target because it is responsible for regulating the early endosome fusion in endocytosis and possibly the budding process. We utilized longtime-scale molecular dynamics simulations to investigate the internal motion of the wild-type Rab5a and its A30P mutant. It was observed that, after binding with GTP, the global flexibility of the two proteins is increasing, while the local flexibility in their sensitive sites (P-loop, switch I and II regions) is decreasing. Also, the mutation of Ala30 to Pro30 can cause notable flexibility variations in the sensitive sites. However, this kind of variations is dramatically reduced after binding with GTP. Such a remarkable feature is mainly caused by the water network rearrangements in the sensitive sites. These findings might be of use for revealing the profound mechanism of the displacements of Rab5a switch regions, as well as the mechanism of the GDP dissociation and GTP association.

  14. Unraveling the cellular and molecular mechanisms of repetitive magnetic stimulation

    Directory of Open Access Journals (Sweden)

    Florian eMüller-Dahlhaus

    2013-12-01

    Full Text Available Despite numerous clinical studies, which have investigated the therapeutic potential of repetitive transcranial magnetic stimulation (rTMS in various brain diseases, our knowledge of the cellular and molecular mechanisms underlying rTMS-based therapies remains limited. Thus, a deeper understanding of rTMS-induced neural plasticity is required to optimize current treatment protocols. Studies in small animals or appropriate in vitro preparations (including models of brain diseases provide highly useful experimental approaches in this context. State-of-the-art electrophysiological and live-cell imaging techniques that are well established in basic neuroscience can help answering some of the major questions in the field, such as (i which neural structures are activated during TMS, (ii how does rTMS induce Hebbian plasticity, and (iii are other forms of plasticity (e.g., metaplasticity, structural plasticity induced by rTMS? We argue that data gained from these studies will support the development of more effective and specific applications of rTMS in clinical practice.

  15. Molecular dynamics and Monte Carlo calculations in statistical mechanics

    International Nuclear Information System (INIS)

    Wood, W.W.; Erpenbeck, J.J.

    1976-01-01

    Monte Carlo and molecular dynamics calculations on statistical mechanical systems is reviewed giving some of the more significant recent developments. It is noted that the term molecular dynamics refers to the time-averaging technique for hard-core and square-well interactions and for continuous force-law interactions. Ergodic questions, methodology, quantum mechanical, Lorentz, and one-dimensional, hard-core, and square and triangular-well systems, short-range soft potentials, and other systems are included. 268 references

  16. Molecular and cellular mechanisms of pulmonary fibrosis

    Science.gov (United States)

    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

  17. Molecular and cellular mechanisms of cadmium carcinogenesis

    International Nuclear Information System (INIS)

    Waisberg, Michael; Joseph, Pius; Hale, Beverley; Beyersmann, Detmar

    2003-01-01

    Cadmium is a heavy metal, which is widely used in industry, affecting human health through occupational and environmental exposure. In mammals, it exerts multiple toxic effects and has been classified as a human carcinogen by the International Agency for Research on Cancer. Cadmium affects cell proliferation, differentiation, apoptosis and other cellular activities. Cd 2+ does not catalyze Fenton-type reactions because it does not accept or donate electrons under physiological conditions, and it is only weakly genotoxic. Hence, indirect mechanisms are implicated in the carcinogenicity of cadmium. In this review multiple mechanisms are discussed, such as modulation of gene expression and signal transduction, interference with enzymes of the cellular antioxidant system and generation of reactive oxygen species (ROS), inhibition of DNA repair and DNA methylation, role in apoptosis and disruption of E-cadherin-mediated cell-cell adhesion. Cadmium affects both gene transcription and translation. The major mechanisms of gene induction by cadmium known so far are modulation of cellular signal transduction pathways by enhancement of protein phosphorylation and activation of transcription and translation factors. Cadmium interferes with antioxidant defense mechanisms and stimulates the production of reactive oxygen species, which may act as signaling molecules in the induction of gene expression and apoptosis. The inhibition of DNA repair processes by cadmium represents a mechanism by which cadmium enhances the genotoxicity of other agents and may contribute to the tumor initiation by this metal. The disruption of E-cadherin-mediated cell-cell adhesion by cadmium probably further stimulates the development of tumors. It becomes clear that there exist multiple mechanisms which contribute to the carcinogenicity of cadmium, although the relative weights of these contributions are difficult to estimate

  18. Molecular mechanisms of synaptic remodeling in alcoholism.

    Science.gov (United States)

    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.

  19. Molecular Signatures of Hepatitis C Virus (HCV-Induced Type II Mixed Cryoglobulinemia (MCII

    Directory of Open Access Journals (Sweden)

    Roberto Burioni

    2012-11-01

    Full Text Available The role of hepatitis C virus (HCV infection in the induction of type II mixed cryoglobulinemia (MCII and the possible establishment of related lymphoproliferative disorders, such as B-cell non-Hodgkin lymphoma (B-NHL, is well ascertained. However, the molecular pathways involved and the factors predisposing to the development of these HCV-related extrahepatic complications deserve further consideration and clarification. To date, several host- and virus-related factors have been implicated in the progression to MCII, such as the virus-induced expansion of selected subsets of B-cell clones expressing discrete immunoglobulin variable (IgV gene subfamilies, the involvement of complement factors and the specific role of some HCV proteins. In this review, we will analyze the host and viral factors taking part in the development of MCII in order to give a general outlook of the molecular mechanisms implicated.

  20. Xenon preconditioning: molecular mechanisms and biological effects

    Directory of Open Access Journals (Sweden)

    Liu Wenwu

    2013-01-01

    Full Text Available Abstract Xenon is one of noble gases and has been recognized as an anesthetic for more than 50 years. Xenon possesses many of the characteristics of an ideal anesthetic, but it is not widely applied in clinical practice mainly because of its high cost. In recent years, numerous studies have demonstrated that xenon as an anesthetic can exert neuroprotective and cardioprotective effects in different models. Moreover, xenon has been applied in the preconditioning, and the neuroprotective and cardioprotective effects of xenon preconditioning have been investigated in a lot of studies in which some mechanisms related to these protections are proposed. In this review, we summarized these mechanisms and the biological effects of xenon preconditioning.

  1. Vancomycin Molecular Interactions: Antibiotic and Enantioselective Mechanisms

    Science.gov (United States)

    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.

  2. Physical mechanisms of biological molecular motors

    Energy Technology Data Exchange (ETDEWEB)

    Miller, John H. Jr. [Department of Physics and Texas Center for Superconductivity, University of Houston, 4800 Calhoun Road, Ste. 617 SR1 Houston, TX 77204-5005 (United States)], E-mail: jhmiller@uh.edu; Vajrala, Vijayanand; Infante, Hans L. [Department of Physics and Texas Center for Superconductivity, University of Houston, 4800 Calhoun Road, Ste. 617 SR1 Houston, TX 77204-5005 (United States); Claycomb, James R. [Department of Physics and Texas Center for Superconductivity, University of Houston, 4800 Calhoun Road, Ste. 617 SR1 Houston, TX 77204-5005 (United States); Department of Mathematics and Physics, Houston Baptist University, 7502 Fondren Road, Houston, TX 77074-3298 (United States); Palanisami, Akilan; Fang Jie; Mercier, George T. [Department of Physics and Texas Center for Superconductivity, University of Houston, 4800 Calhoun Road, Ste. 617 SR1 Houston, TX 77204-5005 (United States)

    2009-03-01

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

  3. Physical mechanisms of biological molecular motors

    International Nuclear Information System (INIS)

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

    2009-01-01

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

  4. Cellular and molecular mechanisms of muscle atrophy

    Directory of Open Access Journals (Sweden)

    Paolo Bonaldo

    2013-01-01

    Full Text Available 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.

  5. Molecular mechanisms in radiation damage to DNA: Final report

    International Nuclear Information System (INIS)

    Osman, R.

    1996-01-01

    The objectives of this work were to elucidate the molecular mechanisms that were responsible for radiation-induced DNA damage. The studies were based on theoretical explorations of possible mechanisms that link initial radiation damage in the form of base and sugar damage to conformational changes in DNA

  6. Molecular Mechanisms of Circadian Regulation During Spaceflight

    Science.gov (United States)

    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

  7. Molecular cytotoxic mechanisms of anticancer hydroxychalcones.

    Science.gov (United States)

    Sabzevari, Omid; Galati, Giuseppe; Moridani, Majid Y; Siraki, Arno; O'Brien, Peter J

    2004-06-30

    Chalcones are being considered as anticancer agents as they are natural compounds that are particularly cytotoxic towards K562 leukemia or melanoma cells. In this study, we have investigated phloretin, isoliquiritigenin, and 10 other hydroxylated chalcones for their cytotoxic mechanisms towards isolated rat hepatocytes. All hydroxychalcones partly depleted hepatocyte GSH and oxidized GSH to GSSG. These chalcones also caused a collapse of mitochondrial membrane potential and increased oxygen uptake. Furthermore, glycolytic or citric acid cycle substrates prevented cytotoxicity and mitochondrial membrane potential collapse. The highest pKa chalcones were the most effective at collapsing the mitochondrial membrane potential which suggests that the cytotoxic activity of hydroxychalcones are likely because of their ability to uncouple mitochondria.

  8. [Molecular mechanisms of skeletal muscle hypertrophy].

    Science.gov (United States)

    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.

  9. Molecular and neuroendocrine mechanisms of cancer cachexia.

    Science.gov (United States)

    Mendes, Maria Carolina S; Pimentel, Gustavo D; Costa, Felipe O; Carvalheira, José B C

    2015-09-01

    Cancer and its morbidities, such as cancer cachexia, constitute a major public health problem. Although cancer cachexia has afflicted humanity for centuries, its underlying multifactorial and complex physiopathology has hindered the understanding of its mechanism. During the last few decades we have witnessed a dramatic increase in the understanding of cancer cachexia pathophysiology. Anorexia and muscle and adipose tissue wasting are the main features of cancer cachexia. These apparently independent symptoms have humoral factors secreted by the tumor as a common cause. Importantly, the hypothalamus has emerged as an organ that senses the peripheral signals emanating from the tumoral environment, and not only elicits anorexia but also contributes to the development of muscle and adipose tissue loss. Herein, we review the roles of factors secreted by the tumor and its effects on the hypothalamus, muscle and adipose tissue, as well as highlighting the key targets that are being exploited for cancer cachexia treatment. © 2015 Society for Endocrinology.

  10. Neurotrophin Propeptides: Biological Functions and Molecular Mechanisms.

    Science.gov (United States)

    Rafieva, Lola M; Gasanov, Eugene V

    2016-01-01

    Neurotrophins constitute a family of growth factors that play a key role in the regulation of the development and function of the central and peripheral nervous systems. A common feature of all the neurotrophins is their synthesis in cells as long precursors (pre-pro-neurotrophins) that contain an N-terminal signal peptide, a following propeptide and the mature neurotrophin. Although the signal peptide functions have been well studied, the role of neurotrophin propeptides is not so clear. Here, we briefly summarize the biochemistry of neurotrophin propeptides, including their role as folding-assistants for the mature factor and their role in processing and in secretion of neurotrophins. In the main part of the review we summarize our current state of knowledge of the biological activity of neurotrophin propeptides, their possible mechanisms of action, and their potential influence on the activity of the mature neurotrophins.

  11. Cellular and molecular mechanisms coordinating pancreas development.

    Science.gov (United States)

    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.

  12. Performance assessment of semiempirical molecular orbital methods in describing halogen bonding: quantum mechanical and quantum mechanical/molecular mechanical-molecular dynamics study.

    Science.gov (United States)

    Ibrahim, Mahmoud A A

    2011-10-24

    The performance of semiempirical molecular-orbital methods--MNDO, MNDO-d, AM1, RM1, PM3 and PM6--in describing halogen bonding was evaluated, and the results were compared with molecular mechanical (MM) and quantum mechanical (QM) data. Three types of performance were assessed: (1) geometrical optimizations and binding energy calculations for 27 halogen-containing molecules complexed with various Lewis bases (Two of the tested methods, AM1 and RM1, gave results that agree with the QM data.); (2) charge distribution calculations for halobenzene molecules, determined by calculating the solvation free energies of the molecules relative to benzene in explicit and implicit generalized Born (GB) solvents (None of the methods gave results that agree with the experimental data.); and (3) appropriateness of the semiempirical methods in the hybrid quantum-mechanical/molecular-mechanical (QM/MM) scheme, investigated by studying the molecular inhibition of CK2 protein by eight halobenzimidazole and -benzotriazole derivatives using hybrid QM/MM molecular-dynamics (MD) simulations with the inhibitor described at the QM level by the AM1 method and the rest of the system described at the MM level. The pure MM approach with inclusion of an extra point of positive charge on the halogen atom approach gave better results than the hybrid QM/MM approach involving the AM1 method. Also, in comparison with the pure MM-GBSA (generalized Born surface area) binding energies and experimental data, the calculated QM/MM-GBSA binding energies of the inhibitors were improved by replacing the G(GB,QM/MM) solvation term with the corresponding G(GB,MM) term.

  13. Characterization of the Structural, Mechanical, and Electronic Properties of Fullerene Mixtures: A Molecular Simulations Description

    KAUST Repository

    Tummala, Naga Rajesh

    2017-10-06

    We investigate mixtures of fullerenes and fullerene derivatives, the most commonly used electron accepting materials in organic solar cells, by using a combination of molecular dynamics and density functional theory methods. Our goal is to describe how mixing affects the molecular packing, mechanical properties, and electronic parameters (site energy disorder, electronic couplings) of interest for solar-cell applications. Specifically, we consider mixtures of: (i) C60 and C70; (ii) C60, C70, and C84, and (iii) PC61BM and PC71BM.

  14. Mechanical design of the CDF SVX II silicon vertex detector

    International Nuclear Information System (INIS)

    Skarha, J.E.

    1994-08-01

    A next generation silicon vertex detector is planned at CDF for the 1998 Tevatron collider run with the Main Injector. The SVX II silicon vertex detector will allow high luminosity data-taking, enable online triggering of secondary vertex production, and greatly increase the acceptance for heavy flavor physics at CDF. The design specifications, geometric layout, and early mechanical prototyping work for this detector are discussed

  15. Molecular Theory of the Living Cell Concepts, Molecular Mechanisms, and Biomedical Applications

    CERN Document Server

    Ji, Sungchul

    2012-01-01

    This book presents a comprehensive molecular theory of the living cell based on over thirty concepts, principles and laws imported from thermodynamics, statistical mechanics, quantum mechanics, chemical kinetics, informatics, computer science, linguistics, semiotics, and philosophy. The author formulates physically, chemically and enzymologically realistic molecular mechanisms to account for the basic living processes such as ligand-receptor interactions, protein folding, single-molecule enzymic catalysis, force-generating mechanisms in molecular motors, signal transduction, regulation of the genome-wide RNA metabolism, morphogenesis, the micro-macro coupling in coordination dynamics, the origin of life, and the mechanisms of biological evolution itself. Possible solutions to basic and practical problems facing contemporary biology and biomedical sciences have been suggested, including pharmacotheragnostics and personalized medicine.

  16. Mini-review: Molecular mechanisms of antifouling compounds

    KAUST Repository

    Qian, Pei-Yuan

    2013-04-01

    Various antifouling (AF) coatings have been developed to protect submerged surfaces by deterring the settlement of the colonizing stages of fouling organisms. A review of the literature shows that effective AF compounds with specific targets are ones often considered non-toxic. Such compounds act variously on ion channels, quorum sensing systems, neurotransmitters, production/release of adhesive, and specific enzymes that regulate energy production or primary metabolism. In contrast, AF compounds with general targets may or may not act through toxic mechanisms. These compounds affect a variety of biological activities including algal photosynthesis, energy production, stress responses, genotoxic damage, immunosuppressed protein expression, oxidation, neurotransmission, surface chemistry, the formation of biofilms, and adhesive production/release. Among all the targets, adhesive production/release is the most common, possibly due to a more extensive research effort in this area. Overall, the specific molecular targets and the molecular mechanisms of most AF compounds have not been identified. Thus, the information available is insufficient to draw firm conclusions about the types of molecular targets to be used as sensitive biomarkers for future design and screening of compounds with AF potential. In this review, the relevant advantages and disadvantages of the molecular tools available for studying the molecular targets of AF compounds are highlighted briefly and the molecular mechanisms of the AF compounds, which are largely a source of speculation in the literature, are discussed. © 2013 Copyright Taylor and Francis Group, LLC.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Physiological and molecular biochemical mechanisms of bile formation

    Science.gov (United States)

    Reshetnyak, Vasiliy Ivanovich

    2013-01-01

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

  20. Prediction of mechanical properties for hexagonal boron nitride nanosheets using molecular mechanics model

    Energy Technology Data Exchange (ETDEWEB)

    Natsuki, Toshiaki [Shinshu University, Faculty of Textile Science and Technology, Ueda (Japan); Shinshu University, Institute of Carbon Science and Technology, Nagano (Japan); Natsuki, Jun [Shinshu University, Institute of Carbon Science and Technology, Nagano (Japan)

    2017-04-15

    Mechanical behaviors of nanomaterials are not easy to be evaluated in the laboratory because of their extremely small size and difficulty controlling. Thus, a suitable model for the estimation of the mechanical properties for nanomaterials becomes very important. In this study, the elastic properties of boron nitride (BN) nanosheets, including the elastic modulus, the shear modulus, and the Poisson's ratio, are predicted using a molecular mechanics model. The molecular mechanics force filed is established to directly incorporate the Morse potential function into the constitutive model of nanostructures. According to the molecular mechanics model, the chirality effect of hexagonal BN nanosheets on the elastic modulus is investigated through a closed-form solution. The simulated result shows that BN nanosheets exhibit an isotropic elastic property. The present analysis yields a set of very simple formulas and is able to be served as a good approximation on the mechanical properties for the BN nanosheets. (orig.)

  1. Prediction of mechanical properties for hexagonal boron nitride nanosheets using molecular mechanics model

    International Nuclear Information System (INIS)

    Natsuki, Toshiaki; Natsuki, Jun

    2017-01-01

    Mechanical behaviors of nanomaterials are not easy to be evaluated in the laboratory because of their extremely small size and difficulty controlling. Thus, a suitable model for the estimation of the mechanical properties for nanomaterials becomes very important. In this study, the elastic properties of boron nitride (BN) nanosheets, including the elastic modulus, the shear modulus, and the Poisson's ratio, are predicted using a molecular mechanics model. The molecular mechanics force filed is established to directly incorporate the Morse potential function into the constitutive model of nanostructures. According to the molecular mechanics model, the chirality effect of hexagonal BN nanosheets on the elastic modulus is investigated through a closed-form solution. The simulated result shows that BN nanosheets exhibit an isotropic elastic property. The present analysis yields a set of very simple formulas and is able to be served as a good approximation on the mechanical properties for the BN nanosheets. (orig.)

  2. Selective and reusable iron(II)-based molecular sensor for the vapor-phase detection of alcohols.

    Science.gov (United States)

    Naik, Anil D; Robeyns, Koen; Meunier, Christophe F; Léonard, Alexandre F; Rotaru, Aurelian; Tinant, Bernard; Filinchuk, Yaroslav; Su, Bao Lian; Garcia, Yann

    2014-02-03

    A mononuclear iron(II) neutral complex (1) is screened for sensing abilities for a wide spectrum of chemicals and to evaluate the response function toward physical perturbation like temperature and mechanical stress. Interestingly, 1 precisely detects methanol among an alcohol series. The sensing process is visually detectable, fatigue-resistant, highly selective, and reusable. The sensing ability is attributed to molecular sieving and subsequent spin-state change of iron centers, after a crystal-to-crystal transformation.

  3. Resveratrol and Calcium Signaling: Molecular Mechanisms and Clinical Relevance

    Directory of Open Access Journals (Sweden)

    Audrey E. McCalley

    2014-06-01

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

  4. A mechanical actuator driven electrochemically by artificial molecular muscles.

    Science.gov (United States)

    Juluri, Bala Krishna; Kumar, Ajeet S; Liu, Yi; Ye, Tao; Yang, Ying-Wei; Flood, Amar H; Fang, Lei; Stoddart, J Fraser; Weiss, Paul S; Huang, Tony Jun

    2009-02-24

    A microcantilever, coated with a monolayer of redox-controllable, bistable [3]rotaxane molecules (artificial molecular muscles), undergoes reversible deflections when subjected to alternating oxidizing and reducing electrochemical potentials. The microcantilever devices were prepared by precoating one surface with a gold film and allowing the palindromic [3]rotaxane molecules to adsorb selectively onto one side of the microcantilevers, utilizing thiol-gold chemistry. An electrochemical cell was employed in the experiments, and deflections were monitored both as a function of (i) the scan rate (+0.4 V) and reducing (artificial molecular muscles, were compared with (i) data from nominally bare microcantilevers precoated with gold and (ii) those coated with two types of control compounds, namely, dumbbell molecules to simulate the redox activity of the palindromic bistable [3]rotaxane molecules and inactive 1-dodecanethiol molecules. The comparisons demonstrate that the artificial molecular muscles are responsible for the deflections, which can be repeated over many cycles. The microcantilevers deflect in one direction following oxidation and in the opposite direction upon reduction. The approximately 550 nm deflections were calculated to be commensurate with forces per molecule of approximately 650 pN. The thermal relaxation that characterizes the device's deflection is consistent with the double bistability associated with the palindromic [3]rotaxane and reflects a metastable contracted state. The use of the cooperative forces generated by these self-assembled, nanometer-scale artificial molecular muscles that are electrically wired to an external power supply constitutes a seminal step toward molecular-machine-based nanoelectromechanical systems (NEMS).

  5. Advance of Mechanically Controllable Break Junction for Molecular Electronics.

    Science.gov (United States)

    Wang, Lu; Wang, Ling; Zhang, Lei; Xiang, Dong

    2017-06-01

    Molecular electronics stands for the ultimate size of functional elements, keeping up with an unstoppable trend over the past few decades. As a vital component of molecular electronics, single molecular junctions have attracted significant attention from research groups all over the world. Due to its pronounced superiority, the mechanically controllable break junctions (MCBJ) technique has been widely applied to characterize the dynamic performance of single molecular junctions. This review presents a system analysis for single-molecule junctions and offers an overview of four test-beds for single-molecule junctions, thus offering more insight into the mechanisms of electron transport. We mainly focus on the development of state-of-the-art mechanically controlled break junctions. The three-terminal gated MCBJ approaches are introduced to manipulate the electron transport of molecules, and MCBJs are combined with characterization techniques. Additionally, applications of MCBJs and remarkable properties of single molecules are addressed. Finally, the challenges and perspective for the mechanically controllable break junctions technique are provided.

  6. Survival under stress: molecular mechanisms of metabolic rate ...

    African Journals Online (AJOL)

    Studies in my laboratory are analysing the molecular mechanisms and regulatory events that underlie transitions to and from hypometabolic states In systems including anoxia-tolerant turtles and molluscs, estivating snails and toads, hibernating small mammals, and freeze tolerant frogs and insects. Our newest research ...

  7. Quantum Mechanics/Molecular Mechanics Simulations Identify the Ring-Opening Mechanism of Creatininase.

    Science.gov (United States)

    Jitonnom, Jitrayut; Mujika, Jon I; van der Kamp, Marc W; Mulholland, Adrian J

    2017-12-05

    Creatininase catalyzes the conversion of creatinine (a biosensor for kidney function) to creatine via a two-step mechanism: water addition followed by ring opening. Water addition is common to other known cyclic amidohydrolases, but the precise mechanism for ring opening is still under debate. The proton donor in this step is either His178 or a water molecule bound to one of the metal ions, and the roles of His178 and Glu122 are unclear. Here, the two possible reaction pathways have been fully examined by means of combined quantum mechanics/molecular mechanics simulations at the SCC-DFTB/CHARMM22 level of theory. The results indicate that His178 is the main catalytic residue for the whole reaction and explain its role as proton shuttle during the ring-opening step. In the first step, His178 provides electrostatic stabilization to the gem-diolate tetrahedral intermediate. In the second step, His178 abstracts the hydroxyl proton of the intermediate and delivers it to the cyclic amide nitrogen, leading to ring opening. The latter is the rate-limiting step with a free energy barrier of 18.5 kcal/mol, in agreement with the experiment. We find that Glu122 must be protonated during the enzyme reaction, so that it can form a stable hydrogen bond with its neighboring water molecule. Simulations of the E122Q mutant showed that this replacement disrupts the H-bond network formed by three conserved residues (Glu34, Ser78, and Glu122) and water, increasing the energy barrier. Our computational studies provide a comprehensive explanation for previous structural and kinetic observations, including why the H178A mutation causes a complete loss of activity but the E122Q mutation does not.

  8. History of respiratory mechanics prior to World War II.

    Science.gov (United States)

    West, John B

    2012-01-01

    The history of respiratory mechanics is reviewed over a period of some 2,500 years from the ancient Greeks to World War II. A cardinal early figure was Galen (130-199 AD) who made remarkably perceptive statements on the diaphragm and the anatomy of the phrenic nerves. The polymath Leonardo da Vinci (1452-1519) contributed observations on pulmonary mechanics including the pleural space and bronchial airflow that still make good reading. Vesalius (1514-1564) produced magnificent illustrations of the lung, ribcage, and diaphragm. In the 17th century, the Oxford School including Boyle, Hooke, Lower, and Mayow were responsible for many contributions on mechanical functions including the intercostal muscles and the pleura. Hales (1677-1761) calculated the size and surface area of the alveoli, the time spent by the blood in the pulmonary capillaries, and intrathoracic pressures. Poiseuille (1799-1869) carried out classical studies of fluid mechanics including one of the first demonstrations of flow limitation in collapsible vessels. The culmination of the pre-World War II period was the outstanding contributions of Rohrer (1888-1926) and his two Swiss countrymen, Wirz (1896-1978) and von Neergaard (1887-1947). Rohrer developed the first comprehensive, quantitative treatment of respiratory mechanics in the space of 10 years including an analysis of flow in airways, and the pressure-volume behavior of the respiratory system. von Neergaard performed landmark studies on the effects of surface tension on pressure-volume behavior. Progress over the 2,500 years was slow and erratic at times, but by 1940 the stage was set for the spectacular developments of the next 70 years. © 2012 American Physiological Society

  9. Beta II plasma-gun mechanical design and construction

    International Nuclear Information System (INIS)

    Pedrotti, L.; Deis, G.; Wong, R.; Calderon, M.; Chargin, A.; Garner, D.

    1979-01-01

    The magnetized coaxial plasma gun (located on the east end of the Beta II facility at the Lawrence Livermore Laboratory) will be used to test a new method of initiating a field reversed mirror plasma. The field-reversed mirror is expected to improve the mirror-fusion reactor by enhancing the ratio of fusion power to injected power. This paper concentrates on the mechanical design and construction of the magnetized coaxial plasma gun and also discusses the diagnostic devices necessary to demonstrate the formation of field-reversed rings

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  12. Submillisecond elastic recoil reveals molecular origins of fibrin fiber mechanics.

    Science.gov (United States)

    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

    2013-06-18

    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. Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

    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

  14. Substrate binding and catalytic mechanism in phospholipase C from Bacillus cereus. a molecular mechanics and molecular dynamics study

    DEFF Research Database (Denmark)

    da Graça Thrige, D; Buur, J R; Jørgensen, Flemming Steen

    1997-01-01

    cereus including a docked substrate molecule was subjected to a stepwise molecular mechanics energy minimization. Second, the location of the nucleophilic water molecule in the active site of the fully relaxed enzyme-substrate complex was determined by evaluation of nonbonded interaction energies between...... water molecule was verified during a 100 ps molecular dynamics simulation. During the simulation the substrate undergoes a conformational change, but retains its localization in the active site. The contacts between the enzyme, the substrate, and the nucleophilic water molecule display some fluctuations...... the strong electrostatic interactions in the active site realistically during energy minimization, delocalization of the charges from the three zinc ions was considered. Therefore, quantum mechanics calculations on the zinc ions and the zinc-coordinating residues were carried out prior to the molecular...

  15. HYLIFE-II reactor chamber mechanical design: Update

    International Nuclear Information System (INIS)

    House, P.A.

    1992-01-01

    Mechanical design features of the reactor chamber for the HYLIFE-II inertial confinement fusion power plant are presented. A combination of oscillating and steady, molten salt streams (Li 2 BeF 4 ) are used for shielding and blast protection of the chamber walls. The system is designed for a 6 Hz repetition rate. Beam path clearing, between shots, is accomplished with the oscillating flow. The mechanism for generating the oscillating streams is described. A design configuration of the vessel wall allows adequate cooling and provides extra shielding to reduce thermal stresses to tolerable levels. The bottom portion of the reactor chamber is designed to minimize splash back of the high velocity (17 m/s) salt streams and also recover up to half of the dynamic head. Cost estimates for a 1 GW e and 2 GW e reactor chamber are presented

  16. Molecular characterization and interactome analysis of Trypanosoma cruzi tryparedoxin II.

    Science.gov (United States)

    Arias, Diego G; Piñeyro, María Dolores; Iglesias, Alberto A; Guerrero, Sergio A; Robello, Carlos

    2015-04-29

    antioxidant mechanisms constitute an active field of investigation, since they could provide the basis for a rational drug development. Peroxide detoxification in this parasite is achieved by ascorbate peroxidase and different thiol-dependent peroxidases. Among them, both mitochondrial and cytosolic tryparedoxin peroxidases, typical two-cysteine peroxiredoxins, were found to be important for hydrogen peroxide and peroxynitrite detoxification and their expression levels correlated with parasite infectivity and virulence. In trypanosomes tryparedoxins and not thioredoxins act as peroxiredoxin reductases, suggesting that these enzymes substitute thioredoxins in these parasites. T. cruzi possesses two tryparedoxin genes, TcTXNI and TcTXN II. Since thioredoxins are proteins with several targets actively participating of complex redox networks, we have previously investigated if this is the case also for TcTXNI, for which we described relevant partners (J Proteomics. 2011;74(9):1683-92). In this manuscript we investigated the interactions of TcTXNII. We have designed an active site mutant tryparedoxin II lacking the resolving cysteine and, through the expression of this mutant protein and its incubation with T. cruzi proteins, hetero disulfide complexes were isolated by affinity chromatography purification and identified by electrophoresis separation and MS identification. This allowed us to identify sixteen TcTXNII interacting proteins which are involved in different and relevant cellular processes. Moreover, we demonstrate that TcTXNII is a transmembrane protein anchored to the surface of the mitochondria and endoplasmic reticulum. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Molecular analysis of genetic diversity in elite II synthetic hexaploid ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-07-20

    Jul 20, 2009 ... The presence of sufficient genetic diversity in the germplam is an important ..... Figure 1. PCR amplification profile of Elite-II SH Wheat using the primer OPG-2. .... genetic relationships among cowpea breeding lines and local.

  18. Subtypes of the Type II Pit Pattern Reflect Distinct Molecular Subclasses in the Serrated Neoplastic Pathway.

    Science.gov (United States)

    Aoki, Hironori; Yamamoto, Eiichiro; Yamano, Hiro-O; Sugai, Tamotsu; Kimura, Tomoaki; Tanaka, Yoshihito; Matsushita, Hiro-O; Yoshikawa, Kenjiro; Takagi, Ryo; Harada, Eiji; Nakaoka, Michiko; Yoshida, Yuko; Harada, Taku; Sudo, Gota; Eizuka, Makoto; Yorozu, Akira; Kitajima, Hiroshi; Niinuma, Takeshi; Kai, Masahiro; Nojima, Masanori; Suzuki, Hiromu; Nakase, Hiroshi

    2018-03-15

    Colorectal serrated lesions (SLs) are important premalignant lesions whose clinical and biological features are not fully understood. We aimed to establish accurate colonoscopic diagnosis and treatment of SLs through evaluation of associations among the morphological, pathological, and molecular characteristics of SLs. A total of 388 premalignant and 18 malignant colorectal lesions were studied. Using magnifying colonoscopy, microsurface structures were assessed based on Kudo's pit pattern classification system, and the Type II pit pattern was subcategorized into classical Type II, Type II-Open (Type II-O) and Type II-Long (Type II-L). BRAF/KRAS mutations and DNA methylation of CpG island methylator phenotype (CIMP) markers (MINT1, - 2, - 12, - 31, p16, and MLH1) were analyzed through pyrosequencing. Type II-O was tightly associated with sessile serrated adenoma/polyps (SSA/Ps) with BRAF mutation and CIMP-high. Most lesions with simple Type II or Type II-L were hyperplastic polyps, while mixtures of Type II or Type II-L plus more advanced pit patterns (III/IV) were characteristic of traditional serrated adenomas (TSAs). Type II-positive TSAs frequently exhibited BRAF mutation and CIMP-low, while Type II-L-positive TSAs were tightly associated with KRAS mutation and CIMP-low. Analysis of lesions containing both premalignant and cancerous components suggested Type II-L-positive TSAs may develop into KRAS-mutated/CIMP-low/microsatellite stable cancers, while Type II-O-positive SSA/Ps develop into BRAF-mutated/CIMP-high/microsatellite unstable cancers. These results suggest that Type II subtypes reflect distinct molecular subclasses in the serrated neoplasia pathway and that they could be useful hallmarks for identifying SLs at high risk of developing into CRC.

  19. Molecular structure and DFT investigations on new cobalt(II ...

    Indian Academy of Sciences (India)

    tion process was demonstrated.9 Late-transition metals, especially Ni, Pd ..... in table S2 (Supplementary Information). Most of the ... to molecular system because of atomic charges affect ... structure, acidity–basicity behavior and other proper-.

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

    Science.gov (United States)

    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.

  1. Cisplatin in cancer therapy: molecular mechanisms of action

    OpenAIRE

    Dasari, Shaloam; Tchounwou, Paul Bernard

    2014-01-01

    Cisplatin, cisplatinum, or cis-diamminedichloroplatinum (II), is a well-known chemotherapeutic drug. It has been used for treatment of numerous human cancers including bladder, head and neck, lung, ovarian, and testicular cancers. It is effective against various types of cancers, including carcinomas, germ cell tumors, lymphomas, and sarcomas. Its mode of action has been linked to its ability to crosslink with the purine bases on the DNA; interfering with DNA repair mechanisms, causing DNA da...

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

    Science.gov (United States)

    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. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Molecular Mechanisms of Chromium in Alleviating Insulin Resistance

    Science.gov (United States)

    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

  4. Molecular mechanisms of cisplatin resistance in cervical cancer

    Directory of Open Access Journals (Sweden)

    Zhu H

    2016-06-01

    Full Text Available Haiyan Zhu, Hui Luo, Wenwen Zhang, Zhaojun Shen, Xiaoli Hu, Xueqiong Zhu Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China Abstract: Patients with advanced or recurrent cervical cancer have poor prognosis, and their 1-year survival is only 10%–20%. Chemotherapy is considered as the standard treatment for patients with advanced or recurrent cervical cancer, and cisplatin appears to treat the disease effectively. However, resistance to cisplatin may develop, thus substantially compromising the efficacy of cisplatin to treat advanced or recurrent cervical cancer. In this article, we systematically review the recent literature and summarize the recent advances in our understanding of the molecular mechanisms underlying cisplatin resistance in cervical cancer. Keywords: cisplatin, epithelial–mesenchymal transition, microRNA, molecular mechanism, resistance

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

    Science.gov (United States)

    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.

  6. Elucidation of Molecular Pathogenic Mechanisms of Norrie Disease

    OpenAIRE

    Luhmann, Ulrich F.O.

    2010-01-01

    Summary Norrie disease (ND) is a rare X-linked recessive congenital blindness, sometimes associated with deafness and mental retardation. In this thesis the molecular pathogenic mechanisms of this syndrome should be elucidated using the Ndph knockout mouse model. Gene expression studies but also histology and protein biochemistry were used to characterize the affected organs, eye and brain. Gene expression analyses of eyes at p21 using cDNA subtrac...

  7. Molecular dynamics simulation of nanocrystalline nickel: structure and mechanical properties

    Energy Technology Data Exchange (ETDEWEB)

    Swygenhoven, H. van [Paul Scherrer Inst. (PSI), Villigen (Switzerland); Caro, A. [Comision Nacional de Energia Atomica, San Carlos de Bariloche (Argentina). Centro Atomico Bariloche

    1997-09-01

    Molecular dynamics computer simulations of low temperature elastic and plastic deformation of Ni nanophase samples (3-7 nm) are performed. The samples are polycrystals nucleated from different seeds, with random locations and orientations. Bulk and Young`s modulus, onset of plastic deformation and mechanism responsible for the plastic behaviour are studied and compared with the behaviour of coarse grained samples. (author) 1 fig., 3 refs.

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

    Science.gov (United States)

    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. Molecular dynamics simulation of nanocrystalline nickel: structure and mechanical properties

    International Nuclear Information System (INIS)

    Swygenhoven, H. van; Caro, A.

    1997-01-01

    Molecular dynamics computer simulations of low temperature elastic and plastic deformation of Ni nanophase samples (3-7 nm) are performed. The samples are polycrystals nucleated from different seeds, with random locations and orientations. Bulk and Young's modulus, onset of plastic deformation and mechanism responsible for the plastic behaviour are studied and compared with the behaviour of coarse grained samples. (author) 1 fig., 3 refs

  10. Radiotracer studies on molecular mechanisms of death and resuscitation

    International Nuclear Information System (INIS)

    Nikulin, V.J.; Pogossova, A.V.; Konikova, A.S.

    1980-01-01

    Tracer techniques and artificial circulation were applied to rabbits after death by anoxia and deep hypothermia in order to study molecular mechanisms. 60 min after death the biosynthesis and disintegration of protein RNA and DNA practically stopped in all organs. In animals cooled post mortem the process of biosynthesis and degradation of protein, RNA and DNA, as well as the physiological functions of the whole organism, were restored. (author)

  11. Molecular Mechanism and Genetic Determinants of Buprofezin Degradation

    OpenAIRE

    Chen, Xueting; Ji, Junbin; Zhao, Leizhen; Qiu, Jiguo; Dai, Chen; Wang, Weiwu; He, Jian; Jiang, Jiandong; Hong, Qing; Yan, Xin

    2017-01-01

    Buprofezin is a widely used insect growth regulator whose residue has been frequently detected in the environment, posing a threat to aquatic organisms and nontarget insects. Microorganisms play an important role in the degradation of buprofezin in the natural environment. However, the relevant catabolic pathway has not been fully characterized, and the molecular mechanism of catabolism is still completely unknown. Rhodococcus qingshengii YL-1 can utilize buprofezin as a sole source of carbon...

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

    OpenAIRE

    Pan, Tianhui; Xu, Jinghong; Zhu, Yongliang

    2016-01-01

    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 facto...

  13. Combined quantum and molecular mechanics (QM/MM).

    Science.gov (United States)

    Friesner, Richard A

    2004-12-01

    We describe the current state of the art of mixed quantum mechanics/molecular mechanics (QM/MM) methodology, with a particular focus on modeling of enzymatic reactions. Over the past decade, the effectiveness of these methods has increased dramatically, based on improved quantum chemical methods, advances in the description of the QM/MM interface, and reductions in the cost/performance of computing hardware. Two examples of pharmaceutically relevant applications, cytochrome P450 and class C β-lactamase, are presented.: © 2004 Elsevier Ltd . All rights reserved.

  14. Lignin biodegradation: experimental evidence, molecular, biochemical and physiological mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Monties, B

    1985-01-01

    A critical review is presented of English, French and some German language literature, mainly from 1983 onwards. It examines experimental evidence on the behaviour as barriers to biodegradation of lignins and phenolic polymers such as tannins and suberins. The different molecular mechanisms of lignolysis by fungi (mainly), actinomycetes and bacteria are examined. A new biochemical approach to the physiological mechanism of regulation of lignolytic activities is suggested based on the discoveries of ligniolytic enzymes: effects of nitrogen, oxygen and substrate are discussed. It is concluded that a better knowledge of the structure and reactivity of phenolic barriers is needed in order to control the process of lignolysis.

  15. Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

    Directory of Open Access Journals (Sweden)

    Saif Ahmad

    2016-01-01

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

  16. Molecular analysis of genetic diversity in elite II synthetic hexaploid ...

    African Journals Online (AJOL)

    The present study was conducted to assess the genetic diversity of Elite-II synthetic hexaploid (SH) wheat by genome DNA fingerprinting as revealed by random amplified polymorphic DNA (RAPD) analysis. Ten decamer RAPD primers (OPG-1, OPG-2, OPG-3, OPG-4, OPG-5, OPA-3, OPA-4, OPA-5, OPA-8, and OPA-15) ...

  17. Quantum mechanics/coarse-grained molecular mechanics (QM/CG-MM).

    Science.gov (United States)

    Sinitskiy, Anton V; Voth, Gregory A

    2018-01-07

    Numerous molecular systems, including solutions, proteins, and composite materials, can be modeled using mixed-resolution representations, of which the quantum mechanics/molecular mechanics (QM/MM) approach has become the most widely used. However, the QM/MM approach often faces a number of challenges, including the high cost of repetitive QM computations, the slow sampling even for the MM part in those cases where a system under investigation has a complex dynamics, and a difficulty in providing a simple, qualitative interpretation of numerical results in terms of the influence of the molecular environment upon the active QM region. In this paper, we address these issues by combining QM/MM modeling with the methodology of "bottom-up" coarse-graining (CG) to provide the theoretical basis for a systematic quantum-mechanical/coarse-grained molecular mechanics (QM/CG-MM) mixed resolution approach. A derivation of the method is presented based on a combination of statistical mechanics and quantum mechanics, leading to an equation for the effective Hamiltonian of the QM part, a central concept in the QM/CG-MM theory. A detailed analysis of different contributions to the effective Hamiltonian from electrostatic, induction, dispersion, and exchange interactions between the QM part and the surroundings is provided, serving as a foundation for a potential hierarchy of QM/CG-MM methods varying in their accuracy and computational cost. A relationship of the QM/CG-MM methodology to other mixed resolution approaches is also discussed.

  18. Quantum mechanics/coarse-grained molecular mechanics (QM/CG-MM)

    Science.gov (United States)

    Sinitskiy, Anton V.; Voth, Gregory A.

    2018-01-01

    Numerous molecular systems, including solutions, proteins, and composite materials, can be modeled using mixed-resolution representations, of which the quantum mechanics/molecular mechanics (QM/MM) approach has become the most widely used. However, the QM/MM approach often faces a number of challenges, including the high cost of repetitive QM computations, the slow sampling even for the MM part in those cases where a system under investigation has a complex dynamics, and a difficulty in providing a simple, qualitative interpretation of numerical results in terms of the influence of the molecular environment upon the active QM region. In this paper, we address these issues by combining QM/MM modeling with the methodology of "bottom-up" coarse-graining (CG) to provide the theoretical basis for a systematic quantum-mechanical/coarse-grained molecular mechanics (QM/CG-MM) mixed resolution approach. A derivation of the method is presented based on a combination of statistical mechanics and quantum mechanics, leading to an equation for the effective Hamiltonian of the QM part, a central concept in the QM/CG-MM theory. A detailed analysis of different contributions to the effective Hamiltonian from electrostatic, induction, dispersion, and exchange interactions between the QM part and the surroundings is provided, serving as a foundation for a potential hierarchy of QM/CG-MM methods varying in their accuracy and computational cost. A relationship of the QM/CG-MM methodology to other mixed resolution approaches is also discussed.

  19. The Formation of Metal (M=Co(II), Ni(II), and Cu(II)) Complexes by Aminosilanes Immobilized within Mesoporous Molecular Sieves

    International Nuclear Information System (INIS)

    Park, Dong Ho; Park, Sung Soo; Choe, Sang Joon

    1999-01-01

    The immobilization of APTMS(3-(2-aminoethylamino)propyltrimethoxysilane) and AAPTMS(3-(2-(2-aminoethyl) aminoethylamino)propyltrimethoxysilane) on the surface of high quality mesoporous molecular sieves MCM-41 and MCM-48 have been confirmed by F.T.-IR spectroscopy, Raman spectroscopy, 29 Si solid state NMR, and a surface polarity measurement using Reichardt's dye. The formation of metal (Co(II), Ni(II), and Cu(II)) complexes by immobilized aminosilanes have been investigated by photoacoustic spectroscopy(PAS). The assignment of UV-Vis. PAS bands makes it possible to identify the structure of metal complexes within mesoporous molecular sieves. Co(II) ion may be coordinated mainly in a tetrahedral symmetry by two APTMS onto MCM-41, and in an octahedral one by two AAPTMS. Both Ni(II) and Cu(II) coordinated by aminosilanes within MCM-41 form possibly the octahedral complexes such as [Ni(APTMS) 2 (H 2 O) 2 ] 2+ , [Ni(AAPTMS) 2 ] 2+ , [Cu(APTMS) 2 (H 2 O) 2 ] 2+ , and [Cu(AAPTMS)(H 2 O) 3 ] 2+ , respectively. The PAS band shapes of complexes onto MCM-48 are similar to those of corresponding MCM-41 with the variation of PAS intensity. Most of metal ion(II) within MCM-41 and MCM-48 are coordinated by aminosilanes without the impregnation on the surface

  20. A pseudobond parametrization for improved electrostatics in quantum mechanical/molecular mechanical simulations of enzymes.

    Science.gov (United States)

    Parks, Jerry M; Hu, Hao; Cohen, Aron J; Yang, Weitao

    2008-10-21

    The pseudobond method is used in quantum mechanical/molecular mechanical (QM/MM) simulations in which a covalent bond connects the quantum mechanical and classical subsystems. In this method, the molecular mechanical boundary atom is replaced by a special quantum mechanical atom with one free valence that forms a bond with the rest of the quantum mechanical subsystem. This boundary atom is modified through the use of a parametrized effective core potential and basis set. The pseudobond is designed to reproduce the properties of the covalent bond that it has replaced, while invoking as small a perturbation as possible on the system. Following the work of Zhang [J. Chem. Phys. 122, 024114 (2005)], we have developed new pseudobond parameters for use in the simulation of enzymatic systems. Our parameters yield improved electrostatics and deprotonation energies, while at the same time maintaining accurate geometries. We provide parameters for C(ps)(sp(3))-C(sp(3)), C(ps)(sp(3))-C(sp(2),carbonyl), and C(ps)(sp(3))-N(sp(3)) pseudobonds, which allow the interface between the quantum mechanical and molecular mechanical subsystems to be constructed at either the C(alpha)-C(beta) bond of a given amino acid residue or along the peptide backbone. In addition, we demonstrate the efficiency of our parametrization method by generating residue-specific pseudobond parameters for a single amino acid. Such an approach may enable higher accuracy than general purpose parameters for specific QM/MM applications.

  1. Nanostructure and molecular mechanics of spider dragline silk protein assemblies

    Science.gov (United States)

    Keten, Sinan; Buehler, Markus J.

    2010-01-01

    Spider silk is a self-assembling biopolymer that outperforms most known materials in terms of its mechanical performance, despite its underlying weak chemical bonding based on H-bonds. While experimental studies have shown that the molecular structure of silk proteins has a direct influence on the stiffness, toughness and failure strength of silk, no molecular-level analysis of the nanostructure and associated mechanical properties of silk assemblies have been reported. Here, we report atomic-level structures of MaSp1 and MaSp2 proteins from the Nephila clavipes spider dragline silk sequence, obtained using replica exchange molecular dynamics, and subject these structures to mechanical loading for a detailed nanomechanical analysis. The structural analysis reveals that poly-alanine regions in silk predominantly form distinct and orderly beta-sheet crystal domains, while disorderly regions are formed by glycine-rich repeats that consist of 31-helix type structures and beta-turns. Our structural predictions are validated against experimental data based on dihedral angle pair calculations presented in Ramachandran plots, alpha-carbon atomic distances, as well as secondary structure content. Mechanical shearing simulations on selected structures illustrate that the nanoscale behaviour of silk protein assemblies is controlled by the distinctly different secondary structure content and hydrogen bonding in the crystalline and semi-amorphous regions. Both structural and mechanical characterization results show excellent agreement with available experimental evidence. Our findings set the stage for extensive atomistic investigations of silk, which may contribute towards an improved understanding of the source of the strength and toughness of this biological superfibre. PMID:20519206

  2. Affinities of the family Sollasellidae (Porifera, Demospongiae). II. Molecular evidence

    NARCIS (Netherlands)

    Erpenbeck, D.; Hooper, J.N.A.; List-Armitage, S.E.; Degnan, B.M.; Wörheide, G.; Soest, van R.W.M.

    2007-01-01

    This is the second part of a revision and re-classification of the demosponge family Sollasellidae, and an example of a successful use of combined morphological and molecular data. Sollasella had been a poorly known, long forgotten taxon, placed incertae sedis in the order Hadromerida in the last

  3. Multiscale simulations in face-centered cubic metals: A method coupling quantum mechanics and molecular mechanics

    International Nuclear Information System (INIS)

    Yu Xiao-Xiang; Wang Chong-Yu

    2013-01-01

    An effective multiscale simulation which concurrently couples the quantum-mechanical and molecular-mechanical calculations based on the position continuity of atoms is presented. By an iterative procedure, the structure of the dislocation core in face-centered cubic metal is obtained by first-principles calculation and the long-range stress is released by molecular dynamics relaxation. Compared to earlier multiscale methods, the present work couples the long-range strain to the local displacements of the dislocation core in a simpler way with the same accuracy. (condensed matter: electronic structure, electrical, magnetic, and optical properties)

  4. Molecular mechanisms of fertilization: the role of male factor

    Directory of Open Access Journals (Sweden)

    Ewa Maria Kratz

    2011-11-01

    Full Text Available Fertilization, the fusion of male and female gametes, is an incompletely known, multistep, complex process, in which many factors participate. Fertilization is a precisely regulated, species-specific process, but some cellular mechanisms are similar for many mammal species. The studies of mechanisms of male and female gamete production enable understanding of fertilization issues and, as a result, make the analysis of the causes of infertility possible. Male and female infertility is a progressive phenomenon. The development of laboratory medicine enables the analysis of molecular aspects of the reactions between gametes, which may result in better diagnosis of many infertility cases and indicate the direction of therapeutic management. The fertilization process is accompanied by many biochemical reactions, in which glycoproteins present in human ejaculate play a very important role. Glycan structures enable glycoproteins to participate in the interactions between cells, including those between gametes. The analysis of the glycosylation profile and degree of ejaculate glycoproteins not only contributes to deepening the knowledge about mechanisms accompanying the fertilization process, but also may be useful as an additional diagnostic marker of male infertility.The aim of the present review is to approach selected molecular mechanisms occurring in the male genital tract, related to the fertilization process, as well as to analyze their influence on male fertility.

  5. Molecular cloning of the human casein kinase II α subunit

    International Nuclear Information System (INIS)

    Meisner, H.; Heller-Harrison, R.; Buxton, J.; Czech, M.P.

    1989-01-01

    A human cDNA encoding the α subunit of casein kinase II and a partial cDNA encoding the rat homologue were isolated by using a Drosophila casein kinase II cDNA probe. The 2.2-kb human cDNA contains a 1.2-kb open reading frame, 150 nucleotides of 5' leader, and 850 nucleotides of 3' noncoding region. Except for the first 7 deduced amino acids that are missing in the rat cDNA, the 328 amino acids beginning with the amino terminus are identical between human and rat. The Drosophila enzyme sequence is 90% identical with the human casein kinase II sequence, and there is only a single amino acid difference between the published partial bovine sequence and the human sequence. In addition, the C-terminus of the human cDNA has an extra 53 amino acids not present in Drosophila. Northern analysis of rat and human RNA showed predominant bands of 5.5, 3.1, and 1.8 kb. In rat tissues, brain and spleen had the highest levels of casein kinase II α subunit specific RNA, while skeletal muscle showed the lowest. Southern analysis of human cultured cell and tissue genomic DNA using the full-length cDNA probe revealed two bands with restriction enzymes that have no recognition sites within the cDNA and three to six bands with enzymes having single internal sites. These results are consistent with the possibility that two genes encode the α subunits

  6. Molecular models of zinc phthalocyanines: semi-empirical molecular orbital computations and physicochemical properties studied by molecular mechanics simulations

    International Nuclear Information System (INIS)

    Gantchev, Tsvetan G.; van Lier, Johan E.; Hunting, Darel J.

    2005-01-01

    To build 3D-molecular models of Zinc-phthalocyanines (ZnPc) and to study their diverse chemical and photosensitization properties, we performed quantum mechanical molecular orbital (MO) semi-empirical (AM1) computations of the ground, excited singlet and triplet states as well as free radical (ionic) species. RHF and UHF (open shell) geometry optimizations led to near-perfect symmetrical ZnPc. Predicted ionization potentials (IP), electron affinities (EA) and lowest electronic transitions of ZnPc are in good agreement with the published experimental and theoretical data. The computation-derived D 4h /D 2h -symmetry 3D-structures of ground and excited states and free radicals of ZnPc, together with the frontier orbital energies and Mulliken electron population analysis enabled us to build robust molecular models. These models were used to predict important chemical-reactivity entities such as global electronegativity (χ), hardness (η) and local softness based on Fukui-functions analysis. Examples of molecular mechanics (MM) applications of the 3D-molecular models are presented as approaches to evaluate solvation free energy (ΔG 0 ) solv and to estimate ground- and excited- state oxidation/reduction potentials as well as intermolecular interactions and stability of ground and excited state dimers (exciplexes) and radical ion-pairs

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

    Energy Technology Data Exchange (ETDEWEB)

    Mathiazhagan, S., E-mail: smathi.research@gmail.com; Anup, S., E-mail: anupiist@gmail.com

    2016-08-19

    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. - Highlights: • The deformation behaviour of staggered nanocomposites is studied. • Stair-wise staggered model has high stiffness and strength, but low toughness. • Rapid crack growth in overlap region causes this low toughness. • Toughness could be enhanced by arresting interfacial crack in the overlap.

  8. Deformation mechanisms in nanotwinned copper by molecular dynamics simulation

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Xing [School of Mechanical, Materials and Mechatronic Engineering, University of Wollongong, Wollongong, NSW 2522 (Australia); State Key Laboratory of High Performance Complex Manufacturing, Central South University, Changsha 410083 (China); Lu, Cheng, E-mail: chenglu@uow.edu.au [School of Mechanical, Materials and Mechatronic Engineering, University of Wollongong, Wollongong, NSW 2522 (Australia); Tieu, Anh Kiet; Pei, Linqing; Zhang, Liang; Su, Lihong [School of Mechanical, Materials and Mechatronic Engineering, University of Wollongong, Wollongong, NSW 2522 (Australia); Zhan, Lihua [State Key Laboratory of High Performance Complex Manufacturing, Central South University, Changsha 410083 (China)

    2017-02-27

    Nanotwinned materials exhibit simultaneous ultrahigh strength and high ductility which is attributed to the interactions between dislocations and twin boundaries but the specific deformation mechanisms are rarely seen in experiments at the atomic level. Here we use large scale molecular dynamics simulations to explore this intricate interplay during the plastic deformation of nanotwinned Cu. We demonstrate that the dominant deformation mechanism transits dynamically from slip transfer to twin boundary migration to slip-twin interactions as the twin boundary orientation changes from horizontal to slant, and then to a vertical direction. Building on the fundamental physics of dislocation processes from computer simulations and combining the available experimental investigations, we unravel the underlying deformation mechanisms for nanotwinned Cu, incorporating all three distinct dislocation processes. Our results give insights into systematically engineering the nanoscale twins to fabricate nanotwinned metals or alloys that have high strength and considerable ductility.

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

    International Nuclear Information System (INIS)

    Mathiazhagan, S.; Anup, S.

    2016-01-01

    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. - Highlights: • The deformation behaviour of staggered nanocomposites is studied. • Stair-wise staggered model has high stiffness and strength, but low toughness. • Rapid crack growth in overlap region causes this low toughness. • Toughness could be enhanced by arresting interfacial crack in the overlap.

  10. Molecular mechanism of extreme mechanostability in a pathogen adhesin.

    Science.gov (United States)

    Milles, Lukas F; Schulten, Klaus; Gaub, Hermann E; Bernardi, Rafael C

    2018-03-30

    High resilience to mechanical stress is key when pathogens adhere to their target and initiate infection. Using atomic force microscopy-based single-molecule force spectroscopy, we explored the mechanical stability of the prototypical staphylococcal adhesin SdrG, which targets a short peptide from human fibrinogen β. Steered molecular dynamics simulations revealed, and single-molecule force spectroscopy experiments confirmed, the mechanism by which this complex withstands forces of over 2 nanonewtons, a regime previously associated with the strength of a covalent bond. The target peptide, confined in a screwlike manner in the binding pocket of SdrG, distributes forces mainly toward the peptide backbone through an intricate hydrogen bond network. Thus, these adhesins can attach to their target with exceptionally resilient mechanostability, virtually independent of peptide side chains. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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

    Energy Technology Data Exchange (ETDEWEB)

    Calin-Jageman, Robert J

    2009-09-12

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

  12. Homeostasis-altering molecular processes as mechanisms of inflammasome activation.

    Science.gov (United States)

    Liston, Adrian; Masters, Seth L

    2017-03-01

    The innate immune system uses a distinct set of germline-encoded pattern recognition receptors (PRRs) to initiate downstream inflammatory cascades. This recognition system is in stark contrast to the adaptive immune system, which relies on highly variable, randomly generated antigen receptors. A key limitation of the innate immune system's reliance on fixed PRRs is its inflexibility in responding to rapidly evolving pathogens. Recent advances in our understanding of inflammasome activation suggest that the innate immune system also has sophisticated mechanisms for responding to pathogens for which there is no fixed PRR. This includes the recognition of debris from dying cells, known as danger-associated molecular patterns (DAMPs), which can directly activate PRRs in a similar manner to pathogen-associated molecular patterns (PAMPs). Distinct from this, emerging data for the inflammasome components NLRP3 (NOD-, LRR- and pyrin domain-containing 3) and pyrin suggest that they do not directly detect molecular patterns, but instead act as signal integrators that are capable of detecting perturbations in cytoplasmic homeostasis, for example, as initiated by infection. Monitoring these perturbations, which we term 'homeostasis-altering molecular processes' (HAMPs), provides potent flexibility in the capacity of the innate immune system to detect evolutionarily novel infections; however, HAMP sensing may also underlie the sterile inflammation that drives chronic inflammatory diseases.

  13. Deciphering Molecular Mechanism Underlying Hypolipidemic Activity of Echinocystic Acid

    Directory of Open Access Journals (Sweden)

    Li Han

    2014-01-01

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

  14. Molecular mechanisms of aging and immune system regulation in Drosophila.

    Science.gov (United States)

    Eleftherianos, Ioannis; Castillo, Julio Cesar

    2012-01-01

    Aging is a complex process that involves the accumulation of deleterious changes resulting in overall decline in several vital functions, leading to the progressive deterioration in physiological condition of the organism and eventually causing disease and death. The immune system is the most important host-defense mechanism in humans and is also highly conserved in insects. Extensive research in vertebrates has concluded that aging of the immune function results in increased susceptibility to infectious disease and chronic inflammation. Over the years, interest has grown in studying the molecular interaction between aging and the immune response to pathogenic infections. The fruit fly Drosophila melanogaster is an excellent model system for dissecting the genetic and genomic basis of important biological processes, such as aging and the innate immune system, and deciphering parallel mechanisms in vertebrate animals. Here, we review the recent advances in the identification of key players modulating the relationship between molecular aging networks and immune signal transduction pathways in the fly. Understanding the details of the molecular events involved in aging and immune system regulation will potentially lead to the development of strategies for decreasing the impact of age-related diseases, thus improving human health and life span.

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

    International Nuclear Information System (INIS)

    Lee, W.R.

    1985-01-01

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

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

    Science.gov (United States)

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

    2015-11-12

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

  17. Epidemiological bases and molecular mechanisms linking obesity, diabetes, and cancer.

    Science.gov (United States)

    Gutiérrez-Salmerón, María; Chocarro-Calvo, Ana; García-Martínez, José Manuel; de la Vieja, Antonio; García-Jiménez, Custodia

    2017-02-01

    The association between diabetes and cancer was hypothesized almost one century ago. Today, a vast number of epidemiological studies support that obese and diabetic populations are more likely to experience tissue-specific cancers, but the underlying molecular mechanisms remain unknown. Obesity, diabetes, and cancer share many hormonal, immune, and metabolic changes that may account for the relationship between diabetes and cancer. In addition, antidiabetic treatments may have an impact on the occurrence and course of some cancers. Moreover, some anticancer treatments may induce diabetes. These observations aroused a great controversy because of the ethical implications and the associated commercial interests. We report an epidemiological update from a mechanistic perspective that suggests the existence of many common and differential individual mechanisms linking obesity and type 1 and 2 diabetes mellitus to certain cancers. The challenge today is to identify the molecular links responsible for this association. Classification of cancers by their molecular signatures may facilitate future mechanistic and epidemiological studies. Copyright © 2016 SEEN. Publicado por Elsevier España, S.L.U. All rights reserved.

  18. Postischemic revascularization: from cellular and molecular mechanisms to clinical applications.

    Science.gov (United States)

    Silvestre, Jean-Sébastien; Smadja, David M; Lévy, Bernard I

    2013-10-01

    After the onset of ischemia, cardiac or skeletal muscle undergoes a continuum of molecular, cellular, and extracellular responses that determine the function and the remodeling of the ischemic tissue. Hypoxia-related pathways, immunoinflammatory balance, circulating or local vascular progenitor cells, as well as changes in hemodynamical forces within vascular wall trigger all the processes regulating vascular homeostasis, including vasculogenesis, angiogenesis, arteriogenesis, and collateral growth, which act in concert to establish a functional vascular network in ischemic zones. In patients with ischemic diseases, most of the cellular (mainly those involving bone marrow-derived cells and local stem/progenitor cells) and molecular mechanisms involved in the activation of vessel growth and vascular remodeling are markedly impaired by the deleterious microenvironment characterized by fibrosis, inflammation, hypoperfusion, and inhibition of endogenous angiogenic and regenerative programs. Furthermore, cardiovascular risk factors, including diabetes, hypercholesterolemia, hypertension, diabetes, and aging, constitute a deleterious macroenvironment that participates to the abrogation of postischemic revascularization and tissue regeneration observed in these patient populations. Thus stimulation of vessel growth and/or remodeling has emerged as a new therapeutic option in patients with ischemic diseases. Many strategies of therapeutic revascularization, based on the administration of growth factors or stem/progenitor cells from diverse sources, have been proposed and are currently tested in patients with peripheral arterial disease or cardiac diseases. This review provides an overview from our current knowledge regarding molecular and cellular mechanisms involved in postischemic revascularization, as well as advances in the clinical application of such strategies of therapeutic revascularization.

  19. Affinities of the family Sollasellidae (Porifera, Demospongiae). II. Molecular evidence.

    OpenAIRE

    Erpenbeck, D.J.G.; Hooper, J.N.A.; List-Armitage, S.E.; Degman, B.M.; Wördheide, G.; van Soest, R.W.M.

    2007-01-01

    This is the second part of a revision and re-classification of the demosponge family Sollasellidae, and an example of a successful use of combined morphological and molecular data. Sollasella had been a poorly known, long forgotten taxon, placed incertae sedis in the order Hadromerida in the last major revision of the demosponges. It has recently been suggested to belong to Raspailiidae in the order Poecilosclerida due to striking morphological similarities. The present analysis verified this...

  20. Molecular mechanisms of cognitive dysfunction following traumatic brain injury

    Science.gov (United States)

    Walker, Kendall R.; Tesco, Giuseppina

    2013-01-01

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

  1. Molecular mechanisms of cognitive dysfunction following traumatic brain injury.

    Science.gov (United States)

    Walker, Kendall R; Tesco, Giuseppina

    2013-01-01

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

  2. Separating grain boundary migration mechanisms in molecular dynamics simulations

    International Nuclear Information System (INIS)

    Ulomek, Felix; Mohles, Volker

    2016-01-01

    In molecular dynamics (MD) simulations of grain boundary (GB) migration it is quite common to find a temperature dependence of GB mobility that deviates strongly from an Arrhenius-type dependence. This usually indicates that more than one mechanism is actually active. With the goal to separate different GB migration mechanisms we investigate a Σ7 <111> 38.2° GB by MD using an EAM potential for aluminium. To drive the GB with a well-known and adjustable force, the energy conserving orientational driving force (ECO DF) is used that had been introduced recently. The magnitude of the DF and the temperature are varied. This yielded a high and a low temperature range for the GB velocity, with a transition temperature that depends on the magnitude of the DF. A method is introduced which allows both a visual and a statistical characterization of GB motion on a per atom basis. These analyses reveal that two mechanisms are active in this GB, a shuffling mechanism and its initiation. These mechanisms operate in a sequential, coupled manner. Based on this, a simple model is introduced that describes all simulated GB velocities (and hence the mobility) very well, including the transition between the dominating mechanisms.

  3. Molecular mechanisms in compatibility and mechanical properties of Polyacrylamide/Polyvinyl alcohol blends.

    Science.gov (United States)

    Wei, Qinghua; Wang, Yanen; Che, Yu; Yang, Mingming; Li, Xinpei; Zhang, Yingfeng

    2017-01-01

    The objectives of this study were to develop a computational model based on molecular dynamics technique to investigate the compatibility and mechanical properties of Polyacrylamide (PAM)/Polyvinyl alcohol (PVA) blends. Five simulation models of PAM/PVA with different composition ratios (4/0, 3/1, 2/2, 1/3, 0/4) were constructed and simulated by using molecular dynamics (MD) simulation. The interaction mechanisms of molecular chains in PAM/PVA blend system were elaborated from the aspects of the compatibility, mechanical properties, binding energy and pair correlation function, respectively. The computed values of solubility parameters for PAM and PVA indicate PAM has a good miscibility with PVA. The results of the static mechanical analysis, based on the equilibrium structures of blends with differing component ratios, shows us that the elastic coefficient, engineering modulus, and ductility are increased with the addition of PVA content, which is 4/0 PAM/PVAPVAPVAPVAPVA. Moreover, binding energy results indicate that a stronger interaction exists among PVA molecular chains comparing with PAM molecular chains, which is why the mechanical properties of blend system increasing with the addition of PVA content. Finally, the results of pair correlation functions (PCFs) between polar functional groups and its surrounding hydrogen atoms, indicated they interact with each other mainly by hydrogen bonds, and the strength of three types of polar functional groups has the order of O(-OH)>O(-C=O)>N(-NH 2 ). This further elaborates the root reason why the mechanical properties of blend system increase with the addition of PVA content. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Quantum Interactomics and Cancer Molecular Mechanisms: I. Report Outline

    CERN Document Server

    Baianu, I C

    2004-01-01

    Single cell interactomics in simpler organisms, as well as somatic cell interactomics in multicellular organisms, involve biomolecular interactions in complex signalling pathways that were recently represented in modular terms by quantum automata with ‘reversible behavior’ representing normal cell cycling and division. Other implications of such quantum automata, modular modeling of signaling pathways and cell differentiation during development are in the fields of neural plasticity and brain development leading to quantum-weave dynamic patterns and specific molecular processes underlying extensive memory, learning, anticipation mechanisms and the emergence of human consciousness during the early brain development in children. Cell interactomics is here represented for the first time as a mixture of ‘classical’ states that determine molecular dynamics subject to Boltzmann statistics and ‘steady-state’, metabolic (multi-stable) manifolds, together with ‘configuration’ spaces of metastable quant...

  5. Conduction mechanism of nitronyl-nitroxide molecular magnetic compounds

    Science.gov (United States)

    Dotti, N.; Heintze, E.; Slota, M.; Hübner, R.; Wang, F.; Nuss, J.; Dressel, M.; Bogani, L.

    2016-04-01

    We investigate the conduction mechanisms of nitronyl-nitroxide (NIT) molecular radicals, as useful for the creation of nanoscopic molecular spintronic devices, finding that it does not correspond to standard Mott behavior, as previously postulated. We provide a complete investigation using transport measurements, low-energy, sub-THz spectroscopy and introducing differently substituted phenyl appendages. We show that a nontrivial surface-charge-limited regime is present in addition to the standard low-voltage Ohmic conductance. Scaling analysis allows one to determine all the main transport parameters for the compounds and highlights the presence of charge-trapping effects. Comparison among the different compounds shows the relevance of intermolecular stacking between the aromatic ring of the phenyl appendix and the NIT motif in the creation of useful electron transport channels. The importance of intermolecular pathways is further highlighted by electronic structure calculations, which clarify the nature of the electronic channels and their effect on the Mott character of the compounds.

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

    Science.gov (United States)

    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. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  7. Internal force corrections with machine learning for quantum mechanics/molecular mechanics simulations.

    Science.gov (United States)

    Wu, Jingheng; Shen, Lin; Yang, Weitao

    2017-10-28

    Ab initio quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulation is a useful tool to calculate thermodynamic properties such as potential of mean force for chemical reactions but intensely time consuming. In this paper, we developed a new method using the internal force correction for low-level semiempirical QM/MM molecular dynamics samplings with a predefined reaction coordinate. As a correction term, the internal force was predicted with a machine learning scheme, which provides a sophisticated force field, and added to the atomic forces on the reaction coordinate related atoms at each integration step. We applied this method to two reactions in aqueous solution and reproduced potentials of mean force at the ab initio QM/MM level. The saving in computational cost is about 2 orders of magnitude. The present work reveals great potentials for machine learning in QM/MM simulations to study complex chemical processes.

  8. Sexual polyploidization in plants--cytological mechanisms and molecular regulation.

    Science.gov (United States)

    De Storme, Nico; Geelen, Danny

    2013-05-01

    In the plant kingdom, events of whole genome duplication or polyploidization are generally believed to occur via alterations of the sexual reproduction process. Thereby, diploid pollen and eggs are formed that contain the somatic number of chromosomes rather than the gametophytic number. By participating in fertilization, these so-called 2n gametes generate polyploid offspring and therefore constitute the basis for the establishment of polyploidy in plants. In addition, diplogamete formation, through meiotic restitution, is an essential component of apomixis and also serves as an important mechanism for the restoration of F1 hybrid fertility. Characterization of the cytological mechanisms and molecular factors underlying 2n gamete formation is therefore not only relevant for basic plant biology and evolution, but may also provide valuable cues for agricultural and biotechnological applications (e.g. reverse breeding, clonal seeds). Recent data have provided novel insights into the process of 2n pollen and egg formation and have revealed multiple means to the same end. Here, we summarize the cytological mechanisms and molecular regulatory networks underlying 2n gamete formation, and outline important mitotic and meiotic processes involved in the ectopic induction of sexual polyploidization. © 2013 Ghent University. New Phytologist © 2013 New Phytologist Trust.

  9. Cadmium (II) removal mechanisms in microbial electrolysis cells

    Energy Technology Data Exchange (ETDEWEB)

    Colantonio, Natalie; Kim, Younggy, E-mail: younggy@mcmaster.ca

    2016-07-05

    Highlights: • Rapid removal of Cd(II) was achieved in 24 h using microbial electrolysis cells. • Cathodic reduction (electrodeposition) of Cd(II) cannot explain the rapid removal. • H{sub 2} evolution in microbial electrolysis cells increases local pH near the cathode. • High local pH induces Cd(OH){sub 2} and CdCO{sub 3} precipitation only with electric current. • Neutral pH caused by low current and depleted substrate dissolves the precipitated Cd. - Abstract: Cadmium is a toxic heavy metal, causing serious environmental and human health problems. Conventional methods for removing cadmium from wastewater are expensive and inefficient for low concentrations. Microbial electrolysis cells (MECs) can simultaneously treat wastewater, produce hydrogen gas, and remove heavy metals with low energy requirements. Lab-scale MECs were operated to remove cadmium under various electric conditions: applied voltages of 0.4, 0.6, 0.8, and 1.0 V; and a fixed cathode potential of −1.0 V vs. Ag/AgCl. Regardless of the electric condition, rapid removal of cadmium was demonstrated (50–67% in 24 h); however, cadmium concentration in solution increased after the electric current dropped with depleted organic substrate under applied voltage conditions. For the fixed cathode potential, the electric current was maintained even after substrate depletion and thus cadmium concentration did not increase. These results can be explained by three different removal mechanisms: cathodic reduction; Cd(OH){sub 2} precipitation; and CdCO{sub 3} precipitation. When the current decreased with depleted substrates, local pH at the cathode was no longer high due to slowed hydrogen evolution reaction (2H{sup +} + 2e{sup −} → H{sub 2}); thus, the precipitated Cd(OH){sub 2} and CdCO{sub 3} started dissolving. To prevent their dissolution, sufficient organic substrates should be provided when MECs are used for cadmium removal.

  10. [Pharmacogenetics II. Research molecular methods, bioinformatics and ethical concerns].

    Science.gov (United States)

    Daudén, E

    2007-01-01

    Pharmacogenetics refers to the study of the individual pharmacological response based on the genotype. Its objective is to optimize treatment in an individual basis, thereby creating a more efficient and safe personalized therapy. In the second part of this review, the molecular methods of study in pharmacogenetics, including microarray technology or DNA chips, are discussed. Among them we highlight the microarrays used to determine the gene expression that detect specific RNA sequences, and the microarrays employed to determine the genotype that detect specific DNA sequences, including polymorphisms, particularly single nucleotide polymorphisms (SNPs). The relationship between pharmacogenetics, bioinformatics and ethical concerns is reviewed.

  11. Cellular and molecular investigations of the adhesion and mechanics of Listeria monocytogenes

    Science.gov (United States)

    Eskhan, Asma Omar

    Atomic force microscopy has been used to quantify the adherence and mechanical properties of an array of L. monocytogenes strains and their surface biopolymers. First, eight L. monocytogenes strains that represented the two major lineages of the species were compared for their adherence and mechanics at cellular and molecular levels. Our results indicated that strains of lineage' II were characterized by higher adhesion and Young's moduli, longer and more rigid surface biopolymers and lower specific and nonspecific forces when compared to lineage' I strains. Additionally, adherence and mechanical properties of eight L. monocytogenes epidemic and environmental strains were probed. Our results pointed to that environmental and epidemic strains representative of a given lineage were similar in their adherence and mechanical properties when investigated at a cellular level. However, when the molecular properties of the strains were considered, epidemic strains were characterized by higher specific and nonspecific forces, shorter, denser and more flexible biopolymers compared to environmental strains. Second, the role of environmental pH conditions of growth on the adhesion and mechanics of a pathogenic L. monocytogenes EGDe was investigated. Our results pointed to a transition in the adhesion energies for cells cultured at pH 7. In addition, when the types of molecular forces that govern the adhesion were quantified using Poisson statistical approach and using a new proposed method, specific hydrogen-bond energies dominated the bacterial adhesion process. Such a finding is instrumental to researchers designing methods to control bacterial adhesion. Similarly, bacterial cells underwent a transition in their mechanical properties. We have shown that cells cultured at pH 7 were the most rigid compared to those cultured in lower or higher pH conditions of growth. Due to transitions observed in adherence and mechanics when cells were cultured at pH 7, we hypothesized that

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

    Science.gov (United States)

    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

  13. Biology and Mechanics of Blood Flows Part II: Mechanics and Medical Aspects

    CERN Document Server

    Thiriet, Marc

    2008-01-01

    Biology and Mechanics of Blood Flows presents the basic knowledge and state-of-the-art techniques necessary to carry out investigations of the cardiovascular system using modeling and simulation. Part II of this two-volume sequence, Mechanics and Medical Aspects, refers to the extraction of input data at the macroscopic scale for modeling the cardiovascular system, and complements Part I, which focuses on nanoscopic and microscopic components and processes. This volume contains chapters on anatomy, physiology, continuum mechanics, as well as pathological changes in the vasculature walls including the heart and their treatments. Methods of numerical simulations are given and illustrated in particular by application to wall diseases. This authoritative book will appeal to any biologist, chemist, physicist, or applied mathematician interested in the functioning of the cardiovascular system.

  14. Microarrays: Molecular allergology and nanotechnology for personalised medicine (II).

    Science.gov (United States)

    Lucas, J M

    2010-01-01

    Progress in nanotechnology and DNA recombination techniques have produced tools for the diagnosis and investigation of allergy at molecular level. The most advanced examples of such progress are the microarray techniques, which have been expanded not only in research in the field of proteomics but also in application to the clinical setting. Microarrays of allergic components offer results relating to hundreds of allergenic components in a single test, and using a small amount of serum which can be obtained from capillary blood. The availability of new molecules will allow the development of panels including new allergenic components and sources, which will require evaluation for clinical use. Their application opens the door to component-based diagnosis, to the holistic perception of sensitisation as represented by molecular allergy, and to patient-centred medical practice by allowing great diagnostic accuracy and the definition of individualised immunotherapy for each patient. The present article reviews the application of allergenic component microarrays to allergology for diagnosis, management in the form of specific immunotherapy, and epidemiological studies. A review is also made of the use of protein and gene microarray techniques in basic research and in allergological diseases. Lastly, an evaluation is made of the challenges we face in introducing such techniques to clinical practice, and of the future perspectives of this new technology. Copyright 2010 SEICAP. Published by Elsevier Espana. All rights reserved.

  15. Molecular mechanisms of methicillin resistance in Staphylococcus aureus.

    Science.gov (United States)

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

    1997-09-01

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

  16. Mixed 2D molecular systems: Mechanic, thermodynamic and dielectric properties

    Energy Technology Data Exchange (ETDEWEB)

    Beno, Juraj [Department of Physics, Faculty of Electrical Engineering and Information Technology, Slovak University of Technology, Ilkovicova 3, 812 19-SK Bratislava (Slovakia); Weis, Martin [Department of Physics, Faculty of Electrical Engineering and Information Technology, Slovak University of Technology, Ilkovicova 3, 812 19-SK Bratislava (Slovakia)], E-mail: Martin.Weis@stuba.sk; Dobrocka, Edmund [Department of Physics, Faculty of Electrical Engineering and Information Technology, Slovak University of Technology, Ilkovicova 3, 812 19-SK Bratislava (Slovakia); Institute of Electrical Engineering, Slovak Academy of Sciences, Dubravska cesta 9, 841 04-SK Bratislava (Slovakia); Hasko, Daniel [International Laser Centre, Ilkovicova 3, 812 19-SK Bratislava (Slovakia)

    2008-08-15

    Study of Langmuir monolayers consisting of stearic acid (SA) and dipalmitoylphosphatidylcholine (DPPC) molecules was done by surface pressure-area isotherms ({pi}-A), the Maxwell displacement current (MDC) measurement, X-ray reflectivity (XRR) and atomic force microscopy (AFM) to investigate the selected mechanic, thermodynamic and dielectric properties based on orientational structure of monolayers. On the base of {pi}-A isotherms analysis we explain the creation of stable structures and found optimal monolayer composition. The dielectric properties represented by MDC generated monolayers were analyzed in terms of excess dipole moment, proposing the effect of dipole-dipole interaction. XRR and AFM results illustrate deposited film structure and molecular ordering.

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

    Science.gov (United States)

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

    2014-07-28

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

  18. New insights on molecular mechanisms of renal aging.

    Science.gov (United States)

    Schmitt, R; Melk, A

    2012-11-01

    Long-term transplant outcome is importantly influenced by the age of the organ donor. The mechanisms how age carries out its pathophysiological impact on graft survival are still not understood. One major contributing factor for the observed poor performance of old donor kidneys seems in particular the age-related loss in renal regenerative capacity. In this review, we will summarize recent findings about the molecular basis of renal aging with specific focus on the potential role of somatic cellular senescence and mitochondrial aging in renal transplant outcome. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

  19. Molecular mechanisms of cisplatin resistance in cervical cancer.

    Science.gov (United States)

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

    2016-01-01

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

  20. Molecular Mechanisms of Survival Strategies in Extreme Conditions

    Directory of Open Access Journals (Sweden)

    Federica Migliardo

    2012-12-01

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

  1. HBV DNA Integration: Molecular Mechanisms and Clinical Implications

    Science.gov (United States)

    Tu, Thomas; Budzinska, Magdalena A.; Shackel, Nicholas A.; Urban, Stephan

    2017-01-01

    Chronic infection with the Hepatitis B Virus (HBV) is a major cause of liver-related morbidity and mortality. One peculiar observation in cells infected with HBV (or with closely‑related animal hepadnaviruses) is the presence of viral DNA integration in the host cell genome, despite this form being a replicative dead-end for the virus. The frequent finding of somatic integration of viral DNA suggests an evolutionary benefit for the virus; however, the mechanism of integration, its functions, and the clinical implications remain unknown. Here we review the current body of knowledge of HBV DNA integration, with particular focus on the molecular mechanisms and its clinical implications (including the possible consequences of replication-independent antigen expression and its possible role in hepatocellular carcinoma). HBV DNA integration is likely to influence HBV replication, persistence, and pathogenesis, and so deserves greater attention in future studies. PMID:28394272

  2. Studies on Molecular Mechanisms Underlying Spinocerebellar Ataxia Type 3

    DEFF Research Database (Denmark)

    Kristensen, Line Vildbrad

    . Even though a range of mechanisms contributing to polyQ diseases have been uncovered, there is still no treatment available. One of the more common polyQ diseases is SCA3, which is caused by a polyQ expansion in the ataxin-3 protein that normally functions as a deubiquitinating enzyme involved...... in protein quality control. In SCA3 patients polyQ expanded ataxin-3 forms intranuclear inclusions in various brain areas, but why the polyQ expansion of ataxin-3 leads to neuronal dysfunction is still not well understood. This thesis describes molecular biological investigations of ataxin-3 biology, aimed...... at furthering our understanding of SCA3 disease mechanisms. In manuscript I, we investigated if post-translational modifications of ataxin-3 were changed by the polyQ expansion. The ubiquitin chain topology and ubiquitination pattern of ataxin-3 were unaltered by the polyQ expansion. In contrast...

  3. Molecular mechanisms in radiation damage to DNA. Progress report

    International Nuclear Information System (INIS)

    Osman, R.

    1994-01-01

    The objectives of this work are to elucidate the molecular mechanisms that are responsible for radiation-induced DNA damage. The overall goal is to understand the relationship between the chemical and structural changes produced by ionizing radiation in DNA and the resulting impairment of biological function expressed as carcinogenesis or cell death. The studies are based on theoretical explorations of possible mechanisms that link initial radiation damage in the form of base and sugar damage to conformational changes in DNA. These mechanistic explorations should lead to the formulation of testable hypotheses regarding the processes of impairment of regulation of gene expression, alteration in DNA repair, and damage to DNA structure involved in cell death or cancer

  4. Molecular Mechanism Underlying Lymphatic Metastasis in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Zhiwen Xiao

    2014-01-01

    Full Text Available As the most challenging human malignancies, pancreatic cancer is characterized by its insidious symptoms, low rate of surgical resection, high risk of local invasion, metastasis and recurrence, and overall dismal prognosis. Lymphatic metastasis, above all, is recognized as an early adverse event in progression of pancreatic cancer and has been described to be an independent poor prognostic factor. It should be noted that the occurrence of lymphatic metastasis is not a casual or stochastic but an ineluctable and designed event. Increasing evidences suggest that metastasis-initiating cells (MICs and the microenvironments may act as a double-reed style in this crime. However, the exact mechanisms on how they function synergistically for this dismal clinical course remain largely elusive. Therefore, a better understanding of its molecular and cellular mechanisms involved in pancreatic lymphatic metastasis is urgently required. In this review, we will summarize the latest advances on lymphatic metastasis in pancreatic cancer.

  5. Molecular mechanisms of platelet P2Y(12) receptor regulation.

    Science.gov (United States)

    Cunningham, Margaret R; Nisar, Shaista P; Mundell, Stuart J

    2013-02-01

    Platelets are critical for haemostasis, however inappropriate activation can lead to the development of arterial thrombosis, which can result in heart attack and stroke. ADP is a key platelet agonist that exerts its actions via stimulation of two surface GPCRs (G-protein-coupled receptors), P2Y(1) and P2Y(12). Similar to most GPCRs, P2Y receptor activity is tightly regulated by a number of complex mechanisms including receptor desensitization, internalization and recycling. In the present article, we review the molecular mechanisms that underlie P2Y(1) and P2Y(12) receptor regulation, with particular emphasis on the structural motifs within the P2Y(12) receptor, which are required to maintain regulatory protein interaction. The implications of these findings for platelet responsiveness are also discussed.

  6. ANGULAR MOMENTUM IN GIANT MOLECULAR CLOUDS. II. M33

    International Nuclear Information System (INIS)

    Imara, Nia; Bigiel, Frank; Blitz, Leo

    2011-01-01

    We present an analysis comparing the properties of 45 giant molecular clouds (GMCs) in M33 and the atomic hydrogen (H I) with which they are associated. High-resolution Very Large Array observations are used to measure the properties of H I in the vicinity of GMCs and in regions where GMCs have not been detected. The majority of molecular clouds coincide with a local peak in the surface density of atomic gas, though 7% of GMCs in the sample are not associated with high surface density atomic gas. The mean H I surface density in the vicinity of GMCs is 10 M sun pc -2 and tends to increase with GMC mass as Σ HI ∝ M 0.27 GMC . Thirty-nine of the 45 H I regions surrounding GMCs have linear velocity gradients of ∼0.05 km s -1 pc -1 . If the linear gradients previously observed in the GMCs result from rotation, 53% are counterrotating with respect to the local H I. And if the linear gradients in these local H I regions are also from rotation, 62% are counterrotating with respect to the galaxy. If magnetic braking reduced the angular momentum of GMCs early in their evolution, the angular velocity of GMCs would be roughly one order of magnitude lower than what is observed. Based on our observations, we consider the possibility that GMCs may not be rotating. Atomic gas not associated with GMCs has gradients closer to 0.03 km s -1 pc -1 , suggesting that events occur during the course of GMC evolution that may increase the shear in the atomic gas.

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

    Directory of Open Access Journals (Sweden)

    Jose A. Santiago

    2017-05-01

    Full Text Available 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.

  8. DMPD: Molecular mechanisms of the anti-inflammatory functions of interferons. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18086388 Molecular mechanisms of the anti-inflammatory functions of interferons. Ko....csml) Show Molecular mechanisms of the anti-inflammatory functions of interferons. PubmedID 18086388 Title ...Molecular mechanisms of the anti-inflammatory functions of interferons. Authors K

  9. Molecular mechanism and potential targets for bone metastasis

    International Nuclear Information System (INIS)

    Iguchi, Haruo

    2007-01-01

    The incidence of bone metastasis has been increasing in all cancers in recent years. Bone metastasis is associated with substantial morbidity, including bone pain, pathological fracture, neurological deficit and/or hypercalcemia. Thus, the management of bone metastasis in patients is a clinically significant issue. In the process of bone metastasis, the primary mechanism responsible for bone destruction is cancer cell-mediated stimulation of osteoclastic bone resorption, which results in osteolysis and release of various growth factors from the bone matrix. These growth factors are prerequisites for successful colonization and subsequent invasive growth of cancer cells in bone, which is called a 'vicious cycle.' Thus, it is important to elucidate what molecules are involved in this step of bone destruction, and the understanding of these molecular mechanisms could lead to develop molecular-target therapies for bone metastasis. Bisphosphonates introduced in the treatment for bone metastasis have been shown to reduce skeletal morbidity. In Japan, the most potent bisphosphonate, zoledronate (ZOMETA), was introduced in this past April, and a phase III clinical trial of humanized anti-receptor activator of NF-κB ligand (RANKL) monoclonal antibody (Denosumab) against bone metastasis is under way as a global study. These new agents, which are targeted to osteoclasts, are considered to be standard management in the care of bone metastasis patients in combination with chemotherapy and/or hormone therapy. (author)

  10. MATCH: An Atom- Typing Toolset for Molecular Mechanics Force Fields

    Science.gov (United States)

    Yesselman, Joseph D.; Price, Daniel J.; Knight, Jennifer L.; Brooks, Charles L.

    2011-01-01

    We introduce a toolset of program libraries collectively titled MATCH (Multipurpose Atom-Typer for CHARMM) for the automated assignment of atom types and force field parameters for molecular mechanics simulation of organic molecules. The toolset includes utilities for the conversion from multiple chemical structure file formats into a molecular graph. A general chemical pattern-matching engine using this graph has been implemented whereby assignment of molecular mechanics atom types, charges and force field parameters is achieved by comparison against a customizable list of chemical fragments. While initially designed to complement the CHARMM simulation package and force fields by generating the necessary input topology and atom-type data files, MATCH can be expanded to any force field and program, and has core functionality that makes it extendable to other applications such as fragment-based property prediction. In the present work, we demonstrate the accurate construction of atomic parameters of molecules within each force field included in CHARMM36 through exhaustive cross validation studies illustrating that bond increment rules derived from one force field can be transferred to another. In addition, using leave-one-out substitution it is shown that it is also possible to substitute missing intra and intermolecular parameters with ones included in a force field to complete the parameterization of novel molecules. Finally, to demonstrate the robustness of MATCH and the coverage of chemical space offered by the recent CHARMM CGENFF force field (Vanommeslaeghe, et al., JCC., 2010, 31, 671–690), one million molecules from the PubChem database of small molecules are typed, parameterized and minimized. PMID:22042689

  11. Effect of the mechanical processing on the mechanical properties of MA956 alloy. II. Mechanical characterization

    International Nuclear Information System (INIS)

    Chao, J.; Gonzalez-Doncel, G.

    1998-01-01

    The mechanical properties at room and low temperature of MA 956 alloy in some stages of their processing route are evaluated. In this study the influence of crystallographic orientation on plastic deformation and brittle fracture, strongly anisotropic phenomena, is also considered. It is concluded that even though MA 956 alloy was designated for high temperature applications it could be also used for cryogenic temperatures applications. (Author) 8 refs

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

    Science.gov (United States)

    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. Copyright © 2015 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    2015-12-03

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

  14. Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis

    Directory of Open Access Journals (Sweden)

    Thomas A. Milne

    2012-09-01

    Full Text Available Epigenetics is often defined as the study of heritable changes in gene expression or chromosome stability that don’t alter the underlying DNA sequence. Epigenetic changes are established through multiple mechanisms that include DNA methylation, non-coding RNAs and the covalent modification of specific residues on histone proteins. It is becoming clear not only that aberrant epigenetic changes are common in many human diseases such as leukemia, but that these changes by their very nature are malleable, and thus are amenable to treatment. Epigenetic based therapies have so far focused on the use of histone deacetylase (HDAC inhibitors and DNA methyltransferase inhibitors, which tend to have more general and widespread effects on gene regulation in the cell. However, if a unique molecular pathway can be identified, diseases caused by epigenetic mechanisms are excellent candidates for the development of more targeted therapies that focus on specific gene targets, individual binding domains, or specific enzymatic activities. Designing effective targeted therapies depends on a clear understanding of the role of epigenetic mutations during disease progression. The Mixed Lineage Leukemia (MLL protein is an example of a developmentally important protein that controls the epigenetic activation of gene targets in part by methylating histone 3 on lysine 4. MLL is required for normal development, but is also mutated in a subset of aggressive human leukemias and thus provides a useful model for studying the link between epigenetic cell memory and human disease. The most common MLL mutations are chromosome translocations that fuse the MLL gene in frame with partner genes creating novel fusion proteins. In this review, we summarize recent work that argues MLL fusion proteins could function through a single molecular pathway, but we also highlight important data that suggests instead that multiple independent mechanisms underlie MLL mediated leukemogenesis.

  15. Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Ballabio, Erica; Milne, Thomas A., E-mail: thomas.milne@imm.ox.ac.uk [MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital Headington, Oxford OX3 9DS (United Kingdom)

    2012-09-10

    Epigenetics is often defined as the study of heritable changes in gene expression or chromosome stability that don’t alter the underlying DNA sequence. Epigenetic changes are established through multiple mechanisms that include DNA methylation, non-coding RNAs and the covalent modification of specific residues on histone proteins. It is becoming clear not only that aberrant epigenetic changes are common in many human diseases such as leukemia, but that these changes by their very nature are malleable, and thus are amenable to treatment. Epigenetic based therapies have so far focused on the use of histone deacetylase (HDAC) inhibitors and DNA methyltransferase inhibitors, which tend to have more general and widespread effects on gene regulation in the cell. However, if a unique molecular pathway can be identified, diseases caused by epigenetic mechanisms are excellent candidates for the development of more targeted therapies that focus on specific gene targets, individual binding domains, or specific enzymatic activities. Designing effective targeted therapies depends on a clear understanding of the role of epigenetic mutations during disease progression. The Mixed Lineage Leukemia (MLL) protein is an example of a developmentally important protein that controls the epigenetic activation of gene targets in part by methylating histone 3 on lysine 4. MLL is required for normal development, but is also mutated in a subset of aggressive human leukemias and thus provides a useful model for studying the link between epigenetic cell memory and human disease. The most common MLL mutations are chromosome translocations that fuse the MLL gene in frame with partner genes creating novel fusion proteins. In this review, we summarize recent work that argues MLL fusion proteins could function through a single molecular pathway, but we also highlight important data that suggests instead that multiple independent mechanisms underlie MLL mediated leukemogenesis.

  16. Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis

    International Nuclear Information System (INIS)

    Ballabio, Erica; Milne, Thomas A.

    2012-01-01

    Epigenetics is often defined as the study of heritable changes in gene expression or chromosome stability that don’t alter the underlying DNA sequence. Epigenetic changes are established through multiple mechanisms that include DNA methylation, non-coding RNAs and the covalent modification of specific residues on histone proteins. It is becoming clear not only that aberrant epigenetic changes are common in many human diseases such as leukemia, but that these changes by their very nature are malleable, and thus are amenable to treatment. Epigenetic based therapies have so far focused on the use of histone deacetylase (HDAC) inhibitors and DNA methyltransferase inhibitors, which tend to have more general and widespread effects on gene regulation in the cell. However, if a unique molecular pathway can be identified, diseases caused by epigenetic mechanisms are excellent candidates for the development of more targeted therapies that focus on specific gene targets, individual binding domains, or specific enzymatic activities. Designing effective targeted therapies depends on a clear understanding of the role of epigenetic mutations during disease progression. The Mixed Lineage Leukemia (MLL) protein is an example of a developmentally important protein that controls the epigenetic activation of gene targets in part by methylating histone 3 on lysine 4. MLL is required for normal development, but is also mutated in a subset of aggressive human leukemias and thus provides a useful model for studying the link between epigenetic cell memory and human disease. The most common MLL mutations are chromosome translocations that fuse the MLL gene in frame with partner genes creating novel fusion proteins. In this review, we summarize recent work that argues MLL fusion proteins could function through a single molecular pathway, but we also highlight important data that suggests instead that multiple independent mechanisms underlie MLL mediated leukemogenesis

  17. Molecular medicine of fragile X syndrome: based on known molecular mechanisms.

    Science.gov (United States)

    Luo, Shi-Yu; Wu, Ling-Qian; Duan, Ran-Hui

    2016-02-01

    Extensive research on fragile X mental retardation gene knockout mice and mutant Drosophila models has largely expanded our knowledge on mechanism-based treatment of fragile X syndrome (FXS). In light of these findings, several clinical trials are now underway for therapeutic translation to humans. Electronic literature searches were conducted using the PubMed database and ClinicalTrials.gov. The search terms included "fragile X syndrome", "FXS and medication", "FXS and therapeutics" and "FXS and treatment". Based on the publications identified in this search, we reviewed the neuroanatomical abnormalities in FXS patients and the potential pathogenic mechanisms to monitor the progress of FXS research, from basic studies to clinical trials. The pathological mechanisms of FXS were categorized on the basis of neuroanatomy, synaptic structure, synaptic transmission and fragile X mental retardation protein (FMRP) loss of function. The neuroanatomical abnormalities in FXS were described to motivate extensive research into the region-specific pathologies in the brain responsible for FXS behavioural manifestations. Mechanism-directed molecular medicines were classified according to their target pathological mechanisms, and the most recent progress in clinical trials was discussed. Current mechanism-based studies and clinical trials have greatly contributed to the development of FXS pharmacological therapeutics. Research examining the extent to which these treatments provided a rescue effect or FMRP compensation for the developmental impairments in FXS patients may help to improve the efficacy of treatments.

  18. Possible Peroxo State of the Dicopper Site of Particulate Methane Monooxygenase from Combined Quantum Mechanics and Molecular Mechanics Calculations.

    Science.gov (United States)

    Itoyama, Shuhei; Doitomi, Kazuki; Kamachi, Takashi; Shiota, Yoshihito; Yoshizawa, Kazunari

    2016-03-21

    Enzymatic methane hydroxylation is proposed to efficiently occur at the dinuclear copper site of particulate methane monooxygenase (pMMO), which is an integral membrane metalloenzyme in methanotrophic bacteria. The resting state and a possible peroxo state of the dicopper active site of pMMO are discussed by using combined quantum mechanics and molecular mechanics calculations on the basis of reported X-ray crystal structures of the resting state of pMMO by Rosenzweig and co-workers. The dicopper site has a unique structure, in which one copper is coordinated by two histidine imidazoles and another is chelated by a histidine imidazole and primary amine of an N-terminal histidine. The resting state of the dicopper site is assignable to the mixed-valent Cu(I)Cu(II) state from a computed Cu-Cu distance of 2.62 Å from calculations at the B3LYP-D/TZVP level of theory. A μ-η(2):η(2)-peroxo-Cu(II)2 structure similar to those of hemocyanin and tyrosinase is reasonably obtained by using the resting state structure and dioxygen. Computed Cu-Cu and O-O distances are 3.63 and 1.46 Å, respectively, in the open-shell singlet state. Structural features of the dicopper peroxo species of pMMO are compared with those of hemocyanin and tyrosinase and synthetic dicopper model compounds. Optical features of the μ-η(2):η(2)-peroxo-Cu(II)2 state are calculated and analyzed with TD-DFT calculations.

  19. Optimization and benchmarking of a perturbative Metropolis Monte Carlo quantum mechanics/molecular mechanics program.

    Science.gov (United States)

    Feldt, Jonas; Miranda, Sebastião; Pratas, Frederico; Roma, Nuno; Tomás, Pedro; Mata, Ricardo A

    2017-12-28

    In this work, we present an optimized perturbative quantum mechanics/molecular mechanics (QM/MM) method for use in Metropolis Monte Carlo simulations. The model adopted is particularly tailored for the simulation of molecular systems in solution but can be readily extended to other applications, such as catalysis in enzymatic environments. The electrostatic coupling between the QM and MM systems is simplified by applying perturbation theory to estimate the energy changes caused by a movement in the MM system. This approximation, together with the effective use of GPU acceleration, leads to a negligible added computational cost for the sampling of the environment. Benchmark calculations are carried out to evaluate the impact of the approximations applied and the overall computational performance.

  20. Molecular mechanisms of radioadaptive responses in human lymphoblastoid cells

    International Nuclear Information System (INIS)

    Kakimoto, Ayana; Taki, Keiko; Nakajima, Tetsuo

    2008-01-01

    Radioadaptive response is a biodefensive response observed in a variety of mammalian cells and animals where exposure to low dose radiation induces resistance against the subsequent high dose radiation. Elucidation of its mechanisms is important for risk estimation of low dose radiation because the radioadaptive response implies that low dose radiation affects cells/individuals in a different manner from high dose radiation. In the present study, we explored the molecular mechanisms of the radioadaptive response in human lymphoblastoid cells AHH-1 in terms of mutation at the hypoxanthine phosphoribosyltransferase (HPRT) gene locus. First we observed that preexposure to the priming dose in the range from 0.02 Gy to 0.2 Gy significantly reduced mutation frequency at HPRT gene locus after irradiation with 3 Gy of X rays. As no significant adaptive response was observed with the priming dose of 0.005 Gy, it was indicated that the lower limit of the priming dose to induce radioadaptive response may be between 0.005 Gy and 0.02 Gy. Second, we examined the effect of 3-amino-benzamide (3AB), an inhibitor of poly(ADP-ribose)polymerase1, which has been reported to inhibit the radioadaptive response in terms of chromosome aberration. However we could observe significant radioadaptive responses in terms of mutation even in the presence of 3AB. These findings suggested that molecular mechanisms of the radioadaptive response in terms of mutation may be different from that for radioadaptive responses in terms of chromosomal aberration, although we could not exclude a possibility that the differential effects of 3AB was due to cell type difference. Finally, by performing a comprehensive analysis of alterations in gene expression using high coverage expression profiling (HiCEP), we could identify 17 genes whose expressions were significantly altered 6 h after irradiation with 0.02 Gy. We also found 17 and 20 genes, the expressions of which were different with or without priming

  1. Mechanical Properties of Nanostructured Materials Determined Through Molecular Modeling Techniques

    Science.gov (United States)

    Clancy, Thomas C.; Gates, Thomas S.

    2005-01-01

    The potential for gains in material properties over conventional materials has motivated an effort to develop novel nanostructured materials for aerospace applications. These novel materials typically consist of a polymer matrix reinforced with particles on the nanometer length scale. In this study, molecular modeling is used to construct fully atomistic models of a carbon nanotube embedded in an epoxy polymer matrix. Functionalization of the nanotube which consists of the introduction of direct chemical bonding between the polymer matrix and the nanotube, hence providing a load transfer mechanism, is systematically varied. The relative effectiveness of functionalization in a nanostructured material may depend on a variety of factors related to the details of the chemical bonding and the polymer structure at the nanotube-polymer interface. The objective of this modeling is to determine what influence the details of functionalization of the carbon nanotube with the polymer matrix has on the resulting mechanical properties. By considering a range of degree of functionalization, the structure-property relationships of these materials is examined and mechanical properties of these models are calculated using standard techniques.

  2. Natural agents: cellular and molecular mechanisms of photoprotection.

    Science.gov (United States)

    Afaq, Farrukh

    2011-04-15

    The skin is the largest organ of the body that produces a flexible and self-repairing barrier and protects the body from most common potentially harmful physical, environmental, and biological insults. Solar ultraviolet (UV) radiation is one of the major environmental insults to the skin and causes multi-tiered cellular and molecular events eventually leading to skin cancer. The past decade has seen a surge in the incidence of skin cancer due to changes in life style patterns that have led to a significant increase in the amount of UV radiation that people receive. Reducing excessive exposure to UV radiation is desirable; nevertheless this approach is not easy to implement. Therefore, there is an urgent need to develop novel strategies to reduce the adverse biological effects of UV radiation on the skin. A wide variety of natural agents have been reported to possess substantial skin photoprotective effects. Numerous preclinical and clinical studies have elucidated that natural agents act by several cellular and molecular mechanisms to delay or prevent skin cancer. In this review article, we have summarized and discussed some of the selected natural agents for skin photoprotection. Copyright © 2010 Elsevier Inc. All rights reserved.

  3. Neuroprotection and its molecular mechanism following spinal cord injury☆

    Science.gov (United States)

    Liu, Nai-Kui; Xu, Xiao-Ming

    2012-01-01

    Acute spinal cord injury initiates a complex cascade of molecular events termed ‘secondary injury’, which leads to progressive degeneration ranging from early neuronal apoptosis at the lesion site to delayed degeneration of intact white matter tracts, and, ultimately, expansion of the initial injury. These secondary injury processes include, but are not limited to, inflammation, free radical-induced cell death, glutamate excitotoxicity, phospholipase A2 activation, and induction of extrinsic and intrinsic apoptotic pathways, which are important targets in developing neuroprotective strategies for treatment of spinal cord injury. Recently, a number of studies have shown promising results on neuroprotection and recovery of function in rodent models of spinal cord injury using treatments that target secondary injury processes including inflammation, phospholipase A2 activation, and manipulation of the PTEN-Akt/mTOR signaling pathway. The present review outlines our ongoing research on the molecular mechanisms of neuroprotection in experimental spinal cord injury and briefly summarizes our earlier findings on the therapeutic potential of pharmacological treatments in spinal cord injury. PMID:25624837

  4. Nanoparticles and potential neurotoxicity: focus on molecular mechanisms

    Directory of Open Access Journals (Sweden)

    Davide Lovisolo

    2018-01-01

    Full Text Available The last decades have seen an explosive increase in the development of nanoparticles and in their use in consumer, industrial and medical applications. Their fast diffusion has also raised widespread concern about the potential toxic effects on living organisms, including humans: at the nanoscale, they can interact with subcellular components such as membranes, proteins, lipids, nucleic acids, thus inducing unpredicted functional perturbations in cells and tissues. The nervous tissue is a particular sensitive target, because its cellular components (mainly neurons and glial cells are tightly regulated and metabolically exigent biological entities. While the literature on the potential toxicity of nanoparticles has grown in parallel with their utilization, the available data on neurotoxicity are less abundant. In particular, information on the neuronal molecular targets of nanoparticles is still largely incomplete. A better understanding of this issue is highly relevant for the rational and controlled design of nanoparticles, both for their general utilization and more specifically for their use in the promising field of nanoneuromedicine. In this review, we will discuss the available information on the mechanisms involved in the interaction between nanoobjects and cells of the nervous system, focusing on the known molecular actors, both at the plasma membrane and in intracellular compartments.

  5. Quantum mechanical force fields for condensed phase molecular simulations

    Science.gov (United States)

    Giese, Timothy J.; York, Darrin M.

    2017-09-01

    Molecular simulations are powerful tools for providing atomic-level details into complex chemical and physical processes that occur in the condensed phase. For strongly interacting systems where quantum many-body effects are known to play an important role, density-functional methods are often used to provide the model with the potential energy used to drive dynamics. These methods, however, suffer from two major drawbacks. First, they are often too computationally intensive to practically apply to large systems over long time scales, limiting their scope of application. Second, there remain challenges for these models to obtain the necessary level of accuracy for weak non-bonded interactions to obtain quantitative accuracy for a wide range of condensed phase properties. Quantum mechanical force fields (QMFFs) provide a potential solution to both of these limitations. In this review, we address recent advances in the development of QMFFs for condensed phase simulations. In particular, we examine the development of QMFF models using both approximate and ab initio density-functional models, the treatment of short-ranged non-bonded and long-ranged electrostatic interactions, and stability issues in molecular dynamics calculations. Example calculations are provided for crystalline systems, liquid water, and ionic liquids. We conclude with a perspective for emerging challenges and future research directions.

  6. Anticancer Chemodiversity of Ranunculaceae Medicinal Plants: Molecular Mechanisms and Functions.

    Science.gov (United States)

    Hao, Da-Cheng; He, Chun-Nian; Shen, Jie; Xiao, Pei-Gen

    2017-02-01

    The buttercup family, Ranunculaceae, comprising more than 2,200 species in at least 62 genera, mostly herbs, has long been used in folk medicine and worldwide ethnomedicine since the beginning of human civilization. Various medicinal phytometabolites have been found in Ranunculaceae plants, many of which, such as alkaloids, terpenoids, saponins, and polysaccharides, have shown anti-cancer activities in vitro and in vivo. Most concerns have been raised for two epiphany molecules, the monoterpene thymoquinone and the isoquinoline alkaloid berberine. At least 17 genera have been enriched with anti-cancer phytometabolites. Some Ranunculaceae phytometabolites induce the cell cycle arrest and apoptosis of cancer cells or enhance immune activities, while others inhibit the proliferation, invasion, angiogenesis, and metastasis, or reverse the multi-drug resistance of cancer cells thereby regulating all known hallmarks of cancer. These phytometabolites could exert their anti-cancer activities via multiple signaling pathways. In addition, absorption, distribution, metabolism, and excretion/toxicity properties and structure/activity relationships of some phytometabolites have been revealed assisting in the early drug discovery and development pipelines. However, a comprehensive review of the molecular mechanisms and functions of Ranunculaceae anti-cancer phytometabolites is lacking. Here, we summarize the recent progress of the anti-cancer chemo- and pharmacological diversity of Ranunculaceae medicinal plants, focusing on the emerging molecular machineries and functions of anti-cancer phytometabolites. Gene expression profiling and relevant omics platforms (e.g. genomics, transcriptomics, proteomics, and metabolomics) could reveal differential effects of phytometabolites on the phenotypically heterogeneous cancer cells.

  7. Molecular mechanisms of maternal vascular dysfunction in preeclampsia.

    Science.gov (United States)

    Goulopoulou, Styliani; Davidge, Sandra T

    2015-02-01

    In preeclampsia, as a heterogeneous syndrome, multiple pathways have been proposed for both the causal as well as the perpetuating factors leading to maternal vascular dysfunction. Postulated mechanisms include imbalance in the bioavailability and activity of endothelium-derived contracting and relaxing factors and oxidative stress. Studies have shown that placenta-derived factors [antiangiogenic factors, microparticles (MPs), cell-free nucleic acids] are released into the maternal circulation and act on the vascular wall to modify the secretory capacity of endothelial cells and alter the responsiveness of vascular smooth muscle cells to constricting and relaxing stimuli. These molecules signal their deleterious effects on the maternal vascular wall via pathways that provide the molecular basis for novel and effective therapeutic interventions. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. DNA replication stress: from molecular mechanisms to human disease.

    Science.gov (United States)

    Muñoz, Sergio; Méndez, Juan

    2017-02-01

    The genome of proliferating cells must be precisely duplicated in each cell division cycle. Chromosomal replication entails risks such as the possibility of introducing breaks and/or mutations in the genome. Hence, DNA replication requires the coordinated action of multiple proteins and regulatory factors, whose deregulation causes severe developmental diseases and predisposes to cancer. In recent years, the concept of "replicative stress" (RS) has attracted much attention as it impinges directly on genomic stability and offers a promising new avenue to design anticancer therapies. In this review, we summarize recent progress in three areas: (1) endogenous and exogenous factors that contribute to RS, (2) molecular mechanisms that mediate the cellular responses to RS, and (3) the large list of diseases that are directly or indirectly linked to RS.

  9. The molecular mechanisms of offspring effects from obese pregnancy.

    LENUS (Irish Health Repository)

    Dowling, Daniel

    2013-01-01

    The incidence of obesity, increased weight gain and the popularity of high-fat \\/ high-sugar diets are seriously impacting upon the global population. Billions of individuals are affected, and although diet and lifestyle are of paramount importance to the development of adult obesity, compelling evidence is emerging which suggests that maternal obesity and related disorders may be passed on to the next generation by non-genetic means. The processes acting within the uteri of obese mothers may permanently predispose offspring to a diverse plethora of diseases ranging from obesity and diabetes to psychiatric disorders. This review aims to summarise some of the molecular mechanisms and active processes currently known about maternal obesity and its effect on foetal and neonatal physiology and metabolism. Complex and multifactorial networks of molecules are intertwined and culminate in a pathologically synergistic manner to cause disruption and disorganisation of foetal physiology. This altered phenotype may potentiate the cycle of intergenerational transmission of obesity and related disorders.

  10. Recent Advances in Methamphetamine Neurotoxicity Mechanisms and Its Molecular Pathophysiology

    Directory of Open Access Journals (Sweden)

    Shaobin Yu

    2015-01-01

    Full Text Available Methamphetamine (METH is a sympathomimetic amine that belongs to phenethylamine and amphetamine class of psychoactive drugs, which are widely abused for their stimulant, euphoric, empathogenic, and hallucinogenic properties. Many of these effects result from acute increases in dopamine and serotonin neurotransmission. Subsequent to these acute effects, METH produces persistent damage to dopamine and serotonin release in nerve terminals, gliosis, and apoptosis. This review summarized the numerous interdependent mechanisms including excessive dopamine, ubiquitin-proteasome system dysfunction, protein nitration, endoplasmic reticulum stress, p53 expression, inflammatory molecular, D3 receptor, microtubule deacetylation, and HIV-1 Tat protein that have been demonstrated to contribute to this damage. In addition, the feasible therapeutic strategies according to recent studies were also summarized ranging from drug and protein to gene level.

  11. Quantum-Mechanical Calculations on Molecular Substructures Involved in Nanosystems

    Directory of Open Access Journals (Sweden)

    Beata Szefler

    2014-09-01

    Full Text Available In this review article, four ideas are discussed: (a aromaticity of fullerenes patched with flowers of 6-and 8-membered rings, optimized at the HF and DFT levels of theory, in terms of HOMA and NICS criteria; (b polybenzene networks, from construction to energetic and vibrational spectra computations; (c quantum-mechanical calculations on the repeat units of various P-type crystal networks and (d construction and stability evaluation, at DFTB level of theory, of some exotic allotropes of diamond D5, involved in hyper-graphenes. The overall conclusion was that several of the yet hypothetical molecular nanostructures herein described are serious candidates to the status of real molecules.

  12. Complement Involvement in Periodontitis: Molecular Mechanisms and Rational Therapeutic Approaches.

    Science.gov (United States)

    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.

  13. A Hybrid Imperative and Functional Molecular Mechanics Application

    Directory of Open Access Journals (Sweden)

    Thomas Deboni

    1996-01-01

    Full Text Available Molecular mechanics applications model the interactions among large ensembles of discrete particles. They are used where probabilistic methods are inadequate, such as drug chemistry. This methodology is difficult to parallelize with good performance, due to its poor locality, uneven partitions, and dynamic behavior. Imperative programs have been written that attempt this on shared and distributed memory machines. Given such a program, the computational kernel can be rewritten in Sisal, a functional programming language, and integrated with the rest of the imperative program under the Sisal Foreign Language Interface. This allows minimal effort and maximal return from parallelization work, and leaves the work appropriate to imperative implementation in its original form. We describe such an effort, focusing on the parts of the application that are appropriate for Sisal implementation, the specifics of mixed-language programming, and the complex performance behavior of the resulting hybrid code.

  14. Obstructive renal injury: from fluid mechanics to molecular cell biology.

    Science.gov (United States)

    Ucero, Alvaro C; Gonçalves, Sara; Benito-Martin, Alberto; Santamaría, Beatriz; Ramos, Adrian M; Berzal, Sergio; Ruiz-Ortega, Marta; Egido, Jesus; Ortiz, Alberto

    2010-04-22

    Urinary tract obstruction is a frequent cause of renal impairment. The physiopathology of obstructive nephropathy has long been viewed as a mere mechanical problem. However, recent advances in cell and systems biology have disclosed a complex physiopathology involving a high number of molecular mediators of injury that lead to cellular processes of apoptotic cell death, cell injury leading to inflammation and resultant fibrosis. Functional studies in animal models of ureteral obstruction using a variety of techniques that include genetically modified animals have disclosed an important role for the renin-angiotensin system, transforming growth factor-β1 (TGF-β1) and other mediators of inflammation in this process. In addition, high throughput techniques such as proteomics and transcriptomics have identified potential biomarkers that may guide clinical decision-making.

  15. Recent Advances in Molecular Mechanisms of Taste Signaling and Modifying.

    Science.gov (United States)

    Shigemura, Noriatsu; Ninomiya, Yuzo

    2016-01-01

    The sense of taste conveys crucial information about the quality and nutritional value of foods before it is ingested. Taste signaling begins with taste cells via taste receptors in oral cavity. Activation of these receptors drives the transduction systems in taste receptor cells. Then particular transmitters are released from the taste cells and activate corresponding afferent gustatory nerve fibers. Recent studies have revealed that taste sensitivities are defined by distinct taste receptors and modulated by endogenous humoral factors in a specific group of taste cells. Such peripheral taste generations and modifications would directly influence intake of nutritive substances. This review will highlight current understanding of molecular mechanisms for taste reception, signal transduction in taste bud cells, transmission between taste cells and nerves, regeneration from taste stem cells, and modification by humoral factors at peripheral taste organs. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Molecular mechanisms of water transport in the eye

    DEFF Research Database (Denmark)

    Hamann, Steffen

    2002-01-01

    The four major sites for ocular water transport, the corneal epithelium and endothelium, the ciliary epithelium, and the retinal pigment epithelium, are reviewed. The cornea has an inherent tendency to swell, which is counteracted by its two surface cell layers, the corneal epithelium...... and endothelium. The bilayered ciliary epithelium secretes the aqueous humor into the posterior chamber, and the retinal pigment epithelium transports water from the retinal to the choroidal site. For each epithelium, ion transport mechanisms are associated with fluid transport, but the exact molecular coupling...... sites between ion and water transport remain undefined. In the retinal pigment epithelium, a H+-lactate cotransporter transports water. This protein could be the site of coupling between salt and water in this epithelium. The distribution of aquaporins does not suggest a role for these proteins...

  17. Molecular mechanism for inhibition of twinfilin by phosphoinositides

    DEFF Research Database (Denmark)

    Hakala, Markku; Kalimeri, Maria; Enkavi, Giray

    2018-01-01

    actin-depolymerizing factor (ADF)/cofilin-like ADF homology domains of twinfilin bind phosphoinositides only with low affinity. Mutagenesis and biochemical experiments combined with atomistic molecular dynamics simulations reveal that the C-terminal tail of twinfilin interacts with membranes through......Membrane phosphoinositides control organization and dynamics of the actin cytoskeleton by regulating the activities of several key actin-binding proteins. Twinfilin is an evolutionarily conserved protein that contributes to cytoskeletal dynamics by interacting with actin monomers, filaments......, and the heterodimeric capping protein. Twinfilin also binds phosphoinositides, which inhibit its interactions with actin, but the underlying mechanism has remained unknown. Here, we show that the high-affinity binding site of twinfilin for phosphoinositides is located at the C-terminal tail region, whereas the two...

  18. Molecular spectroscopic study for suggested mechanism of chrome tanned leather

    Science.gov (United States)

    Nashy, Elshahat H. A.; Osman, Osama; Mahmoud, Abdel Aziz; Ibrahim, Medhat

    2012-03-01

    Collagen represents the structural protein of the extracellular matrix, which gives strength of hides and/or skin under tanning process. Chrome tan is the most important tanning agent all over the world. The methods for production of leather evolved over several centuries as art and engineering with little understanding of the underlying science. The present work is devoted to suggest the most probable mechanistic action of chrome tan on hide proteins. First the affect of Cr upon hide protein is indicated by the studied mechanical properties. Then the spectroscopic characterization of the hide protein as well as chrome tanned leather was carried out with Horizontal Attenuated Total Reflection (HATR) FT-IR. The obtained results indicate how the chromium can attached with the active sites of collagen. Molecular modeling confirms that chromium can react with amino as well as carboxylate groups. Four schemes were obtained to describe the possible interactions of chrome tan with hide proteins.

  19. THE NATURE OF TRANSITION CIRCUMSTELLAR DISKS. II. SOUTHERN MOLECULAR CLOUDS

    Energy Technology Data Exchange (ETDEWEB)

    Romero, Gisela A.; Schreiber, Matthias R.; Rebassa-Mansergas, Alberto [Departamento de Fisica y Astronomia, Universidad de Valparaiso, Valparaiso (Chile); Cieza, Lucas A. [Institute for Astronomy, University of Hawaii at Manoa, Honolulu, HI 96822 (United States); Merin, Bruno [Herschel Science Centre, ESAC (ESA), P.O. Box 78, 28691 Villanueva de la Canada, Madrid (Spain); Smith Castelli, Analia V. [Consejo Nacional de Investigaciones Cientificas y Tecnicas, Rivadavia 1917, C1033AAJ Buenos Aires (Argentina); Allen, Lori E. [Department of Astronomy, University of Arizona, 933 North Cherry Avenue, Tucson, AZ 85721-0065 (United States); Morrell, Nidia [Las Campanas Observatory, Carnegie Observatories, Casilla 601, La Serena (Chile)

    2012-04-10

    Transition disk objects are pre-main-sequence stars with little or no near-IR excess and significant far-IR excess, implying inner opacity holes in their disks. Here we present a multifrequency study of transition disk candidates located in Lupus I, III, IV, V, VI, Corona Australis, and Scorpius. Complementing the information provided by Spitzer with adaptive optics (AO) imaging (NaCo, VLT), submillimeter photometry (APEX), and echelle spectroscopy (Magellan, Du Pont Telescopes), we estimate the multiplicity, disk mass, and accretion rate for each object in our sample in order to identify the mechanism potentially responsible for its inner hole. We find that our transition disks show a rich diversity in their spectral energy distribution morphology, have disk masses ranging from {approx}<1 to 10 M{sub JUP}, and accretion rates ranging from {approx}<10{sup -11} to 10{sup -7.7} M{sub Sun} yr{sup -1}. Of the 17 bona fide transition disks in our sample, three, nine, three, and two objects are consistent with giant planet formation, grain growth, photoevaporation, and debris disks, respectively. Two disks could be circumbinary, which offers tidal truncation as an alternative origin of the inner hole. We find the same heterogeneity of the transition disk population in Lupus III, IV, and Corona Australis as in our previous analysis of transition disks in Ophiuchus while all transition disk candidates selected in Lupus V, VI turned out to be contaminating background asymptotic giant branch stars. All transition disks classified as photoevaporating disks have small disk masses, which indicates that photoevaporation must be less efficient than predicted by most recent models. The three systems that are excellent candidates for harboring giant planets potentially represent invaluable laboratories to study planet formation with the Atacama Large Millimeter/Submillimeter Array.

  20. THE NATURE OF TRANSITION CIRCUMSTELLAR DISKS. II. SOUTHERN MOLECULAR CLOUDS

    International Nuclear Information System (INIS)

    Romero, Gisela A.; Schreiber, Matthias R.; Rebassa-Mansergas, Alberto; Cieza, Lucas A.; Merín, Bruno; Smith Castelli, Analía V.; Allen, Lori E.; Morrell, Nidia

    2012-01-01

    Transition disk objects are pre-main-sequence stars with little or no near-IR excess and significant far-IR excess, implying inner opacity holes in their disks. Here we present a multifrequency study of transition disk candidates located in Lupus I, III, IV, V, VI, Corona Australis, and Scorpius. Complementing the information provided by Spitzer with adaptive optics (AO) imaging (NaCo, VLT), submillimeter photometry (APEX), and echelle spectroscopy (Magellan, Du Pont Telescopes), we estimate the multiplicity, disk mass, and accretion rate for each object in our sample in order to identify the mechanism potentially responsible for its inner hole. We find that our transition disks show a rich diversity in their spectral energy distribution morphology, have disk masses ranging from ∼ JUP , and accretion rates ranging from ∼ –11 to 10 –7.7 M ☉ yr –1 . Of the 17 bona fide transition disks in our sample, three, nine, three, and two objects are consistent with giant planet formation, grain growth, photoevaporation, and debris disks, respectively. Two disks could be circumbinary, which offers tidal truncation as an alternative origin of the inner hole. We find the same heterogeneity of the transition disk population in Lupus III, IV, and Corona Australis as in our previous analysis of transition disks in Ophiuchus while all transition disk candidates selected in Lupus V, VI turned out to be contaminating background asymptotic giant branch stars. All transition disks classified as photoevaporating disks have small disk masses, which indicates that photoevaporation must be less efficient than predicted by most recent models. The three systems that are excellent candidates for harboring giant planets potentially represent invaluable laboratories to study planet formation with the Atacama Large Millimeter/Submillimeter Array.

  1. Effects of expanding compact H II regions upon molecular clouds: Molecular dissociation waves, shock waves, and carbon ionization

    International Nuclear Information System (INIS)

    Hill, J.K.; Hollenbach, D.J.

    1978-01-01

    The effect of young expanding compact H II regions upon their molecular environments are studied, emphasizing the simultaneous evolution of the molecular hydrogen dissociation front and the shocked shell of gas surrounding the nebula. For H II regions powered by 05 stars embedded in molecular clouds of ambient density 10 3 -10 4 cm -3 the dissociation wave initially travels outward much more rapidly than the shock, but later decelerates and is swept up by the shock about 10 5 yr after the expansion begins. The 21 cm line of atomic hydrogen will be optically thick in both the preshock and postshock gas for most of this period. The most important coolant transitions are the [O I] 63 μm line and, for t> or approx. =10 5 yr, the rotational transitions of H 2 and/or the rotational transitions of CO. The vibrational transitions of H 2 are excited predominantly by ultraviolet pumping. We estimate the preshock and postshock carbon recombination-line emission measures

  2. Molecular mechanism and genetic determinants of buprofezin degradation.

    Science.gov (United States)

    Chen, Xueting; Ji, Junbin; Zhao, Leizhen; Qiu, Jiguo; Dai, Chen; Wang, Weiwu; He, Jian; Jiang, Jiandong; Hong, Qing; Yan, Xin

    2017-07-14

    Buprofezin is a widely used insect growth regulator whose residue has been frequently detected in the environment, posing a threat to aquatic organisms and non-target insects. Microorganisms play an important role in the degradation of buprofezin in the natural environment. However, the relevant catabolic pathway has not been fully characterized, and the molecular mechanism of catabolism is still completely unknown. Rhodococcus qingshengii YL-1 can utilize buprofezin as a sole source of carbon and energy for growth. In this study, the upstream catabolic pathway in strain YL-1 was identified using tandem mass spectrometry. Buprofezin is composed of a benzene ring and a heterocyclic ring. The degradation is initiated by the dihydroxylation of the benzene ring and continues via dehydrogenation, aromatic ring cleavage, breaking of an amide bond and the release of the heterocyclic ring 2- tert -butylimino-3-isopropyl-1,3,5-thiadiazinan-4-one (2-BI). A buprofezin degradation-deficient mutant strain YL-0 was isolated. Comparative genomic analysis combined with gene deletion and complementation experiments revealed that the gene cluster bfzBA3A4A1A2C is responsible for the upstream catabolic pathway of buprofezin. bfzA3A4A1A2 encodes a novel Rieske non-heme iron oxygenase (RHO) system that is responsible for the dihydroxylation of buprofezin at the benzene ring; bfzB is involved in dehydrogenation, and bfzC is in charge of benzene ring cleavage. Furthermore, the products of bfzBA3A4A1A2C can also catalyze dihydroxylation, dehydrogenation and aromatic ring cleavage of biphenyl, flavanone, flavone and bifenthrin. In addition, a transcriptional study revealed that bfzBA3A4A1A2C is organized in one transcriptional unit that is constitutively expressed in strain YL-1. Importance There is an increasing concern about the residue and environmental fate of buprofezin. Microbial metabolism is an important mechanism responsible for the buprofezin degradation in natural environment

  3. Mechanism of the Glycosidic Bond Cleavage of Mismatched Thymine in Human Thymine DNA Glycosylase Revealed by Classical Molecular Dynamics and Quantum Mechanical/Molecular Mechanical Calculations.

    Science.gov (United States)

    Kanaan, Natalia; Crehuet, Ramon; Imhof, Petra

    2015-09-24

    Base excision of mismatched or damaged nucleotides catalyzed by glycosylase enzymes is the first step of the base excision repair system, a machinery preserving the integrity of DNA. Thymine DNA glycosylase recognizes and removes mismatched thymine by cleaving the C1'-N1 bond between the base and the sugar ring. Our quantum mechanical/molecular mechanical calculations of this reaction in human thymine DNA glycosylase reveal a requirement for a positive charge in the active site to facilitate C1'-N1 bond scission: protonation of His151 significantly lowers the free energy barrier for C1'-N1 bond dissociation compared to the situation with neutral His151. Shuttling a proton from His151 to the thymine base further reduces the activation free energy for glycosidic bond cleavage. Classical molecular dynamics simulations of the H151A mutant suggest that the mutation to the smaller, neutral, residue increases the water accessibility of the thymine base, rendering direct proton transfer from the bulk feasible. Quantum mechanical/molecular mechanical calculations of the glycosidic bond cleavage reaction in the H151A mutant show that the activation free energy is slightly lower than in the wild-type enzyme, explaining the experimentally observed higher reaction rates in this mutant.

  4. Solving the cardiac hypertrophy riddle: The angiotensin II-mechanical stress connection.

    Science.gov (United States)

    Zablocki, Daniela; Sadoshima, Junichi

    2013-11-08

    A series of studies conducted 20 years ago, documenting the cardiac hypertrophy phenotype and its underlying signaling mechanism induced by angiotensin II (Ang II) and mechanical stress, showed a remarkable similarity between the effect of the Gαq agonist and that of mechanical forces on cardiac hypertrophy. Subsequent studies confirmed the involvement of autocrine/paracrine mechanisms, including stretch-induced release of Ang II in load-induced cardiac hypertrophy. Recent studies showed that the Ang II type 1 (AT1) receptor is also directly activated by mechanical forces, suggesting that AT1 receptors play an important role in mediating load-induced cardiac hypertrophy through both ligand- and mechanical stress-dependent mechanisms.

  5. Molecular Mechanisms of Particle Ration Induced Apoptosis in Lymphocyte

    Science.gov (United States)

    Shi, Yufang

    Space radiation, composed of high-energy charged nuclei (HZE particles) and protons, has been previously shown to severely impact immune homeostasis in mice. To determine the molecular mechanisms that mediate acute lymphocyte depletion following exposure to HZE particle radiation mice were exposed to particle radiation beams at Brookhaven National Laboratory. We found that mice given whole body 5 6Fe particle irradiation (1GeV /n) had dose-dependent losses in total lymphocyte numbers in the spleen and thymus (using 200, 100 and 50 cGy), with thymocytes being more sensitive than splenocytes. All phenotypic subsets were reduced in number. In general, T cells and B cells were equally sensitive, while CD8+ T cells were more senstive than CD4+ T cells. In the thymus, immature CD4+CD8+ double-positive thymocytes were exquisitely sensitive to radiation-induced losses, single-positive CD4 or CD8 cells were less sensitive, and the least mature double negative cells were resistant. Irradiation of mice deficient in genes encoding essential apoptosis-inducing proteins revealed that the mechanism of lymphocyte depletion is independent of Fas ligand and TRAIL (TNF-ralated apoptosis-inducing ligand), in contrast to γ-radiation-induced lymphocyte losses which require the Fas-FasL pathway. Using inhibitors in vitro, lymphocyte apoptosis induced by HZE particle radiation was found to be caspase dependent, and not involve nitric oxide or oxygen free radicals.

  6. Molecular Mechanisms of Liver Fibrosis in HIV/HCV Coinfection

    Directory of Open Access Journals (Sweden)

    Claudio M. Mastroianni

    2014-05-01

    Full Text Available Chronic hepatitis C virus (HCV infection is an important cause of morbidity and mortality in people coinfected with human immunodeficiency virus (HIV. Several studies have shown that HIV infection promotes accelerated HCV hepatic fibrosis progression, even with HIV replication under full antiretroviral control. The pathogenesis of accelerated hepatic fibrosis among HIV/HCV coinfected individuals is complex and multifactorial. The most relevant mechanisms involved include direct viral effects, immune/cytokine dysregulation, altered levels of matrix metalloproteinases and fibrosis biomarkers, increased oxidative stress and hepatocyte apoptosis, HIV-associated gut depletion of CD4 cells, and microbial translocation. In addition, metabolic alterations, heavy alcohol use, as well drug use, may have a potential role in liver disease progression. Understanding the pathophysiology and regulation of liver fibrosis in HIV/HCV co-infection may lead to the development of therapeutic strategies for the management of all patients with ongoing liver disease. In this review, we therefore discuss the evidence and potential molecular mechanisms involved in the accelerated liver fibrosis seen in patients coinfected with HIV and HCV.

  7. Cellular and molecular mechanisms of metformin: an overview

    Science.gov (United States)

    Viollet, Benoit; Guigas, Bruno; Sanz Garcia, Nieves; Leclerc, Jocelyne; Foretz, Marc; Andreelli, Fabrizio

    2012-01-01

    Considerable efforts have been made since the 1950s to better understand the cellular and molecular mechanisms of action of metformin, a potent antihyperglycemic agent now recommended as the first line oral therapy for type 2 diabetes (T2D). The main effect of this drug from the biguanide family is to acutely decrease hepatic glucose production, mostly through a mild and transient inhibition of the mitochondrial respiratory-chain complex 1. In addition, the resulting decrease in hepatic energy status activates the AMP-activated protein kinase (AMPK), a cellular metabolic sensor, providing a generally accepted mechanism for metformin action on hepatic gluconeogenic program. The demonstration that the respiratory-chain complex 1, but not AMPK, is the primary target of metformin was recently strengthened by showing that the metabolic effect of the drug is preserved in liver-specific AMPK-deficient mice. Beyond its effect on glucose metabolism, metformin was reported to restore ovarian function in polycystic ovary syndrome, reduce fatty liver and to lower microvascular and macrovascular complications associated with T2D. Its use was also recently suggested as an adjuvant treatment for cancer or gestational diabetes, and for the prevention in pre-diabetic populations. These emerging new therapeutic areas for metformin will be reviewed together with recent data from pharmacogenetic studies linking genetic variations to drug response, a promising new step towards personalized medicine in the treatment of T2D. PMID:22117616

  8. Multiresolution molecular mechanics: Surface effects in nanoscale materials

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Qingcheng, E-mail: qiy9@pitt.edu; To, Albert C., E-mail: albertto@pitt.edu

    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), ) is applied to capture surface effect for nanosized structures by designing a surface summation rule SR{sup S} within the framework of MMM. Combined with previously proposed bulk summation rule SR{sup B}, the MMM summation rule SR{sup MMM} is completed. SR{sup S} and SR{sup B} are consistently formed within SR{sup MMM} for general finite element shape functions. Analogous to quadrature rules in finite element method (FEM), the key idea to the good performance of SR{sup MMM} 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, SR{sup S} and SR{sup B} 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 SR{sup MMM} 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 SR{sup MMM} 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 SR{sup MMM} that is analogous to numerical integration error with quadrature rule in FEM is very small. - Highlights:

  9. Solving nucleic acid structures by molecular replacement: examples from group II intron studies

    International Nuclear Information System (INIS)

    Marcia, Marco; Humphris-Narayanan, Elisabeth; Keating, Kevin S.; Somarowthu, Srinivas; Rajashankar, Kanagalaghatta; Pyle, Anna Marie

    2013-01-01

    Strategies for phasing nucleic acid structures by molecular replacement, using both experimental and de novo designed models, are discussed. Structured RNA molecules are key players in ensuring cellular viability. It is now emerging that, like proteins, the functions of many nucleic acids are dictated by their tertiary folds. At the same time, the number of known crystal structures of nucleic acids is also increasing rapidly. In this context, molecular replacement will become an increasingly useful technique for phasing nucleic acid crystallographic data in the near future. Here, strategies to select, create and refine molecular-replacement search models for nucleic acids are discussed. Using examples taken primarily from research on group II introns, it is shown that nucleic acids are amenable to different and potentially more flexible and sophisticated molecular-replacement searches than proteins. These observations specifically aim to encourage future crystallographic studies on the newly discovered repertoire of noncoding transcripts

  10. Molecular mechanisms controlling proton pumping by bacteriorhodopsin. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Crouch, Rosalie K.; Ebrey, Thomas G.

    2000-02-10

    Bacteriorhodopsin (bR) is the simplest biological system for the transduction of light energy. Light energy is directly converted to transmembrane proton gradient by a single, small membrane protein. The extraordinary stability of bR makes it an outstanding subject for bioenergetic studies. This project has focused on the role of interactions between key residues of the pigment involved in light-induced proton transfer. Methods to estimate the strength of these interactions and their correlation with the rate and efficiency of proton transfer have been developed. The concept of the coupling of the protonation states of key groups has been applied to individual steps of the proton transfer with the ultimate goal of understanding on the molecular level the driving forces for proton transport and the pathway of the transported proton in bT. The mechanism of light-induced proton release, uptake and the mechanism of recovery of initial state of bT has been examined. The experiments were performed with genetically engineered, site-specific mutants of bR. This has enabled us to characterize the role of individual amino acid residues in bR. Time resolved and low temperature absorption spectroscopy and light-induced photocurrent measurements were used in order to study the photochemical cycle and proton transfer in mutant pigments. Chemical modification and crosslinking of both the specific amino acids to the chromophore or to other amino acids were used to elucidate the role of light-induced conformational changes in the photocycle and the structure of the protein in the ground state. The results of this project provided new knowledge on the architecture of the proton transfer pathways inside the protein, on the mechanism of proton release in bR, and on the role of specific amino acid residues in the structure and function of bR.

  11. Molecular and cellular mechanisms of aldosterone producing adenoma development

    Directory of Open Access Journals (Sweden)

    Sheerazed eBoulkroun

    2015-06-01

    Full Text Available Primary aldosteronism (PA is the most common form of secondary hypertension with an estimated prevalence of ~10% in referred patients. PA occurs as a result of a dysregulation of the normal mechanisms controlling adrenal aldosterone production. It is characterized by hypertension with low plasma renin and elevated aldosterone and often associated with hypokalemia. The two major causes of PA are unilateral aldosterone producing adenoma (APA and bilateral adrenal hyperplasia, accounting together for ~95% of cases. In addition to the well-characterized effect of excess mineralocorticoids on blood pressure, high levels of aldosterone also have cardiovascular, renal and metabolic consequences. Hence, long-term consequences of PA include increased risk of coronary artery disease, myocardial infarction, heart failure and atrial fibrillation. Despite recent progress in the management of patients with PA, critical issues related to diagnosis, subtype differentiation and treatment of non-surgically correctable forms still persist. A better understanding of the pathogenic mechanisms of the disease should lead to the identification of more reliable diagnostic and prognostic biomarkers for a more sensitive and specific screening and new therapeutic options. In this review we will summarize our current knowledge on the molecular and cellular mechanisms of APA development. On one hand, we will discuss how various animal models have improved our understanding of the pathophysiology of excess aldosterone production. On the other hand, we will summarize the major advances made during the last few years in the genetics of APA due to transcriptomic studies and whole exome sequencing. The identification of recurrent and somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D and ATPases (ATP1A1 and ATP2B3 allowed highlighting the central role of calcium signaling in autonomous aldosterone production by the adrenal.

  12. Insulin-like growth factor-II (IGF II) receptor from rat brain is of lower apparent molecular weight than the IGF II receptor from rat liver

    International Nuclear Information System (INIS)

    McElduff, A.; Poronnik, P.; Baxter, R.C.

    1987-01-01

    The binding subunits of the insulin and insulin-like growth factor-I (IGF I) receptors from rat brain are of lower molecular weight than the corresponding receptor in rat liver, possibly due to variations in sialic acid content. We have compared the IGF II receptor from rat brain and rat liver. The brain receptor is of smaller apparent mol wt (about 10 K) on sodium dodecyl sulfate polyacrylamide gel electrophoresis. This size difference is independent of ligand binding as it persists in iodinated and specifically immunoprecipitated receptors. From studies of wheat germ agglutinin binding and the effect of neuraminidase on receptor mobility, we conclude that this difference is not simply due to variations in sialic acid content. Treatment with endoglycosidase F results in reduction in the molecular size of both liver and brain receptors and after this treatment the aglycoreceptors are of similar size. We conclude that in rat brain tissue the IGF II receptor like the binding subunits of the insulin and IGF I receptors is of lower molecular size than the corresponding receptors in rat liver. This difference is due to differences in N-linked glycosylation

  13. Survivin-T34A: molecular mechanism and therapeutic potential

    Directory of Open Access Journals (Sweden)

    Jonathan R Aspe

    2010-12-01

    Full Text Available Jonathan R Aspe, Nathan R WallCenter for Health Disparities Research and Molecular Medicine, Division of Biochemistry and Microbiology, Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USAAbstract: The inhibitor of apoptosis protein survivin's threonine 34 to alanine (T34A mutation abolishes a phosphorylation site for p34(cdc2–cyclin B1, resulting in initiation of the mitochondrial apoptotic pathway in cancer cells; however, it has little known direct effects on normal cells. The possibility that targeting survivin in this way may provide a novel approach for selective cancer gene therapy has yet to be fully evaluated. Although a flurry of work was undertaken in the late 1990s and early 2000s, only minor advances on this mutant have recently taken place. We recently described that cells generated to express a stable form of the mutant protein released this survivin-T34A to the conditioned medium. When this conditioned medium was collected and deposited on naive tumor cells, conditioned medium T34A was as effective as some chemotherapeutics in the induction of tumor cell apoptosis, and when combined with other forms of genotoxic stressors potentiated their killing effects. We hope with this review to revitalize the T34A field, as there is still much that needs to be investigated. In addition to determining the therapeutic dose and the duration of drug therapy required at the disease site, a better understanding of other key factors is also important. These include knowledge of target cell populations, cell-surface receptors, changes that occur in the target tissue at the molecular and cellular level with progression of the disease, and the mechanism and site of therapeutic action.Keywords: survivin, T34A, apoptosis, proliferation, therapy

  14. Molecular mechanisms for sweet-suppressing effect of gymnemic acids.

    Science.gov (United States)

    Sanematsu, Keisuke; Kusakabe, Yuko; Shigemura, Noriatsu; Hirokawa, Takatsugu; Nakamura, Seiji; Imoto, Toshiaki; Ninomiya, Yuzo

    2014-09-12

    Gymnemic acids are triterpene glycosides that selectively suppress taste responses to various sweet substances in humans but not in mice. This sweet-suppressing effect of gymnemic acids is diminished by rinsing the tongue with γ-cyclodextrin (γ-CD). However, little is known about the molecular mechanisms underlying the sweet-suppressing effect of gymnemic acids and the interaction between gymnemic acids versus sweet taste receptor and/or γ-CD. To investigate whether gymnemic acids directly interact with human (h) sweet receptor hT1R2 + hT1R3, we used the sweet receptor T1R2 + T1R3 assay in transiently transfected HEK293 cells. Similar to previous studies in humans and mice, gymnemic acids (100 μg/ml) inhibited the [Ca(2+)]i responses to sweet compounds in HEK293 cells heterologously expressing hT1R2 + hT1R3 but not in those expressing the mouse (m) sweet receptor mT1R2 + mT1R3. The effect of gymnemic acids rapidly disappeared after rinsing the HEK293 cells with γ-CD. Using mixed species pairings of human and mouse sweet receptor subunits and chimeras, we determined that the transmembrane domain of hT1R3 was mainly required for the sweet-suppressing effect of gymnemic acids. Directed mutagenesis in the transmembrane domain of hT1R3 revealed that the interaction site for gymnemic acids shared the amino acid residues that determined the sensitivity to another sweet antagonist, lactisole. Glucuronic acid, which is the common structure of gymnemic acids, also reduced sensitivity to sweet compounds. In our models, gymnemic acids were predicted to dock to a binding pocket within the transmembrane domain of hT1R3. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. Phosphorus physiological ecology and molecular mechanisms in marine phytoplankton.

    Science.gov (United States)

    Lin, Senjie; Litaker, Richard Wayne; Sunda, William G

    2016-02-01

    Phosphorus (P) is an essential nutrient for marine phytoplankton and indeed all life forms. Current data show that P availability is growth-limiting in certain marine systems and can impact algal species composition. Available P occurs in marine waters as dissolved inorganic phosphate (primarily orthophosphate [Pi]) or as a myriad of dissolved organic phosphorus (DOP) compounds. Despite numerous studies on P physiology and ecology and increasing research on genomics in marine phytoplankton, there have been few attempts to synthesize information from these different disciplines. This paper is aimed to integrate the physiological and molecular information on the acquisition, utilization, and storage of P in marine phytoplankton and the strategies used by these organisms to acclimate and adapt to variations in P availability. Where applicable, we attempt to identify gaps in our current knowledge that warrant further research and examine possible metabolic pathways that might occur in phytoplankton from well-studied bacterial models. Physical and chemical limitations governing cellular P uptake are explored along with physiological and molecular mechanisms to adapt and acclimate to temporally and spatially varying P nutrient regimes. Topics covered include cellular Pi uptake and feedback regulation of uptake systems, enzymatic utilization of DOP, P acquisition by phagotrophy, P-limitation of phytoplankton growth in oceanic and coastal waters, and the role of P-limitation in regulating cell size and toxin levels in phytoplankton. Finally, we examine the role of P and other nutrients in the transition of phytoplankton communities from early succession species (diatoms) to late succession ones (e.g., dinoflagellates and haptophytes). © 2015 Phycological Society of America.

  16. Molecular nucleation mechanisms and control strategies for crystal polymorph selection

    Science.gov (United States)

    van Driessche, Alexander E. S.; van Gerven, Nani; Bomans, Paul H. H.; Joosten, Rick R. M.; Friedrich, Heiner; Gil-Carton, David; Sommerdijk, Nico A. J. M.; Sleutel, Mike

    2018-04-01

    The formation of condensed (compacted) protein phases is associated with a wide range of human disorders, such as eye cataracts, amyotrophic lateral sclerosis, sickle cell anaemia and Alzheimer’s disease. However, condensed protein phases have their uses: as crystals, they are harnessed by structural biologists to elucidate protein structures, or are used as delivery vehicles for pharmaceutical applications. The physiochemical properties of crystals can vary substantially between different forms or structures (‘polymorphs’) of the same macromolecule, and dictate their usability in a scientific or industrial context. To gain control over an emerging polymorph, one needs a molecular-level understanding of the pathways that lead to the various macroscopic states and of the mechanisms that govern pathway selection. However, it is still not clear how the embryonic seeds of a macromolecular phase are formed, or how these nuclei affect polymorph selection. Here we use time-resolved cryo-transmission electron microscopy to image the nucleation of crystals of the protein glucose isomerase, and to uncover at molecular resolution the nucleation pathways that lead to two crystalline states and one gelled state. We show that polymorph selection takes place at the earliest stages of structure formation and is based on specific building blocks for each space group. Moreover, we demonstrate control over the system by selectively forming desired polymorphs through site-directed mutagenesis, specifically tuning intermolecular bonding or gel seeding. Our results differ from the present picture of protein nucleation, in that we do not identify a metastable dense liquid as the precursor to the crystalline state. Rather, we observe nucleation events that are driven by oriented attachments between subcritical clusters that already exhibit a degree of crystallinity. These insights suggest ways of controlling macromolecular phase transitions, aiding the development of protein

  17. Functioning and nonfunctioning thyroid adenomas involve different molecular pathogenetic mechanisms.

    Science.gov (United States)

    Tonacchera, M; Vitti, P; Agretti, P; Ceccarini, G; Perri, A; Cavaliere, R; Mazzi, B; Naccarato, A G; Viacava, P; Miccoli, P; Pinchera, A; Chiovato, L

    1999-11-01

    The molecular biology of follicular cell growth in thyroid nodules is still poorly understood. Because gain-of-function (activating) mutations of the thyroid-stimulating hormone receptor (TShR) and/or Gs alpha genes may confer TSh-independent growth advantage to neoplastic thyroid cells, we searched for somatic mutations of these genes in a series of hyperfunctioning and nonfunctioning follicular thyroid adenomas specifically selected for their homogeneous gross anatomy (single nodule in an otherwise normal thyroid gland). TShR gene mutations were identified by direct sequencing of exons 9 and 10 of the TShR gene in genomic DNA obtained from surgical specimens. Codons 201 and 227 of the Gs alpha gene were also analyzed. At histology, all hyperfunctioning nodules and 13 of 15 nonfunctioning nodules were diagnosed as follicular adenomas. Two nonfunctioning thyroid nodules, although showing a prevalent microfollicular pattern of growth, had histological features indicating malignant transformation (a minimally invasive follicular carcinoma and a focal papillary carcinoma). Activating mutations of the TShR gene were found in 12 of 15 hyperfunctioning follicular thyroid adenomas. In one hyperfunctioning adenoma, which was negative for TShR mutations, a mutation in codon 227 of the Gs alpha gene was identified. At variance with hyperfunctioning thyroid adenomas, no mutation of the TShR or Gs alpha genes was detected in nonfunctioning thyroid nodules. In conclusion, our findings clearly define a different molecular pathogenetic mechanism in hyperfunctioning and nonfunctioning follicular thyroid adenomas. Activation of the cAMP cascade, which leads to proliferation but maintains differentiation of follicular thyroid cells, typically occurs in hyperfunctioning thyroid adenomas. Oncogenes other than the TShR and Gs alpha genes are probably involved in nonfunctioning follicular adenomas.

  18. Molecular biology - Part II: Beneficial liaisons: Radiobiology meets cellular and molecular biology

    International Nuclear Information System (INIS)

    Stevenson, Mary Ann; Coleman, C. Norman

    1997-01-01

    Purpose: The purpose of this course is to familiarize radiation oncologists with the concepts and terminology of molecular and cellular biology that are especially relevant to radiation oncology. The ability of radiation oncologists to remain current with the new discoveries of modern biology is essential to the development of improved therapeutic strategies and, importantly, to the proper balance between investment in technology and biology. Objective: This year, this Refresher Course is part of a three-part ''series'' including Drs. McKenna and Dritschilo. The objective is to provide continuing education for the academic and practicing radiation oncologist, physicist and biologist in the modern biologic concepts of cancer and its treatment. An effort will be made to relate these general concepts to the clinic by providing a broad view as to potential new biological treatments which might enhance the efficacy of radiation therapy. The specific focus of this Course will vary from year to year. Some of the classic radiation biology models which form the basis of clinical practice and laboratory research will be examined and 'newer' models will be presented which take into account the emerging knowledge of cellular and molecular biology. A few techniques in molecular and cellular biology will be described to the extent necessary to understand their basic concepts and their applicability. Aspects of radiation biology which will be covered include cell cycle, radiation-induced changes in the cellular phenotype, and considerations of the effect of the tumor microenvironment. It is not the expectation that the attendees will become experts in the particular subjects presented. Rather, it is the intent to increase their curiosity as to the new knowledge that is emerging and to demonstrate that these seemingly complicated areas can be understood and appreciated with a modicum of the effort

  19. Molecular biology - Part II: Beneficial liaisons: Radiobiology meets cellular and molecular biology

    International Nuclear Information System (INIS)

    Stevenson, Mary Ann; Coleman, C. Norman

    1996-01-01

    Purpose: The purpose of this course is to familiarize radiation oncologists with the concepts and terminology of molecular and cellular biology that are especially relevant to radiation oncology. The ability of radiation oncologists to remain current with the new discoveries of modern biology is essential to the development of improved therapeutic strategies and, importantly, to the proper balance between investment in technology and biology. Objective: This year, this Refresher Course is part of a three-part 'series' including Drs. Martin Brown and Amato Giaccia. The objective is to provide continuing education for the academic and practicing radiation oncologist, physicist and biologist in the modern biologic concepts of cancer and its treatment. An effort will be made to relate these general concepts to the clinic by providing a broad view as to potential new biological treatments which might enhance the efficacy of radiation therapy. The specific focus of this Course will vary from year to year. Some of the classic radiation biology models which form the basis of clinical practice and laboratory research will be examined and 'newer' models will be presented which take into account the emerging knowledge of cellular and molecular biology. A few techniques in molecular and cellular biology will be described to the extent necessary to understand their basic concepts and their applicability. Aspects of radiation biology which will be covered include cell cycle, radiation-induced changes in the cellular phenotype, and considerations of the effect of the tumor microenvironment. It is not the expectation that the attendees will become experts in the particular subjects presented. Rather, it is the intent to increase their curiosity as to the new knowledge that is emerging and to demonstrate that these seemingly complicated areas can be understood and appreciated with a modicum of the effort

  20. Macroscopic and molecular approaches of enrofloxacin retention in soils in presence of Cu(II).

    Science.gov (United States)

    Graouer-Bacart, Mareen; Sayen, Stéphanie; Guillon, Emmanuel

    2013-10-15

    The co-adsorption of copper and the fluoroquinolone antibiotic enrofloxacin (ENR) at the water-soil interface was studied by means of batch adsorption experiments, and extended X-ray absorption fine structure (EXAFS) spectroscopy. The system was investigated over a pH range between 6 and 10, at different contact times, ionic strengths, and ENR concentrations. Adsorption coefficient - Kd - was determined at relevant environmental concentrations and the value obtained in water at a ionic strength imposed by the soil and at soil natural pH was equal to 0.66Lg(-1). ENR adsorption onto the soil showed strong pH dependence illustrating the influence of the electrostatic interactions in the sorption processes. The simultaneous co-adsorption of ENR and Cu(II) on the soil was also investigated. The presence of Cu(II) strongly influenced the retention of the antibiotic, leading to an increase up to 35% of adsorbed ENR amount. The combined quantitative and spectroscopic results showed that Cu(II) and ENR directly interacted at the water-soil interface to form ternary surface complexes. Cu K-edge EXAFS data indicated a molecular structure where the carboxylate and carbonyl groups of ENR coordinate to Cu(II) to form a 6-membered chelate ring and where Cu(II) bridges between ENR and the soil surface sites. Cu(II) bonds bidentately to the surface in an inner-sphere mode. Thus, the spectroscopic data allowed us to propose the formation of ternary surface complexes with the molecular architecture soil-Cu(II)-ENR. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Purification, molecular cloning, and enzymatic properties of a family 12 endoglucanase (EG-II) from fomitopsis palustris: role of EG-II in larch holocellulose hydrolysis.

    Science.gov (United States)

    Shimokawa, Tomoko; Shibuya, Hajime; Nojiri, Masanobu; Yoshida, Shigeki; Ishihara, Mitsuro

    2008-09-01

    A family 12 endoglucanase with a molecular mass of 23,926 Da (EG-II) from the brown-rot basidiomycete Fomitopsis palustris was purified and characterized. One of the roles of EG-II in wood degradation is thought to be to loosen the polysaccharide network in cell walls by disentangling hemicelluloses that are associated with cellulose.

  2. Toward a microrealistic version of quantum mechanics. II

    International Nuclear Information System (INIS)

    Maxwell, N.

    1976-01-01

    Possible objections to the propensity microrealistic version of quantum mechanics proposed previously are answered. This version of quantum mechanics is compared with the statistical, particle, microrealistic viewpoint, and a crucial experiment is proposed designed to distinguish between these two microrealistic versions of quantum mechanics

  3. Molecular mechanism of APC/C activation by mitotic phosphorylation.

    Science.gov (United States)

    Zhang, Suyang; Chang, Leifu; Alfieri, Claudio; Zhang, Ziguo; Yang, Jing; Maslen, Sarah; Skehel, Mark; Barford, David

    2016-05-12

    In eukaryotes, the anaphase-promoting complex (APC/C, also known as the cyclosome) regulates the ubiquitin-dependent proteolysis of specific cell-cycle proteins to coordinate chromosome segregation in mitosis and entry into the G1 phase. The catalytic activity of the APC/C and its ability to specify the destruction of particular proteins at different phases of the cell cycle are controlled by its interaction with two structurally related coactivator subunits, Cdc20 and Cdh1. Coactivators recognize substrate degrons, and enhance the affinity of the APC/C for its cognate E2 (refs 4-6). During mitosis, cyclin-dependent kinase (Cdk) and polo-like kinase (Plk) control Cdc20- and Cdh1-mediated activation of the APC/C. Hyperphosphorylation of APC/C subunits, notably Apc1 and Apc3, is required for Cdc20 to activate the APC/C, whereas phosphorylation of Cdh1 prevents its association with the APC/C. Since both coactivators associate with the APC/C through their common C-box and Ile-Arg tail motifs, the mechanism underlying this differential regulation is unclear, as is the role of specific APC/C phosphorylation sites. Here, using cryo-electron microscopy and biochemical analysis, we define the molecular basis of how phosphorylation of human APC/C allows for its control by Cdc20. An auto-inhibitory segment of Apc1 acts as a molecular switch that in apo unphosphorylated APC/C interacts with the C-box binding site and obstructs engagement of Cdc20. Phosphorylation of the auto-inhibitory segment displaces it from the C-box-binding site. Efficient phosphorylation of the auto-inhibitory segment, and thus relief of auto-inhibition, requires the recruitment of Cdk-cyclin in complex with a Cdk regulatory subunit (Cks) to a hyperphosphorylated loop of Apc3. We also find that the small-molecule inhibitor, tosyl-l-arginine methyl ester, preferentially suppresses APC/C(Cdc20) rather than APC/C(Cdh1), and interacts with the binding sites of both the C-box and Ile-Arg tail motifs. Our

  4. Protein Machineries Involved in the Attachment of Heme to Cytochrome c: Protein Structures and Molecular Mechanisms

    Directory of Open Access Journals (Sweden)

    Carlo Travaglini-Allocatelli

    2013-01-01

    Full Text Available Cytochromes c (Cyt c are ubiquitous heme-containing proteins, mainly involved in electron transfer processes, whose structure and functions have been and still are intensely studied. Surprisingly, our understanding of the molecular mechanism whereby the heme group is covalently attached to the apoprotein (apoCyt in the cell is still largely unknown. This posttranslational process, known as Cyt c biogenesis or Cyt c maturation, ensures the stereospecific formation of the thioether bonds between the heme vinyl groups and the cysteine thiols of the apoCyt heme binding motif. To accomplish this task, prokaryotic and eukaryotic cells have evolved distinctive protein machineries composed of different proteins. In this review, the structural and functional properties of the main maturation apparatuses found in gram-negative and gram-positive bacteria and in the mitochondria of eukaryotic cells will be presented, dissecting the Cyt c maturation process into three functional steps: (i heme translocation and delivery, (ii apoCyt thioreductive pathway, and (iii apoCyt chaperoning and heme ligation. Moreover, current hypotheses and open questions about the molecular mechanisms of each of the three steps will be discussed, with special attention to System I, the maturation apparatus found in gram-negative bacteria.

  5. Molecular mechanism in the formation of a human ring chromosome 21

    International Nuclear Information System (INIS)

    Wong, C.; Kazazian, H.H. Jr.; Stetten, G.; Earnshaw, W.C.; Antonarakis, S.E.; Van Keuren, M.L.

    1989-01-01

    The authors have characterized the structural rearrangements of a chromosome 21 that led to the de novo formation of a human ring chromosome 21 [r(21)]. Molecular cloning and chromosomal localization of the DNA regions flanking the ring junction provide evidence for a long arm to long arm fusion in formation of the r(21). In addition, the centromere and proximal long arm region of a maternal chromosome 21 are duplicated in the r(21). Therefore, the mechanism in formation of the r(21) was complex involving two sequential chromosomal rearrangements. (i) Duplication of the centromere and long arm of one maternal chromosome 21 occurred forming a rearranged intermediate. (ii) Chromosomal breaks in both the proximal and telomeric long arm regions on opposite arms of this rearranged chromosome occurred with subsequent reunion producing the r(21)

  6. Instant Update: Considering the Molecular Mechanisms of Mutation & Natural Selection

    Science.gov (United States)

    Hubler, Tina; Adams, Patti; Scammell, Jonathan

    2015-01-01

    The molecular basis of evolution is an important concept to understand but one that students and teachers often find challenging. This article provides training and guidance for teachers on how to present molecular evolution concepts so that students will associate molecular changes with the evolution of form and function in organisms. Included…

  7. Molecular Mechanisms of Insulin Resistance in Chronic Kidney Disease

    Science.gov (United States)

    Thomas, Sandhya S.; Zhang, Liping; Mitch, William E.

    2015-01-01

    Insulin resistance refers to reduced sensitivity of organs to insulin-initiated biologic processes that result in metabolic defects. Insulin resistance is common in patients with end-stage renal disease but also occurs in patients with chronic kidney disease (CKD), even when the serum creatinine is minimally increased. Following insulin binding to its receptor, auto-phosphorylation of the insulin receptor is followed by kinase reactions that phosphorylate insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase (PI3K) and Akt. In fact, low levels of Akt phosphorylation (p-Akt) identifies the presence of the insulin resistance that leads to metabolic defects in insulin-initiated metabolism of glucose, lipids and muscle proteins. Besides CKD, other complex conditions (e.g., inflammation, oxidative stress, metabolic acidosis, aging and excess angiotensin II) reduce p-Akt resulting in insulin resistance. Insulin resistance in each of these conditions is due to activation of different, E3 ubiquitin ligases which specifically conjugate ubiquitin to IRS-1 marking it for degradation in the ubiquitin-proteasome system (UPS). Consequently, IRS-1 degradation suppresses insulin-induced intracellular signaling, causing insulin resistance. Understanding mechanisms of insulin resistance could lead to therapeutic strategies that improve the metabolism of patients with CKD. PMID:26444029

  8. Insulin-like growth factor II (IGF II) in human brain: regional distribution of IGF II and of higher molecular mass forms

    International Nuclear Information System (INIS)

    Haselbacher, G.K.; Schwab, M.E.; Pasi, A.; Humbel, R.E.

    1985-01-01

    Twenty-four distinct areas of human brain were analyzed for the presence of insulin-like growth factor (IGF). As reported for cerebrospinal fluid, only IGF II-like immunoreactivity, but no significant amounts of IGF I-like immunoreactivity, could be found. Upon gel permeation chromatography, two to five distinct size classes were separated on the basis of their immunoreactivity. Radioimmunoassays and a bioassay also gave results indistinguishable from those of serum IGF II. The highest amounts of IGF II-like immunoreactivity occur in the anterior pituitary. This is up to 100 times more than in most other brain regions analyzed. The higher molecular mass immunoreactive species were partially characterized. After immunoaffinity purification, the 38- and 26-kDa species are active in a bioassay. Specific IGF-binding protein activity could be shown after purification of the 38- and 26-kDa species on an IGF-affinity column. The 13-kDa species released significant amounts of 7.5-kDa material. The results are interpreted as evidence for the presence of IGF II synthesized locally in human brain

  9. Molecular Mechanisms of Microcystin Toxicity in Animal Cells

    Directory of Open Access Journals (Sweden)

    Alexandre Campos

    2010-01-01

    Full Text Available Microcystins (MC are potent hepatotoxins produced by the cyanobacteria of the genera Planktothrix, Microcystis, Aphanizomenon, Nostoc and Anabaena. These cyclic heptapeptides have strong affinity to serine/threonine protein phosphatases (PPs thereby acting as an inhibitor of this group of enzymes. Through this interaction a cascade of events responsible for the MC cytotoxic and genotoxic effects in animal cells may take place. Moreover MC induces oxidative stress in animal cells and together with the inhibition of PPs, this pathway is considered to be one of the main mechanisms of MC toxicity. In recent years new insights on the key enzymes involved in the signal-transduction and toxicity have been reported demonstrating the complexity of the interaction of these toxins with animal cells. Key proteins involved in MC up-take, biotransformation and excretion have been identified, demonstrating the ability of aquatic animals to metabolize and excrete the toxin. MC have shown to interact with the mitochondria. The consequences are the dysfunction of the organelle, induction of reactive oxygen species (ROS and cell apoptosis. MC activity leads to the differential expression/activity of transcriptional factors and protein kinases involved in the pathways of cellular differentiation, proliferation and tumor promotion activity. This activity may result from the direct inhibition of the protein phosphatases PP1 and PP2A. This review aims to summarize the increasing data regarding the molecular mechanisms of MC toxicity in animal systems, reporting for direct MC interacting proteins and key enzymes in the process of toxicity biotransformation/excretion of these cyclic peptides.

  10. Molecular Mechanisms of Curcumin Renoprotection in Experimental Acute Renal Injury

    Directory of Open Access Journals (Sweden)

    Youling Fan

    2017-12-01

    Full Text Available As a highly perfused organ, the kidney is especially sensitive to ischemia and reperfusion. Ischemia-reperfusion (IR-induced acute kidney injury (AKI has a high incidence during the perioperative period in the clinic and is an important link in ischemic acute renal failure (IARF. Therefore, IR-induced AKI has important clinical significance and it is necessary to explore to develop drugs to prevent and alleviate IR-induced AKI. Curcumin [diferuloylmethane, 1,7-bis(4-hydroxy-3-methoxiphenyl-1,6-heptadiene-3,5-dione] is a polyphenol compound derived from Curcuma longa (turmeric and was shown to have a renoprotective effect on ischemia-reperfusion injury (IRI in a previous study. However, the specific mechanisms underlying the protective role of curcumin in IR-induced AKI are not completely understood. APPL1 is a protein coding gene that has been shown to be involved in the crosstalk between the adiponectin-signaling and insulin-signaling pathways. In the study, to investigate the molecular mechanisms of curcumin effects in kidney ischemia/reperfusion model, we observed the effect of curcumin in experimental models of IR-induced AKI and we found that curcumin treatment significantly increased the expression of APPL1 and inhibited the activation of Akt after IR treatment in the kidney. Our in vitro results showed that apoptosis of renal tubular epithelial cells was exacerbated with hypoxia-reoxygenation (HR treatment compared to sham control cells. Curcumin significantly decreased the rate of apoptosis in renal tubular epithelial cells with HR treatment. Moreover, knockdown of APPL1 activated Akt and subsequently aggravated apoptosis in HR-treated renal tubular epithelial cells. Conversely, inhibition of Akt directly reversed the effects of APPL1 knockdown. In summary, our study demonstrated that curcumin mediated upregulation of APPL1 protects against ischemia reperfusion induced AKI by inhibiting Akt phosphorylation.

  11. Molecular mechanism of allosteric communication in Hsp70 revealed by molecular dynamics simulations.

    Directory of Open Access Journals (Sweden)

    Federica Chiappori

    Full Text Available Investigating ligand-regulated allosteric coupling between protein domains is fundamental to understand cell-life regulation. The Hsp70 family of chaperones represents an example of proteins in which ATP binding and hydrolysis at the Nucleotide Binding Domain (NBD modulate substrate recognition at the Substrate Binding Domain (SBD. Herein, a comparative analysis of an allosteric (Hsp70-DnaK and a non-allosteric structural homolog (Hsp110-Sse1 of the Hsp70 family is carried out through molecular dynamics simulations, starting from different conformations and ligand-states. Analysis of ligand-dependent modulation of internal fluctuations and local deformation patterns highlights the structural and dynamical changes occurring at residue level upon ATP-ADP exchange, which are connected to the conformational transition between closed and open structures. By identifying the dynamically responsive protein regions and specific cross-domain hydrogen-bonding patterns that differentiate Hsp70 from Hsp110 as a function of the nucleotide, we propose a molecular mechanism for the allosteric signal propagation of the ATP-encoded conformational signal.

  12. Molecular mechanisms of circulatory dysfunction in cirrhotic portal hypertension

    Directory of Open Access Journals (Sweden)

    Hsin-Ling Ho

    2015-04-01

    Full Text Available Acute or chronic insults to the liver are usually followed by a tissue repairing process. Unfortunately, this action, in most cases, is not effective enough to restore the normal hepatic structure and function. Instead, fibrogenesis and regenerative nodules formation ensue, which are relatively nonfunctioning. The common final stage of the process is liver cirrhosis with increased intrahepatic resistance to portal venous blood flow. Throughout the entire course, the extrahepatic circulatory dysfunction, including increased splanchnic blood flow, elevated portal venous blood flow and pressure, decreased splanchnic and peripheral vascular resistance, tachycardia, and increased cardiac output, are noted and denoted as portal hypertension with hyperdynamic circulatory dysfunction. When such a condition is established, patients may suffer from fatal complications such as gastroesophageal variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome. The cause of such a circulatory dysfunction is not fully elucidated. Nevertheless, clarification of the pathophysiology definitely contributes to the control of portal hypertension-related complications. Herein, the molecular mechanism of this intriguing disaster is reviewed and discussed.

  13. Mechanical properties of irradiated nanowires – A molecular dynamics study

    Energy Technology Data Exchange (ETDEWEB)

    Figueroa, Emilio [Grupo de NanoMateriales, Departamento de Física, Facultad de Ciencias, Universidad de Chile, Casilla, 653 Santiago (Chile); Departamento de Física, Facultad de Ciencias Naturales, Matemática y del Medio Ambiente, Universidad Tecnológica Metropolitana, Santiago 7800002 (Chile); Tramontina, Diego [Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Cuyo, 5500 Mendoza (Argentina); Instituto de Bioingeniería, Universidad de Mendoza, 5500 Mendoza (Argentina); Gutiérrez, Gonzalo, E-mail: gonzalo@fisica.ciencias.uchile.cl [Grupo de NanoMateriales, Departamento de Física, Facultad de Ciencias, Universidad de Chile, Casilla, 653 Santiago (Chile); Bringa, Eduardo [Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Cuyo, 5500 Mendoza (Argentina)

    2015-12-15

    In this work we study, by means of molecular dynamics simulation, the change in the mechanical properties of a gold nanowire with pre-existing radiation damage. The gold nanowire is used as a simple model for a nanofoam, made of connected nanowires. Radiation damage by keV ions leads to the formation of a stacking fault tetrahedron (SFT), and this defect leads to a reduced plastic threshold, as expected, when the nanowire is subjected to tension. We quantify dislocation and twin density during the deformation, and find that the early activation of the SFT as a dislocation source leads to reduced dislocation densities compared to the case without radiation damage. In addition, we observed a total destruction of the SFT, as opposed to a recent simulation study where it was postulated that SFTs might act as self-generating dislocation sources. The flow stress at large deformation is also found to be slightly larger for the irradiated case, in agreement with recent experiments. - Highlights: • Stacking Fault Tetrahedra (SFT) formation proceeds by cascades, containing typically a vacancy cluster and interstitials. • Applied tension leads to the destruction of the SFT, in contrast to a recently reported case of a SFT which soften the NW. • After the initial dislocation activity, strength is controlled by a few surviving dislocations.

  14. Molecular Mechanisms in the shock induced decomposition of FOX-7

    Science.gov (United States)

    Mishra, Ankit; Tiwari, Subodh C.; Nakano, Aiichiro; Vashishta, Priya; Kalia, Rajiv; CACS Team

    Experimental and first principle computational studies on FOX 7 have either involved a very small system consisting of a few atoms or they did not take into account the decomposition mechanisms under extreme conditions of temperature and pressure. We have performed a large-scale reactive MD simulation using ReaxFF-lg force field to study the shock decomposition of FOX 7. The chemical composition of the principal decomposition products correlates well with experimental observations. Furthermore, we observed that the production of N2 and H2O was inter molecular in nature and was through different chemical pathways. Moreover, the production of CO and CO2 was delayed due to production of large stable C,O atoms cluster. These critical insights into the initial processes involved in the shock induced decomposition of FOX-7 will greatly help in understanding the factors playing an important role in the insensitiveness of this high energy material. This research is supported by AFOSR Award No. FA9550-16-1-0042.

  15. The Molecular Mechanisms of Offspring Effects from Obese Pregnancy

    Directory of Open Access Journals (Sweden)

    Daniel Dowling

    2013-04-01

    Full Text Available The incidence of obesity, increased weight gain and the popularity of high-fat / high-sugar diets are seriously impacting upon the global population. Billions of individuals are affected, and although diet and lifestyle are of paramount importance to the development of adult obesity, compelling evidence is emerging which suggests that maternal obesity and related disorders may be passed on to the next generation by non-genetic means. The processes acting within the uteri of obese mothers may permanently predispose offspring to a diverse plethora of diseases ranging from obesity and diabetes to psychiatric disorders. This review aims to summarise some of the molecular mechanisms and active processes currently known about maternal obesity and its effect on foetal and neonatal physiology and metabolism. Complex and multifactorial networks of molecules are intertwined and culminate in a pathologically synergistic manner to cause disruption and disorganisation of foetal physiology. This altered phenotype may potentiate the cycle of intergenerational transmission of obesity and related disorders.

  16. Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation.

    Science.gov (United States)

    Sirish, Padmini; Li, Ning; Timofeyev, Valeriy; Zhang, Xiao-Dong; Wang, Lianguo; Yang, Jun; Lee, Kin Sing Stephen; Bettaieb, Ahmed; Ma, Sin Mei; Lee, Jeong Han; Su, Demetria; Lau, Victor C; Myers, Richard E; Lieu, Deborah K; López, Javier E; Young, J Nilas; Yamoah, Ebenezer N; Haj, Fawaz; Ripplinger, Crystal M; Hammock, Bruce D; Chiamvimonvat, Nipavan

    2016-05-01

    Atrial fibrillation represents the most common arrhythmia leading to increased morbidity and mortality, yet, current treatment strategies have proven inadequate. Conventional treatment with antiarrhythmic drugs carries a high risk for proarrhythmias. The soluble epoxide hydrolase enzyme catalyzes the hydrolysis of anti-inflammatory epoxy fatty acids, including epoxyeicosatrienoic acids from arachidonic acid to the corresponding proinflammatory diols. Therefore, the goal of the study is to directly test the hypotheses that inhibition of the soluble epoxide hydrolase enzyme can result in an increase in the levels of epoxyeicosatrienoic acids, leading to the attenuation of atrial structural and electric remodeling and the prevention of atrial fibrillation. For the first time, we report findings that inhibition of soluble epoxide hydrolase reduces inflammation, oxidative stress, atrial structural, and electric remodeling. Treatment with soluble epoxide hydrolase inhibitor significantly reduces the activation of key inflammatory signaling molecules, including the transcription factor nuclear factor κ-light-chain-enhancer, mitogen-activated protein kinase, and transforming growth factor-β. This study provides insights into the underlying molecular mechanisms leading to atrial fibrillation by inflammation and represents a paradigm shift from conventional antiarrhythmic drugs, which block downstream events to a novel upstream therapeutic target by counteracting the inflammatory processes in atrial fibrillation. © 2016 American Heart Association, Inc.

  17. Cellular and molecular mechanisms of alcohol-induced osteopenia.

    Science.gov (United States)

    Luo, Zhenhua; Liu, Yao; Liu, Yitong; Chen, Hui; Shi, Songtao; Liu, Yi

    2017-12-01

    Alcoholic beverages are widely consumed, resulting in a staggering economic cost in different social and cultural settings. Types of alcohol consumption vary from light occasional to heavy, binge drinking, and chronic alcohol abuse at all ages. In general, heavy alcohol consumption is widely recognized as a major epidemiological risk factor for chronic diseases and is detrimental to many organs and tissues, including bones. Indeed, recent findings demonstrate that alcohol has a dose-dependent toxic effect in promoting imbalanced bone remodeling. This imbalance eventually results in osteopenia, an established risk factor for osteoporosis. Decreased bone mass and strength are major hallmarks of osteopenia, which is predominantly attributed not only to inhibition of bone synthesis but also to increased bone resorption through direct and indirect pathways. In this review, we present knowledge to elucidate the epidemiology, potential pathogenesis, and major molecular mechanisms and cellular effects that underlie alcoholism-induced bone loss in osteopenia. Novel therapeutic targets for correcting alcohol-induced osteopenia are also reviewed, such as modulation of proinflammatory cytokines and Wnt and mTOR signaling and the application of new drugs.

  18. Quantum mechanical simulations of polymers for molecular electronics and photonics

    International Nuclear Information System (INIS)

    Dupuis, M.; Villar, H.O.; Clementi, E.

    1987-01-01

    Ab initio quantum mechanical studies can play an important role in obtaining a detailed understanding of the electronic structure of existing materials, and in predicting the properties of new ones. In this article the authors give a general outline of their research activity in two areas dealing with new materials, specifically, conducting polymers and polymers with non-linear optical properties. The authors present the strategy followed for the study of these molecular systems, and an overview of their findings concerning the structure of the prototypical conducting polymer, i.e. pure and doped polyacetylene (PA). They focused attention on vibrational spectra and infrared and Raman intensities. The results of self-consistent-field (SCF) calculations on charged soliton-like molecules are consistent with experimental observation. In particular, they show that the theoretically established accidental mutual exclusion of infrared and Raman bands invalidates the requirement formulated on the basis of the interpretation of experimental data, that defects in PA must have local C/sub 2h/ symmetry. These conclusions are derived from extensive calculations for which supercomputer performance was imperative and carried out on the parallel supercomputer assembled at IBM-Kingston as a loosely coupled array of processors (LCAP). The authors briefly describe this computer system which has proven to be ideally suited to the methods of ab initio quantum chemistry

  19. Molecular mechanisms of Ebola virus pathogenesis: focus on cell death.

    Science.gov (United States)

    Falasca, L; Agrati, C; Petrosillo, N; Di Caro, A; Capobianchi, M R; Ippolito, G; Piacentini, M

    2015-08-01

    Ebola virus (EBOV) belongs to the Filoviridae family and is responsible for a severe disease characterized by the sudden onset of fever and malaise accompanied by other non-specific signs and symptoms; in 30-50% of cases hemorrhagic symptoms are present. Multiorgan dysfunction occurs in severe forms with a mortality up to 90%. The EBOV first attacks macrophages and dendritic immune cells. The innate immune reaction is characterized by a cytokine storm, with secretion of numerous pro-inflammatory cytokines, which induces a huge number of contradictory signals and hurts the immune cells, as well as other tissues. Other highly pathogenic viruses also trigger cytokine storms, but Filoviruses are thought to be particularly lethal because they affect a wide array of tissues. In addition to the immune system, EBOV attacks the spleen and kidneys, where it kills cells that help the body to regulate its fluid and chemical balance and that make proteins that help the blood to clot. In addition, EBOV causes liver, lungs and kidneys to shut down their functions and the blood vessels to leak fluid into surrounding tissues. In this review, we analyze the molecular mechanisms at the basis of Ebola pathogenesis with a particular focus on the cell death pathways induced by the virus. We also discuss how the treatment of the infection can benefit from the recent experience of blocking/modulating cell death in human degenerative diseases.

  20. Molecular Mechanisms of Anticancer Effects of Phytoestrogens in Breast Cancer.

    Science.gov (United States)

    Hsieh, Chia-Jung; Hsu, Ya-Ling; Huang, Ya-Fang; Tsai, Eing-Mei

    2018-01-01

    Phytoestrogens derived from plants exert estrogenic as well as antiestrogenic effects and multiple actions within breast cancer cells. Chemopreventive properties of phytoestrogens have emerged from epidemiological observations. In recent clinical research studies, phytoestrogens are safe and may even protect against breast cancer. In this brief review, the molecular mechanisms of phytoestrogens on regulation of cell cycle, apoptosis, estrogen receptors, cell signaling pathways, and epigenetic modulations in relation to breast cancer are discussed. Phytoestrogens have a preferential affinity for estrogen receptor (ER)-β, which appears to be associated with antiproliferative and anticarcinogenic effects. Moreover, while phytoestrogens not only inhibit ER-positive but also ER-negative breast cancer cells, the possibility of epigenetic modulation playing an important role is also discussed. In conclusion, as there are multiple targets and actions of phytoestrogens, extensive research is still necessary. However, due to low toxicity, low cost, and easy availability, their potent chemoprevention effects deserve further study. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  1. Understanding the mechanisms of amorphous creep through molecular simulation.

    Science.gov (United States)

    Cao, Penghui; Short, Michael P; Yip, Sidney

    2017-12-26

    Molecular processes of creep in metallic glass thin films are simulated at experimental timescales using a metadynamics-based atomistic method. Space-time evolutions of the atomic strains and nonaffine atom displacements are analyzed to reveal details of the atomic-level deformation and flow processes of amorphous creep in response to stress and thermal activations. From the simulation results, resolved spatially on the nanoscale and temporally over time increments of fractions of a second, we derive a mechanistic explanation of the well-known variation of creep rate with stress. We also construct a deformation map delineating the predominant regimes of diffusional creep at low stress and high temperature and deformational creep at high stress. Our findings validate the relevance of two original models of the mechanisms of amorphous plasticity: one focusing on atomic diffusion via free volume and the other focusing on stress-induced shear deformation. These processes are found to be nonlinearly coupled through dynamically heterogeneous fluctuations that characterize the slow dynamics of systems out of equilibrium.

  2. Evaluation of carbohydrate molecular mechanical force fields by quantum mechanical calculations

    DEFF Research Database (Denmark)

    Hemmingsen, Lars Bo Stegeager; Madsen, D.E.; Esbensen, A.L.

    2004-01-01

    of the (gg, gt and tg) rotamers of methyl alpha-D-glucopyranoside and methyl alpha-D-galactopyranoside are (0.13, 0.00, 0.15) and (0.64, 0.00, 0.77) kcal/mol. respectively. The results of the quantum mechanical calculations are compared with the results of calculations using the 20 second...... for monosaccharide carbohydrate benchmark systems. Selected results are: (i) The interaction energy of the alpha-D-alucopyranose-H2O heterodimer is estimated to be 4.9 kcal/mol, using a composite method including terms at highly correlated (CCSD(T)) level. Most molecular mechanics force fields are in error...

  3. Trends in nanoscale mechanics mechanics of carbon nanotubes, graphene, nanocomposites and molecular dynamics

    CERN Document Server

    2014-01-01

    This book contains a collection of the state-of-the-art reviews written by the leading researchers in the areas of nanoscale mechanics, molecular dynamics, nanoscale modeling of nanocomposites and mechanics of carbon nanotubes. No other book has reviews of the recent discoveries such as a nanoscale analog of the Pauli’s principle, i.e., effect of the spatial exclusion of electrons or the SEE effect, a new Registry Matrix Analysis for the nanoscale interfacial sliding and new data on the effective viscosity of interfacial electrons in nanoscale stiction at the interfaces. This volume is also an exceptional resource on the well tested nanoscale modeling of carbon nanotubes and nanocomposites, new nanoscale effects, unique evaluations of the effective thickness of carbon nanotubes under different loads, new data on which size of carbon nanotubes is safer and many other topics. Extensive bibliography concerning all these topics is included along with the lucid short reviews. Numerous illustrations are provided...

  4. [Molecular pathogenesis of Waardenburg syndrome type II resulting from SOX10 gene mutation].

    Science.gov (United States)

    Zhang, Hua; Chen, Hongsheng; Feng, Yong; Qian, Minfei; Li, Jiping; Liu, Jun; Zhang, Chun

    2016-08-01

    To explore the molecular mechanism of Waardenburg syndrome type II (WS2) resulting from SOX10 gene mutation E248fs through in vitro experiment. 293T cells were transiently transfected with wild type (WT) SOX10 and mutant type (MT) E248fs plasmids. The regulatory effect of WT/MT SOX10 on the transcriptional activity of MITF gene and influence of E248fs on WT SOX10 function were determined with a luciferase activity assay. The DNA binding capacity of the WT/MT SOX10 with the promoter of the MITF gene was determined with a biotinylated double-stranded oligonucleotide probe containing the SOX10 binding sequence cattgtc to precipitate MITF and E248fs, respectively. The stability of SOX10 and E248fs were also analyzed. As a loss-of-function mutation, the E248fs mutant failed to transactivate the MITF promoter as compared with the WT SOX10 (P<0.01), which also showed a dominant-negative effect on WT SOX10. The WT SOX10 and E248fs mutant were also able to bind specifically to the cattgtc motif in the MITF promoter, whereas E248fs had degraded faster than WT SOX10. Despite the fact that the E248fs has a dominant-negative effect on SOX10, its reduced stability may down-regulate the transcription of MITF and decrease the synthesis of melanin, which may result in haploinsufficiency of SOX10 protein and cause the milder WS2 phenotype.

  5. SEACAS Theory Manuals: Part II. Nonlinear Continuum Mechanics

    Energy Technology Data Exchange (ETDEWEB)

    Attaway, S.W.; Laursen, T.A.; Zadoks, R.I.

    1998-09-01

    This report summarizes the key continuum mechanics concepts required for the systematic prescription and numerical solution of finite deformation solid mechanics problems. Topics surveyed include measures of deformation appropriate for media undergoing large deformations, stress measures appropriate for such problems, balance laws and their role in nonlinear continuum mechanics, the role of frame indifference in description of large deformation response, and the extension of these theories to encompass two dimensional idealizations, structural idealizations, and rigid body behavior. There are three companion reports that describe the problem formulation, constitutive modeling, and finite element technology for nonlinear continuum mechanics systems.

  6. Characterization of Angiotensin II Molecular Determinants Involved in AT1 Receptor Functional Selectivity.

    Science.gov (United States)

    Domazet, Ivana; Holleran, Brian J; Richard, Alexandra; Vandenberghe, Camille; Lavigne, Pierre; Escher, Emanuel; Leduc, Richard; Guillemette, Gaétan

    2015-06-01

    The octapeptide angiotensin II (AngII) exerts a variety of cardiovascular effects through the activation of the AngII type 1 receptor (AT1), a G protein-coupled receptor. The AT1 receptor engages and activates several signaling pathways, including heterotrimeric G proteins Gq and G12, as well as the extracellular signal-regulated kinases (ERK) 1/2 pathway. Additionally, following stimulation, βarrestin is recruited to the AT1 receptor, leading to receptor desensitization. It is increasingly recognized that specific ligands selectively bind and favor the activation of some signaling pathways over others, a concept termed ligand bias or functional selectivity. A better understanding of the molecular basis of functional selectivity may lead to the development of better therapeutics with fewer adverse effects. In the present study, we developed assays allowing the measurement of six different signaling modalities of the AT1 receptor. Using a series of AngII peptide analogs that were modified in positions 1, 4, and 8, we sought to better characterize the molecular determinants of AngII that underlie functional selectivity of the AT1 receptor in human embryonic kidney 293 cells. The results reveal that position 1 of AngII does not confer functional selectivity, whereas position 4 confers a bias toward ERK signaling over Gq signaling, and position 8 confers a bias toward βarrestin recruitment over ERK activation and Gq signaling. Interestingly, the analogs modified in position 8 were also partial agonists of the protein kinase C (PKC)-dependent ERK pathway via atypical PKC isoforms PKCζ and PKCι. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  7. Distribution and Molecular Characterization of Acinetobacter baumannii International Clone II Lineage in Japan.

    Science.gov (United States)

    Matsui, Mari; Suzuki, Masato; Suzuki, Masahiro; Yatsuyanagi, Jun; Watahiki, Masanori; Hiraki, Yoichi; Kawano, Fumio; Tsutsui, Atsuko; Shibayama, Keigo; Suzuki, Satowa

    2018-02-01

    Multidrug-resistant (MDR) Acinetobacter spp. have been globally disseminated in association with the successful clonal lineage Acinetobacter baumannii international clone II (IC II). Because the prevalence of MDR Acinetobacter spp. in Japan remains very low, we characterized all Acinetobacter spp. ( n = 866) from 76 hospitals between October 2012 and March 2013 to describe the entire molecular epidemiology of Acinetobacter spp. The most prevalent species was A. baumannii ( n = 645; 74.5%), with A. baumannii IC II ( n = 245) accounting for 28.3% of the total. Meropenem-resistant isolates accounted for 2.0% ( n = 17) and carried IS Aba1-bla OXA-23-like ( n = 10), bla IMP ( n = 4), or IS Aba1-bla OXA-51-like ( n = 3). Multilocus sequence typing of 110 representative A. baumannii isolates revealed the considerable prevalence of domestic sequence types (STs). A. baumannii IC II isolates were divided into the domestic sequence type 469 (ST469) ( n = 18) and the globally disseminated STs ST208 ( n = 14) and ST219 ( n = 4). ST469 isolates were susceptible to more antimicrobial agents, while ST208 and ST219 overproduced the intrinsic AmpC β-lactamase. A. baumannii IC II and some A. baumannii non-IC II STs (e.g., ST149 and ST246) were associated with fluoroquinolone resistance. This study revealed that carbapenem-susceptible A. baumannii IC II was moderately disseminated in Japan. The low prevalence of acquired carbapenemase genes and presence of domestic STs could contribute to the low prevalence of MDR A. baumannii A similar epidemiology might have appeared before the global dissemination of MDR epidemic lineages. In addition, fluoroquinolone resistance associated with A. baumannii IC II may provide insight into the significance of A. baumannii epidemic clones. Copyright © 2018 American Society for Microbiology.

  8. Mechanical Engineering and Design of the LHC Phase II Collimators

    CERN Document Server

    Bertarelli, A; Gentini, L; Mariani, N; Perret, R; Timmins, M A

    2010-01-01

    Phase II collimators will complement the existing system to improve the expected high RF impedance and limited efficiency of Phase I jaws. An international collaborative effort has been launched to identify novel advanced materials responding to the very challenging requirements of the new collimators. Complex numerical calculations simulating extreme conditions and experimental tests are in progress. In parallel, an innovative modular design concept of the jaw assembly is being developed to allow fitting in alternative materials, minimizing the thermally induced deformations, withstanding accidents and accepting high radiation doses. Phase II jaw assembly is made up of a molybdenum back-stiffener ensuring high geometrical stability and a modular jaw split in threes sectors. Each sector is equipped with a high-efficiency independent cooling circuit. Beam position monitors (BPM) are embedded in the jaws to fasten setup time and improve beam monitoring. An adjustment system will permit to fine-tune the jaw flat...

  9. The equivalence myth of quantum mechanics-part II

    Science.gov (United States)

    Muller, F. A.

    The author endeavours to show two things: first, that Schrödingers (and Eckarts) demonstration in March (September) 1926 of the equivalence of matrix mechanics, as created by Heisenberg, Born, Jordan and Dirac in 1925, and wave mechanics, as created by Schrödinger in 1926, is not foolproof; and second, that it could not have been foolproof, because at the time matrix mechanics and wave mechanics were neither mathematically nor empirically equivalent. That they were is the Equivalence Myth. In order to make the theories equivalent and to prove this, one has to leave the historical scene of 1926 and wait until 1932, when von Neumann finished his magisterial edifice. During the period 1926-1932 the original families of mathematical structures of matrix mechanics and of wave mechanics were stretched, parts were chopped off and novel structures were added. To Procrustean places we go, where we can demonstrate the mathematical, empirical and ontological equivalence of 'the final versions of' matrix mechanics and wave mechanics. The present paper claims to be a comprehensive analysis of one of the pivotal papers in the history of quantum mechanics: Schrödingers equivalence paper. Since the analysis is performed from the perspective of Suppes structural view ('semantic view') of physical theories, the present paper can be regarded not only as a morsel of the internal history of quantum mechanics, but also as a morsel of applied philosophy of science. The paper is self-contained and presupposes only basic knowledge of quantum mechanics. For reasons of length, the paper is published in two parts; Part I appeared in the previous issue of this journal. Section 1 contains, besides an introduction, also the papers five claims and a preview of the arguments supporting these claims; so Part I, Section 1 may serve as a summary of the paper for those readers who are not interested in the detailed arguments.

  10. Molecular mechanisms of FK506-induced hypertension in solid organ transplantation patients

    Institute of Scientific and Technical Information of China (English)

    Wang Jianglin; Guo Ren; Liu Shikun; Chen Qingjie; Zuo Shanru; Yang Meng; Zuo Xiaocong

    2014-01-01

    Objective Tacrolimus (FK506) is an immunosuppressive drug,which is widely used to prevent rejection of transplanted organs.However,chronic administration of FK506 leads to hypertension in solid organ transplantation patients,and its molecular mechanisms are much more complicated.In this review,we will discuss the above-mentioned molecular mechanisms of FK506-induced hypertension in solid organ transplantation subjects.Data sources The data analyzed in this review were mainly from relevant articles without restriction on the publication date reported in PubMed.The terms "FK506" or "tacrolimus" and "hypertension"were used for the literature search.Study selection Original articles with no limitation of research design and critical reviews containing data relevant to FK506-induced hypertension and its molecular mechanisms were retrieved,reviewed and analyzed.Results There are several molecular mechanisms attributed to FK506-induced hypertension in solid organ transplantation subjects.First,FK506 binds FK506 binding protein 12 and its related isoform 12.6 (FKBP12/12.6) and removes them from intracellular ryanodine receptors that induce a calcium ion leakage from the endoplasmic/sarcoplasmic reticulum.The conventional protein kinase C beta II (cPKCβⅡ)-mediated phosphorylation of endothelial nitric oxide (NO) synthase at Thr495,which reduces the production of NO,was activated by calcium ion leakage.Second,transforming growth factor receptor/SMAD2/3 signaling activation plays an important role in Treg/Th17 cell imbalance in T cells which toget converge to cause inflammation,endothelial dysfunction,and hypertension following tacrolimus treatment.Third,the activation of with-no-K(Lys) kinases/STE20/SPS1-related proline/alanine-rich kinase/thiazide-sensitive sodium chloride co-transporter (WNKs/SPAK/NCC) pathway has a central role in tacrolimus-induced hypertension.Finally,the enhanced activity of renal renin-angiotensin-aldosterone system seems to play a crucial role in

  11. A quantum mechanical/molecular mechanical study of the hydroxylation of phenol and halogeneted derivatives by phenol hydroxylase

    NARCIS (Netherlands)

    Ridder, L.; Mulholland, A.J.; Rietjens, I.M.C.M.; Vervoort, J.

    2000-01-01

    A combined quantum mechanical and molecular mechanical (QM/MM) method (AM1/CHARMM) was used to investigate the mechanism of the aromatic hydroxylation of phenol by a flavin dependent phenol hydroxylase (PH), an essential reaction in the degradation of a wide range of aromatic compounds. The model

  12. The Mechanism of Graviton Exchange between Bodies, Part II

    DEFF Research Database (Denmark)

    Javadi, Hossein; Forouzbakhsh, Farshid

    2016-01-01

    Further to Special Relativity, modern physics includes two great theories which describe universe in a new different way. One of them is Quantum Mechanics which describes elementary particles, atoms and molecules and the other one is General Relativity which has been replaced the Newtonian...... Gravitational Law by space-time curvature. Quantum gravity is a part of quantum mechanics which is expected to combine these two theories, and it describes gravity force according to the principles of quantum mechanics which has not got the desired result, yet. In CPH theory, after reconsidering and analyzing...... the behavior of photon in the gravitational field, a new definition of graviton based on carrying the gravity force is given. By using this definition, graviton exchange mechanism between bodies/objects is described. As the purpose of quantum gravity is describing the force of gravity by using the principles...

  13. Molecular mechanism of reduction in pregnenolone synthesis by cigarette smoke

    International Nuclear Information System (INIS)

    Bose, Mahuya; Whittal, Randy M.; Gairola, C. Gary; Bose, Himangshu S.

    2008-01-01

    Steroidogenic acute regulatory protein (StAR) facilitates the movement of cholesterol from the outer to inner mitochondrial membrane for the synthesis of pregnenolone. Here, we investigated the molecular mechanism of the reduction of pregnenolone synthesis by cigarette smoke condensate (CSC). Pre-exposure or post-exposure of cells with CSC led to reduced pregnenolone synthesis, in a fashion similar to its effect on isolated mitochondria. However, there was no difference in the expression of 30 kDa StAR in cells treated with moderately concentrated CSC by either regimen. The active form of 37 kDa StAR is degraded easily suggesting that the continuous presence of CSC reduces StAR expression. Mitochondrial import of 35 S-methionine-labeled StAR followed by extraction of the StAR-mitochondrial complex with 1% digitonin showed similarly sized complexes in the CSC-treated and untreated mitochondria. Further analysis by sucrose density gradient centrifugation showed a specific complex, 'complex 2', in the untreated mitochondria but absent in the CSC-treated mitochondria. Mass spectrometric analysis revealed that complex 2 is the outer mitochondrial protein, VDAC1. Knockdown of VDAC1 expression by siRNA followed by co-transfection with StAR resulted in a lack of pregnenolone synthesis and 37 kDa StAR expression with reduced expression of the intermediate, 32 kDa StAR. Taken together, these results suggest that in the absence of VDAC1, active StAR expression is reduced indicating that VDAC1 expression is essential for StAR activity. In the absence of VDAC1-StAR interaction, cholesterol cannot be transported into mitochondria; thus the interaction with VDAC1 is a mandatory step for initiating steroidogenesis

  14. Stability mechanisms of a thermophilic laccase probed by molecular dynamics.

    Directory of Open Access Journals (Sweden)

    Niels J Christensen

    Full Text Available 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 T opt (∼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.

  15. On The Molecular Mechanism Of Positive Novolac Resists

    Science.gov (United States)

    Huang, Jian-Ping; Kwei, T. K.; Reiser, Arnost

    1989-08-01

    A molecular mechanism for the dissolution of novolac is proposed, based on the idea of a critical degree of deprotonation as being the condition for the transfer of polymer into solution. The rate at which the critical deprotonation condition is achieved is controlled by the supply of developer into a thin penetration zone, and depends in particular on the rate of diffusion of the base cations which are the developer component with the lowest mobility. The penetration zone contains phenolate ions and ion-bound water, but it retains the structure of a rigid polymer membrane, as evidenced by the diffusion coefficient of cations in the pene;tration zone which is several orders of magnitude slower than in an open gel of the same material. When the critical degree of deprotonation is reached, the membrane structure unravels and all subsequent events, chain rearrangement and transfer into solution, occur rapidly. The supralinear dependence of dissolution rate on base concentration and the effect of the size of the base cation are plausibly interpreted by the model. The diffusion of developer components is assumed to occur preferentially via hydrophilic sites in the polymer matrix. These sites define a diffusion path which acts like a hydrophilic diffusion channel. Suitably designed hydrophobic molecules can block some of the channels and in this way alter the dissolution rate. They reduce in effect the diffusion crossect ion of the material. Hydrophilic additives, on the other hand, introduce additional channels into the system and promote dissolution. The concept of diffusion channels appears to provide a unified interpretation for a number of common observations.

  16. Molecular mechanisms of extensive mitochondrial gene rearrangementin plethodontid salamanders

    Energy Technology Data Exchange (ETDEWEB)

    Mueller, Rachel Lockridge; Boore, Jeffrey L.

    2005-06-01

    Extensive gene rearrangement is reported in the mitochondrial genomes of lungless salamanders (Plethodontidae). In each genome with a novel gene order, there is evidence that the rearrangement was mediated by duplication of part of the mitochondrial genome, including the presence of both pseudogenes and additional, presumably functional, copies of duplicated genes. All rearrangement-mediating duplications include either the origin of light strand replication and the nearby tRNA genes or the regions flanking the origin of heavy strand replication. The latter regions comprise nad6, trnE, cob, trnT, an intergenic spacer between trnT and trnP and, in some genomes, trnP, the control region, trnF, rrnS, trnV, rrnL, trnL1, and nad1. In some cases, two copies of duplicated genes, presumptive regulatory regions, and/or sequences with no assignable function have been retained in the genome following the initial duplication; in other genomes, only one of the duplicated copies has been retained. Both tandem and non-tandem duplications are present in these genomes, suggesting different duplication mechanisms. In some of these mtDNAs, up to 25 percent of the total length is composed of tandem duplications of non-coding sequence that includes putative regulatory regions and/or pseudogenes of tRNAs and protein-coding genes along with otherwise unassignable sequences. These data indicate that imprecise initiation and termination of replication, slipped-strand mispairing, and intra-molecular recombination may all have played a role in generating repeats during the evolutionary history of plethodontid mitochondrial genomes.

  17. Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms.

    Science.gov (United States)

    Stenmark, Kurt R; Fagan, Karen A; Frid, Maria G

    2006-09-29

    Chronic hypoxic exposure induces changes in the structure of pulmonary arteries, as well as in the biochemical and functional phenotypes of each of the vascular cell types, from the hilum of the lung to the most peripheral vessels in the alveolar wall. The magnitude and the specific profile of the changes depend on the species, sex, and the developmental stage at which the exposure to hypoxia occurred. Further, hypoxia-induced changes are site specific, such that the remodeling process in the large vessels differs from that in the smallest vessels. The cellular and molecular mechanisms vary and depend on the cellular composition of vessels at particular sites along the longitudinal axis of the pulmonary vasculature, as well as on local environmental factors. Each of the resident vascular cell types (ie, endothelial, smooth muscle, adventitial fibroblast) undergo site- and time-dependent alterations in proliferation, matrix protein production, expression of growth factors, cytokines, and receptors, and each resident cell type plays a specific role in the overall remodeling response. In addition, hypoxic exposure induces an inflammatory response within the vessel wall, and the recruited circulating progenitor cells contribute significantly to the structural remodeling and persistent vasoconstriction of the pulmonary circulation. The possibility exists that the lung or lung vessels also contain resident progenitor cells that participate in the remodeling process. Thus the hypoxia-induced remodeling of the pulmonary circulation is a highly complex process where numerous interactive events must be taken into account as we search for newer, more effective therapeutic interventions. This review provides perspectives on each of the aforementioned areas.

  18. Preparation and properties of a calcium(II)-based molecular chain decorated with manganese(II) butterfly-like complexes.

    Science.gov (United States)

    Benniston, A C; Melnic, S; Turta, C; Arauzo, A B; Bartolomé, J; Bartolomé, E; Harrington, R W; Probert, M R

    2014-09-21

    The room temperature reaction of [Mn2O2(bipy)4](ClO4)3 (bipy = 2,2'-bipyridine) with Ca(CHCl2COO)2 in methanol produced a yellow crystalline material. The X-ray determined structure comprises of a multiple calcium(II) carboxylate bridged chain-like structure which is decorated with [Mn(bipy)2(OH2)](2+) subunits. The redox behaviour for the complex in H2O and MeCN is reported. In the latter solvent the oxidation of the manganese ions appears to be facilitated by the presence of the calcium ions. Magnetic susceptibility and low temperature magnetization measurements show that the Mn moment is isotropic, with g = 1.99(1) and S = 5/2, confirming it is in the 2+ oxidation state. A very weak antiferromagnetic interaction is also detected. Frequency-dependent ac measurements evidence slow magnetic relaxation of the Mn(bipy)2 units. Two relaxation mechanisms are identified: a very slow direct process and a faster one caused by the Resonant Phonon Trapping mechanism. This is the first example of field-induced single ion magnet (SIM) behavior in a mononuclear Mn(II) complex.

  19. Rapid molecular evolution across amniotes of the IIS/TOR network.

    Science.gov (United States)

    McGaugh, Suzanne E; Bronikowski, Anne M; Kuo, Chih-Horng; Reding, Dawn M; Addis, Elizabeth A; Flagel, Lex E; Janzen, Fredric J; Schwartz, Tonia S

    2015-06-02

    The insulin/insulin-like signaling and target of rapamycin (IIS/TOR) network regulates lifespan and reproduction, as well as metabolic diseases, cancer, and aging. Despite its vital role in health, comparative analyses of IIS/TOR have been limited to invertebrates and mammals. We conducted an extensive evolutionary analysis of the IIS/TOR network across 66 amniotes with 18 newly generated transcriptomes from nonavian reptiles and additional available genomes/transcriptomes. We uncovered rapid and extensive molecular evolution between reptiles (including birds) and mammals: (i) the IIS/TOR network, including the critical nodes insulin receptor substrate (IRS) and phosphatidylinositol 3-kinase (PI3K), exhibit divergent evolutionary rates between reptiles and mammals; (ii) compared with a proxy for the rest of the genome, genes of the IIS/TOR extracellular network exhibit exceptionally fast evolutionary rates; and (iii) signatures of positive selection and coevolution of the extracellular network suggest reptile- and mammal-specific interactions between members of the network. In reptiles, positively selected sites cluster on the binding surfaces of insulin-like growth factor 1 (IGF1), IGF1 receptor (IGF1R), and insulin receptor (INSR); whereas in mammals, positively selected sites clustered on the IGF2 binding surface, suggesting that these hormone-receptor binding affinities are targets of positive selection. Further, contrary to reports that IGF2R binds IGF2 only in marsupial and placental mammals, we found positively selected sites clustered on the hormone binding surface of reptile IGF2R that suggest that IGF2R binds to IGF hormones in diverse taxa and may have evolved in reptiles. These data suggest that key IIS/TOR paralogs have sub- or neofunctionalized between mammals and reptiles and that this network may underlie fundamental life history and physiological differences between these amniote sister clades.

  20. Mechanical feedback in the molecular ISM of luminous IR galaxies

    NARCIS (Netherlands)

    Loenen, A. F.; Spaans, M.; Baan, W. A.; Meijerink, R.

    Aims. Molecular emission lines originating in the nuclei of luminous infra-red galaxies are used to determine the physical properties of the nuclear ISM in these systems. Methods. A large observational database of molecular emission lines is compared with model predictions that include heating by UV

  1. The Belle II silicon vertex detector assembly and mechanics

    Energy Technology Data Exchange (ETDEWEB)

    Adamczyk, K. [H. Niewodniczanski Institute of Nuclear Physics, Krakow 31-342 (Poland); Aihara, H. [Department of Physics, University of Tokyo, Tokyo 113-0033 (Japan); Angelini, C. [Dipartimento di Fisica, Università di Pisa, I-56127 Pisa (Italy); INFN Sezione di Pisa, I-56127 Pisa (Italy); Aziz, T.; Babu, V. [Tata Institute of Fundamental Research, Mumbai 400005 (India); Bacher, S. [H. Niewodniczanski Institute of Nuclear Physics, Krakow 31-342 (Poland); Bahinipati, S. [Indian Institute of Technology Bhubaneswar, Satya Nagar (India); Barberio, E.; Baroncelli, Ti.; Baroncelli, To. [School of Physics, University of Melbourne, Melbourne, Victoria 3010 (Australia); Basith, A.K. [Indian Institute of Technology Madras, Chennai 600036 (India); Batignani, G. [Dipartimento di Fisica, Università di Pisa, I-56127 Pisa (Italy); INFN Sezione di Pisa, I-56127 Pisa (Italy); Bauer, A. [Institute of High Energy Physics, Austrian Academy of Sciences, 1050 Vienna (Austria); Behera, P.K. [Indian Institute of Technology Madras, Chennai 600036 (India); Bergauer, T. [Institute of High Energy Physics, Austrian Academy of Sciences, 1050 Vienna (Austria); Bettarini, S., E-mail: stefano.bettarini@pi.infn.it [Dipartimento di Fisica, Università di Pisa, I-56127 Pisa (Italy); INFN Sezione di Pisa, I-56127 Pisa (Italy); Bhuyan, B. [Indian Institute of Technology Guwahati, Assam 781039 (India); Bilka, T. [Faculty of Mathematics and Physics, Charles University, 121 16 Prague (Czech Republic); Bosi, F. [INFN Sezione di Pisa, I-56127 Pisa (Italy); Bosisio, L. [Dipartimento di Fisica, Università di Trieste, I-34127 Trieste (Italy); INFN Sezione di Trieste, I-34127 Trieste (Italy); and others

    2017-02-11

    The Belle II experiment at the asymmetric SuperKEKB collider in Japan will operate at an instantaneous luminosity approximately 50 times greater than its predecessor (Belle). The central feature of the experiment is a vertex detector comprising two layers of pixelated silicon detectors (PXD) and four layers of double-sided silicon microstrip detectors (SVD). One of the key measurements for Belle II is CP violation asymmetry in the decays of beauty and charm hadrons, which hinges on a precise charged-track vertex determination and low-momentum track measurement. Towards this goal, a proper assembly of the SVD components with precise alignment ought to be performed and the geometrical tolerances should be checked to fall within the design limits. We present an overview of the assembly procedure that is being followed, which includes the precision gluing of the SVD module components, wire-bonding of the various electrical components, and precision 3D coordinate measurements of the final SVD modules. Finally, some results from the latest test-beam are reported.

  2. Molecular Mechanism of AHSP-Mediated Stabilization of Alpha-Hemoglobin

    Energy Technology Data Exchange (ETDEWEB)

    Feng,L.; Gell, D.; Zhou, S.; Gu, L.; Kong, Y.; Li, J.; Hu, M.; Yan, N.; Lee, C.; et al.

    2005-01-01

    Hemoglobin A (HbA), the oxygen delivery system in humans, comprises two alpha and two beta subunits. Free alpha-hemoglobin (alphaHb) is unstable, and its precipitation contributes to the pathophysiology of beta thalassemia. In erythrocytes, the alpha-hemoglobin stabilizing protein (AHSP) binds alphaHb and inhibits its precipitation. The crystal structure of AHSP bound to Fe(II)-alphaHb reveals that AHSP specifically recognizes the G and H helices of alphaHb through a hydrophobic interface that largely recapitulates the alpha1-beta1 interface of hemoglobin. The AHSP-alphaHb interactions are extensive but suboptimal, explaining why beta-hemoglobin can competitively displace AHSP to form HbA. Remarkably, the Fe(II)-heme group in AHSP bound alphaHb is coordinated by the distal but not the proximal histidine. Importantly, binding to AHSP facilitates the conversion of oxy-alphaHb to a deoxygenated, oxidized [Fe(III)], nonreactive form in which all six coordinate positions are occupied. These observations reveal the molecular mechanisms by which AHSP stabilizes free alphaHb.

  3. Far-infrared observations of M17: The interaction of an H II region with a molecular cloud

    International Nuclear Information System (INIS)

    Gatley, I.; Becklin, E.E.; Sellgren, K.; Werner, M.W.

    1979-01-01

    The central 15' of the M17 H II region--molecular cloud complex has been mapped with 1' resolution simultaneously at 30, 50, and 100 μm. The data suggest that the bulk of the luminosity radiated in the far-infrared is supplied by the exciting stars of the H II region; the far-infrared radiation is thermal emission from dust grains located chiefly outside the ionized gas. Large-scale systematic gradients in both the temperature and the column density of the dust are seen across the source. The appearance of the source in the far-infrared reflects the markedly nonuniform distribution of matter around the exciting stars; the H II region is bounded by the molecular cloud to the southwest. The core of the molecular cloud is heated primarily by infrared radiation from dust within and adjacent to the H II region; no evidence is seen for substantial luminosity sources embedded within the molecular cloud

  4. Catecholase activity of dicopper(II)-bispidine complexes: stabilities and structures of intermediates, kinetics and reaction mechanism.

    Science.gov (United States)

    Born, Karin; Comba, Peter; Daubinet, André; Fuchs, Alexander; Wadepohl, Hubert

    2007-01-01

    A mechanism for the oxidation of 3,5-di-tert-butylcatechol (dtbc) with dioxygen to the corresponding quinone (dtbq), catalyzed by bispidine-dicopper complexes (bispidines are various mono- and dinucleating derivatives of 3,7-diazabicyclo[3.3.1]nonane with bis-tertiary-amine-bispyridyl or bis-tertiary-amine-trispyridyl donor sets), is proposed on the basis of (1) the stoichiometry of the reaction as well as the stabilities and structures [X-ray, density functional theory (B3LYP, TZV)] of the bispidine-dicopper(II)-3,4,5,6-tetrachlorcatechol intermediates, (2) formation kinetics and structures (molecular mechanics, MOMEC) of the end-on peroxo-dicopper(II) complexes and (3) kinetics of the stoichiometric (anaerobic) and catalytic (aerobic) copper-complex-assisted oxidation of dtbc. This involves (1) the oxidation of the dicopper(I) complexes with dioxygen to the corresponding end-on peroxo-dicopper(II) complexes, (2) coordination of dtbc as a bridging ligand upon liberation of H(2)O(2) and (3) intramolecular electron transfer to produce dtbq, which is liberated, and the dicopper(I) catalyst. Although the bispidine complexes have reactivities comparable to those of recently published catalysts with macrocyclic ligands, which seem to reproduce the enzyme-catalyzed process in various reaction sequences, a strikingly different oxidation mechanism is derived from the bispidine-dicopper-catalyzed reaction.

  5. Description of ionization in the molecular approach to atomic collisions. II

    International Nuclear Information System (INIS)

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

    2002-01-01

    We complement a previous article [Harel et al., Phys. Rev. A 55, 287 (1997)] that studied the characteristics of the description of ionization by the molecular approach to atomic collisions, by comparing the wave functions with accurate counterparts. We show how the failure of the basis to describe the phase of the ionizing wave function results in a trapping of the corresponding population in some molecular channels. The time evolution of the molecular wave function then departs from the exact one and the ionization and capture mechanisms appear as interlocked. We thus elucidate the question of the 'natural' boundary of the molecular approach and draw further consequences as to the choice of pseudostates and the use of translation factors

  6. Quantum Mechanics/Molecular Mechanics Modeling of Enzymatic Processes: Caveats and Breakthroughs.

    Science.gov (United States)

    Quesne, Matthew G; Borowski, Tomasz; de Visser, Sam P

    2016-02-18

    Nature has developed large groups of enzymatic catalysts with the aim to transfer substrates into useful products, which enables biosystems to perform all their natural functions. As such, all biochemical processes in our body (we drink, we eat, we breath, we sleep, etc.) are governed by enzymes. One of the problems associated with research on biocatalysts is that they react so fast that details of their reaction mechanisms cannot be obtained with experimental work. In recent years, major advances in computational hardware and software have been made and now large (bio)chemical systems can be studied using accurate computational techniques. One such technique is the quantum mechanics/molecular mechanics (QM/MM) technique, which has gained major momentum in recent years. Unfortunately, it is not a black-box method that is easily applied, but requires careful set-up procedures. In this work we give an overview on the technical difficulties and caveats of QM/MM and discuss work-protocols developed in our groups for running successful QM/MM calculations. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

    Science.gov (United States)

    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.

  8. Quantum mechanics on Riemannian manifold in Schwinger's quantization approach II

    International Nuclear Information System (INIS)

    Chepilko, N.M.; Romanenko, A.V.

    2001-01-01

    The extended Schwinger quantization procedure is used for constructing quantum mechanics on a manifold with a group structure. The considered manifold M is a homogeneous Riemannian space with the given action of an isometry transformation group. Using the identification of M with the quotient space G/H, where H is the isotropy group of an arbitrary fixed point of M, we show that quantum mechanics on G/H possesses a gauge structure, described by a gauge potential that is the connection 1-form of the principal fiber bundle G(G/H, H). The coordinate representation of quantum mechanics and the procedure for selecting the physical sector of the states are developed. (orig.)

  9. Molecular mechanics and quantum mechanical modeling of hexane soot structure and interactions with pyrene

    Directory of Open Access Journals (Sweden)

    Kubicki JD

    2000-09-01

    Full Text Available Molecular simulations (energy minimizations and molecular dynamics of an n-hexane soot model developed by Smith and co-workers (M. S. Akhter, A. R. Chughtai and D. M. Smith, Appl. Spectrosc., 1985, 39, 143; ref. 1 were performed. The MM+ (N. L. Allinger, J. Am. Chem. Soc., 1977, 395, 157; ref. 2 and COMPASS (H. Sun, J. Phys. Chem., 1998, 102, 7338; ref. 3 force fields were tested for their ability to produce realistic soot nanoparticle structure. The interaction of pyrene with the model soot was simulated. Quantum mechanical calculations on smaller soot fragments were carried out. Starting from an initial 2D structure, energy minimizations are not able to produce the observed layering within soot with either force field. Results of molecular dynamics simulations indicate that the COMPASS force field does a reasonably accurate job of reproducing observations of soot structure. Increasing the system size from a 683 to a 2732 atom soot model does not have a significant effect on predicted structures. Neither does the addition of water molecules surrounding the soot model. Pyrene fits within the soot structure without disrupting the interlayer spacing. Polycyclic aromatic hydrocarbons (PAH, such as pyrene, may strongly partition into soot and have slow desorption kinetics because the PAH-soot bonding is similar to soot–soot interactions. Diffusion of PAH into soot micropores may allow the PAH to be irreversibly adsorbed and sequestered so that they partition slowly back into an aqueous phase causing dis-equilibrium between soil organic matter and porewater.

  10. Mechanical simulations of sandia II tests OECD ISP 48 benchmark

    International Nuclear Information System (INIS)

    Ghavamian, Sh.; Courtois, A.; Valfort, J.-L.; Heinfling, G.

    2005-01-01

    This paper illustrates the work carried out by EDF within the framework of ISP48 post-test analysis of NUPEC/NRCN 1:4-scale model of a prestressed pressure containment vessel of a nuclear power plant. EDF as a participant of the International Standard Problem n degree 8 has performed several simulations to determine the ultimate response of the scale model. To determine the most influent parameter in such an analysis several studies were carried out. The mesh was built using a parametric tool to measure the influence of discretization on results. Different material laws of concrete were also used. The purpose of this paper is to illustrate the ultimate behaviour of SANDIA II model obtained by Code-Asterwith comparison to tests records, and also to share the lessons learned from the parametric computations and precautions that must be taken. (authors)

  11. Study of effect of gamma radiation on molecular weight and mechanical properties of PHB and PHNV

    International Nuclear Information System (INIS)

    Fechine, Guilhermino J.M.; Terence, Mauro C.; Rabello, M.S.; Willen, Renate M.R.

    2011-01-01

    The effect of gamma radiation on molecular weight and mechanical properties (tensile and flexural) of PHB and PHBV samples was investigated. The values of stress and strain at the break point for both mechanical properties indicated that scission molecular reactions were predominant in PHB and PHBV samples submitted to gamma radiation. These results were confirmed by Size Exclusion Chromatography (SEC) analysis. (author)

  12. A Model of How Different Biology Experts Explain Molecular and Cellular Mechanisms

    Science.gov (United States)

    Trujillo, Caleb M.; Anderson, Trevor R.; Pelaez, Nancy J.

    2015-01-01

    Constructing explanations is an essential skill for all science learners. The goal of this project was to model the key components of expert explanation of molecular and cellular mechanisms. As such, we asked: What is an appropriate model of the components of explanation used by biology experts to explain molecular and cellular mechanisms? Do…

  13. Forcefields based molecular modeling on the mechanical and physical properties of emeraldine base polyaniline

    NARCIS (Netherlands)

    Chen, X.; Yuan, C.A.; Wong, K.Y.; Zhang, G.Q.

    2010-01-01

    Molecular dynamics (MD) and molecular mechanical (MM) analysis are carried out to provide reliable and accurate model for emeraldine base polyaniline. This study validate the forcefields and model with the physical and mechanical properties of the polyaniline. The temperature effects on non-bond

  14. Lectures on the mathematics of quantum mechanics II selected topics

    CERN Document Server

    Dell'Antonio, Gianfausto

    2016-01-01

    The first volume (General Theory) differs from most textbooks as it emphasizes the mathematical structure and mathematical rigor, while being adapted to the teaching the first semester of an advanced course in Quantum Mechanics (the content of the book are the lectures of courses actually delivered.). It differs also from the very few texts in Quantum Mechanics that give emphasis to the mathematical aspects because this book, being written as Lecture Notes, has the structure of lectures delivered in a course, namely introduction of the problem, outline of the relevant points, mathematical tools needed, theorems, proofs. This makes this book particularly useful for self-study and for instructors in the preparation of a second course in Quantum Mechanics (after a first basic course). With some minor additions it can be used also as a basis of a first course in Quantum Mechanics for students in mathematics curricula. The second part (Selected Topics) are lecture notes of a more advanced course aimed at giving th...

  15. Braid group, knot theory and statistical mechanics II

    CERN Document Server

    Yang Chen Ning

    1994-01-01

    The present volume is an updated version of the book edited by C N Yang and M L Ge on the topics of braid groups and knot theory, which are related to statistical mechanics. This book is based on the 1989 volume but has new material included and new contributors.

  16. AUTOMOTIVE DIESEL MAINTENANCE 2. UNIT II, MECHANICAL TRANSMISSIONS.

    Science.gov (United States)

    Human Engineering Inst., Cleveland, OH.

    THIS MODULE OF A 25-MODULE COURSE IS DESIGNED TO DEVELOP AN UNDERSTANDING OF THE OPERATION AND MAINTENANCE OF MECHANICAL TRANSMISSIONS USED ON DIESEL POWERED VEHICLES. TOPICS ARE (1) PURPOSE OF TRANSMISSIONS, (2) RATIO DIFFERENCE, (3) CONSTANT MESH TRANSMISSIONS, (4) FOUR-SPEED TRUCK TRANSMISSION POWER FLOW, AND (5) TRANSMISSION TROUBLESHOOTING.…

  17. Zinc electrode shape change II. Process and mechanism

    NARCIS (Netherlands)

    Einerhand, R.E.F.; Visscher, W.; de Goeij, J.J.M.; Barendrecht, E.

    1991-01-01

    The process and mechanism of zinc electrode shape change is investigated with the radiotracer technique. It is shownthat during repeated cycling of the nickel oxide/zinc battery zinc material is transported over the zinc electrode via the battery electrolyte. During charge as well as during

  18. Mechanical Properties of High Performance Cementitious Grout (II)

    DEFF Research Database (Denmark)

    Sørensen, Eigil V.

    The present report is an update of the report “Mechanical Properties of High Performance Cementitious Grout (I)” [1] and describes tests carried out on the high performance grout MASTERFLOW 9500, marked “WMG 7145 FP”, developed by BASF Construction Chemicals A/S and designed for use in grouted...

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

    Science.gov (United States)

    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.

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

    International Nuclear Information System (INIS)

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

    2016-01-01

    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 TiO 2 anatase (1 0 1) solid–liquid interface. This investigation suggests that the inclusion of a second monolayer of H 2 O 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. (paper)

  1. Insights into the catalytic mechanism of dehydrogenase BphB: A quantum mechanics/molecular mechanics study.

    Science.gov (United States)

    Zhang, Ruiming; Shi, Xiangli; Sun, Yanhui; Zhang, Qingzhu; Wang, Wenxing

    2018-05-17

    The present study delineated the dehydrogenation mechanism of cis-2,3-dihydro-2,3-dihydroxybiphenyl (2,3-DDBPH) and cis-2,3-dihydro-2,3-dihydroxy-4,4'-dichlorobiphenyl (2,3-DD-4,4'-DBPH) by Pandoraea pnomenusa strain B-356 cis-2,3-dihydro-2,3-dihydroxybiphenyl dehydrogenase (BphB) in atomistic detail. The enzymatic process was investigated by a combined quantum mechanics/molecular mechanics (QM/MM) approach. Five different snapshots were extracted and calculated, which revealed that the Boltzmann-weighted average barriers of 2,3-DDBPH and 2,3-DD-4,4'-DBPH dehydrogenation processes are 10.7 and 11.5 kcal mol -1 , respectively. The established dehydrogenation mechanism provides new insight into the degradation processes of other chlorinated 2,3-DDBPH. In addition to Asn115, Ser142, and Lys149, the importance of Ile 89, Asn143, Pro184, Met 187, Thr189, and Lue 191 during the dehydrogenation process of 2,3-DDBPH and 2,3-DD-4,4'-DBPH were also highlighted to search for promising mutation targets for improving the catalytic efficiency of BphB. Copyright © 2018. Published by Elsevier Ltd.

  2. Insights into the Thiamine Diphosphate Enzyme Activation Mechanism: Computational Model for Transketolase Using a Quantum Mechanical/Molecular Mechanical Method.

    Science.gov (United States)

    Nauton, Lionel; Hélaine, Virgil; Théry, Vincent; Hecquet, Laurence

    2016-04-12

    We propose the first computational model for transketolase (TK), a thiamine diphosphate (ThDP)-dependent enzyme, using a quantum mechanical/molecular mechanical method on the basis of crystallographic TK structures from yeast and Escherichia coli, together with experimental kinetic data reported in the literature with wild-type and mutant TK. This model allowed us to define a new route for ThDP activation in the enzyme environment. We evidenced a strong interaction between ThDP and Glu418B of the TK active site, itself stabilized by Glu162A. The crucial point highlighted here is that deprotonation of ThDP C2 is not performed by ThDP N4' as reported in the literature, but by His481B, involving a HOH688A molecule bridge. Thus, ThDP N4' is converted from an amino form to an iminium form, ensuring the stabilization of the C2 carbanion or carbene. Finally, ThDP activation proceeds via an intermolecular process and not by an intramolecular one as reported in the literature. More generally, this proposed ThDP activation mechanism can be applied to some other ThDP-dependent enzymes and used to define the entire TK mechanism with donor and acceptor substrates more accurately.

  3. Angiotensin II regulation of neuromodulation: downstream signaling mechanism from activation of mitogen-activated protein kinase.

    Science.gov (United States)

    Lu, D; Yang, H; Raizada, M K

    1996-12-01

    Angiotensin II (Ang II) stimulates expression of tyrosine hydroxylase and norepinephrine transporter genes in brain neurons; however, the signal-transduction mechanism is not clearly defined. This study was conducted to determine the involvement of the mitogen-activated protein (MAP) kinase signaling pathway in Ang II stimulation of these genes. MAP kinase was localized in the perinuclear region of the neuronal soma. Ang II caused activation of MAP kinase and its subsequent translocation from the cytoplasmic to nuclear compartment, both effects being mediated by AT1 receptor subtype. Ang II also stimulated SRE- and AP1-binding activities and fos gene expression and its translocation in a MAP kinase-dependent process. These observations are the first demonstration of a downstream signaling pathway involving MAP kinase in Ang II-mediated neuromodulation in noradrenergic neurons.

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

    Directory of Open Access Journals (Sweden)

    Pajeva Ilza

    2008-10-01

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

  5. THE Fe II EMISSION IN ACTIVE GALACTIC NUCLEI: EXCITATION MECHANISMS AND LOCATION OF THE EMITTING REGION

    International Nuclear Information System (INIS)

    Marinello, M.; Rodríguez-Ardila, A.; Garcia-Rissmann, A.; Sigut, T. A. A.; Pradhan, A. K.

    2016-01-01

    We present a study of Fe ii emission in the near-infrared region (NIR) for 25 active galactic nuclei (AGNs) to obtain information about the excitation mechanisms that power it and the location where it is formed. We employ an NIR Fe ii template derived in the literature and find that it successfully reproduces the observed Fe ii spectrum. The Fe ii bump at 9200 Å detected in all objects studied confirms that Lyα fluorescence is always present in AGNs. The correlation found between the flux of the 9200 Å bump, the 1 μm lines, and the optical Fe ii implies that Lyα fluorescence plays an important role in Fe ii production. We determined that at least 18% of the optical Fe ii is due to this process, while collisional excitation dominates the production of the observed Fe ii. The line profiles of Fe ii λ10502, O i λ11287, Ca ii λ8664, and Paβ were compared to gather information about the most likely location where they are emitted. We found that Fe ii, O i and Ca ii have similar widths and are, on average, 30% narrower than Paβ. Assuming that the clouds emitting the lines are virialized, we show that the Fe ii is emitted in a region twice as far from the central source than Paβ. The distance, though, strongly varies: from 8.5 light-days for NGC 4051 to 198.2 light-days for Mrk 509. Our results reinforce the importance of the Fe ii in the NIR to constrain critical parameters that drive its physics and the underlying AGN kinematics, as well as more accurate models aimed at reproducing this complex emission

  6. THE Fe II EMISSION IN ACTIVE GALACTIC NUCLEI: EXCITATION MECHANISMS AND LOCATION OF THE EMITTING REGION

    Energy Technology Data Exchange (ETDEWEB)

    Marinello, M. [Universidade Federal de Itajubá, Rua Doutor Pereira Cabral 1303, 37500-903, Itajubá, MG (Brazil); Rodríguez-Ardila, A.; Garcia-Rissmann, A. [Laboratório Nacional de Astrofísica, Rua Estados Unidos 154, Itajubá, MG, 37504-364 (Brazil); Sigut, T. A. A. [The University of Western Ontario, London, ON N6A 3K7 (Canada); Pradhan, A. K., E-mail: murilo.marinello@gmail.com [McPherson Laboratory, The Ohio State University, 140 W. 18th Ave., Columbus, OH 43210-1173 (United States)

    2016-04-01

    We present a study of Fe ii emission in the near-infrared region (NIR) for 25 active galactic nuclei (AGNs) to obtain information about the excitation mechanisms that power it and the location where it is formed. We employ an NIR Fe ii template derived in the literature and find that it successfully reproduces the observed Fe ii spectrum. The Fe ii bump at 9200 Å detected in all objects studied confirms that Lyα fluorescence is always present in AGNs. The correlation found between the flux of the 9200 Å bump, the 1 μm lines, and the optical Fe ii implies that Lyα fluorescence plays an important role in Fe ii production. We determined that at least 18% of the optical Fe ii is due to this process, while collisional excitation dominates the production of the observed Fe ii. The line profiles of Fe ii λ10502, O i λ11287, Ca ii λ8664, and Paβ were compared to gather information about the most likely location where they are emitted. We found that Fe ii, O i and Ca ii have similar widths and are, on average, 30% narrower than Paβ. Assuming that the clouds emitting the lines are virialized, we show that the Fe ii is emitted in a region twice as far from the central source than Paβ. The distance, though, strongly varies: from 8.5 light-days for NGC 4051 to 198.2 light-days for Mrk 509. Our results reinforce the importance of the Fe ii in the NIR to constrain critical parameters that drive its physics and the underlying AGN kinematics, as well as more accurate models aimed at reproducing this complex emission.

  7. Atomic and molecular excitation mechanisms in the interstellar medium

    International Nuclear Information System (INIS)

    Sternberg, A.

    1986-01-01

    The detailed infrared response of dense molecular hydrogen gas to intense ultraviolet radiation fields in photodissociation regions is presented. The thermal and chemical structures of photodissociation regions are analyzed, and the relationship between the emission by molecular hydrogen and trace atomic and molecular species is explored. The ultraviolet spectrum of radiation generated by cosmic rays inside dense molecular clouds is presented, and the resulting rates of photodissociation for a variety of interstellar molecules are calculated. Effects of this radiation on the chemistry of dense molecular clouds are discussed, and it is argued that the cosmic ray induced photons will significantly inhibit the production of complex molecular species. It is argued that the annihilation of electrons and positrons at the galactic center may result in observable infrared line emission by atomic hydrogen. A correlation between the intensity variations of the 511 keV line and the hydrogen infrared lines emitted by the annihilation region is predicted. The observed infrared fluxes from compact infrared sources at the galactic center may be used to constrain theories of pair production there

  8. Mechanical and molecular studies of biocomposites filled with oil palm empty fruit bunches microfibers

    Science.gov (United States)

    Nikmatin, S.; Saepulloh, D. R.; Irmansyah; Syafiuddin, A.

    2017-05-01

    The present work aims to investigate mechanical and molecular characteristics of acrylonitrile butadiene styrene (ABS) composites filled with oil palm empty fruit bunches (OPEFB) microfibers. OPEFB microfibers were produced using mechanical milling. Composite granules were fabricated using single screw extruder. These composites were then used for fabricating helmet according to the Indonesian National Standard (SNI). Mechanical testing confirms that the helmet produced using this biocomposites are suitable to the SNI. Molecular interaction between matrix with OPEFB can be described using orbital hybridization theory. In general, this study has successfully investigated mechanical and molecular properties of the biocomposites.

  9. Deformation mechanism of the Cryostat in the CADS Injector II

    Science.gov (United States)

    Yuan, Jiandong; Zhang, Bin; Wan, Yuqin; Sun, Guozhen; Bai, Feng; Zhang, Juihui; He, Yuan

    2018-01-01

    Thermal contraction and expansion of the Cryostat will affect its reliability and stability. To optimize and upgrade the Cryostat, we analyzed the heat transfer in a cryo-vacuum environment from the theoretical point first. The simulation of cryo-vacuum deformation based on a finite element method was implemented respectively. The completed measurement based on a Laser Tracker and a Micro Alignment Telescope was conducted to verify its correctness. The monitored deformations were consistent with the simulated ones. After the predictable deformations in vertical direction have been compensated, the superconducting solenoids and Half Wave Resonator cavities approached the ideal "zero" position under liquid helium conditions. These guaranteed the success of 25 MeV@170 uA continuous wave protons of Chinese accelerator driven subcritical system Injector II. By correlating the vacuum and cryo-deformation, we have demonstrated that the complete deformation was the superposition effect of the atmospheric pressure, gravity and thermal stress during both the process of cooling down and warming up. The results will benefit to an optimization for future Cryostat's design.

  10. Single molecular switch based on thiol tethered iron(II)clathrochelate on gold

    Energy Technology Data Exchange (ETDEWEB)

    Viswanathan, Subramanian [Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Tuwima 10, 10-747 Olsztyn (Poland); Voloshin, Yan Z. [Nesmeyanov Institute of Organoelement Compounds of the Russian Academy of Sciences, 119991 Moscow (Russian Federation); Radecka, Hanna [Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Tuwima 10, 10-747 Olsztyn (Poland); Radecki, Jerzy [Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Tuwima 10, 10-747 Olsztyn (Poland)], E-mail: radecki@pan.olsztyn.pl

    2009-09-30

    Molecular electronics has been associated with high density nano-electronic devices. Developments of molecular electronic devices were based on reversible switching of molecules between the two conductive states. In this paper, self-assembled monolayers of dodecanethiol (DDT) and thiol tethered iron(II)clathrochelate (IC) have been prepared on gold film. The electrochemical and electronic properties of IC molecules inserted into the dodecanethiol monolayer (IC-DDT SAM) were investigated using voltammetric, electrochemical impedance spectroscopy (EIS), scanning tunneling microscopy (STM) and cross-wire tunneling measurements. The voltage triggered switching behaviour of IC molecules on mixed SAM was demonstrated. Deposition of polyaniline on the redox sites of IC-DDT SAM using electrochemical polymerization of aniline was performed in order to confirm that this monolayer acts as nano-patterned semiconducting electrode surface.

  11. Parametrization of Combined Quantum Mechanical and Molecular Mechanical Methods: Bond-Tuned Link Atoms.

    Science.gov (United States)

    Wu, Xin-Ping; Gagliardi, Laura; Truhlar, Donald G

    2018-05-30

    Combined quantum mechanical and molecular mechanical (QM/MM) methods are the most powerful available methods for high-level treatments of subsystems of very large systems. The treatment of the QM-MM boundary strongly affects the accuracy of QM/MM calculations. For QM/MM calculations having covalent bonds cut by the QM-MM boundary, it has been proposed previously to use a scheme with system-specific tuned fluorine link atoms. Here, we propose a broadly parametrized scheme where the parameters of the tuned F link atoms depend only on the type of bond being cut. In the proposed new scheme, the F link atom is tuned for systems with a certain type of cut bond at the QM-MM boundary instead of for a specific target system, and the resulting link atoms are call bond-tuned link atoms. In principle, the bond-tuned link atoms can be as convenient as the popular H link atoms, and they are especially well adapted for high-throughput and accurate QM/MM calculations. Here, we present the parameters for several kinds of cut bonds along with a set of validation calculations that confirm that the proposed bond-tuned link-atom scheme can be as accurate as the system-specific tuned F link-atom scheme.

  12. Parametrization of Combined Quantum Mechanical and Molecular Mechanical Methods: Bond-Tuned Link Atoms

    Directory of Open Access Journals (Sweden)

    Xin-Ping Wu

    2018-05-01

    Full Text Available Combined quantum mechanical and molecular mechanical (QM/MM methods are the most powerful available methods for high-level treatments of subsystems of very large systems. The treatment of the QM−MM boundary strongly affects the accuracy of QM/MM calculations. For QM/MM calculations having covalent bonds cut by the QM−MM boundary, it has been proposed previously to use a scheme with system-specific tuned fluorine link atoms. Here, we propose a broadly parametrized scheme where the parameters of the tuned F link atoms depend only on the type of bond being cut. In the proposed new scheme, the F link atom is tuned for systems with a certain type of cut bond at the QM−MM boundary instead of for a specific target system, and the resulting link atoms are call bond-tuned link atoms. In principle, the bond-tuned link atoms can be as convenient as the popular H link atoms, and they are especially well adapted for high-throughput and accurate QM/MM calculations. Here, we present the parameters for several kinds of cut bonds along with a set of validation calculations that confirm that the proposed bond-tuned link-atom scheme can be as accurate as the system-specific tuned F link-atom scheme.

  13. Radiation toxins: molecular mechanisms of action and radiomimetic properties .

    Science.gov (United States)

    Popov, Dmitri; Maliev, Vecheslav

    Introduction: Acute Radiation Disease (ARD) or Acute Radiation Syndromes (ARS) were defined as a toxic poisonous with development of the acute pathological processes in irradi-ated animals: systemic inflammatory response syndrome(SIRS), toxic multiple organ injury (TMOI), toxic multiple organ dysfunction syndromes (TMOD), toxic multiple organ failure (TMOF). However, the nature of radiation toxins, their mechanisms of formation, molecular structure, and mechanism of actions remain uncertain. Moderate and high doses of radiation induce apoptotic necrosis of radiosensitive cells with formation of Radiation Toxins and in-flammation development. Mild doses of radiation induce apoptosis or controlled programmed death of radiosensitive cells without Radiation Toxins formation and development of inflam-mation processes. Only radiation induced apoptotic necrosis initiates formation of Radiation Toxins(RT). Radiation Toxins are playing an important role as the trigger mechanisms for in-flammation development and cell lysis. The systemic inflammatory response syndrome after radiation involves an influence of various endogenous agents and mediators of inflammation such as bradykinin, histamine, serotonin and phospholipases activation, prostaglandins biosyn-thesis. Although, formation of non-specific toxins such as Reactive Oxygen Species (ROS) is an important pathological process at mild or high doses of radiation. Reactive Oxygen Species play an important role in molecules damage and development of peroxidation of lipids and pro-teins which are the structural parts of cell and mitochondrial membranes. ROS and bio-radicals induce damage of DNA and RNA and peroxidation of their molecules. But high doses of radia-tion, severe and extremely severe physiological stress, result in cells death by apoptotic necrosis and could be defined as the neuroimmune acute disease. Excitotoxicity is an important patho-logical mechanism which damages the central nervous system. We postulate that

  14. Relativistic-particle quantum mechanics (applications and approximations) II

    International Nuclear Information System (INIS)

    Coester, F.

    1981-01-01

    In this lecture I hope to show that relativistic-particle quantum mechanics with direct interactions is a useful tool for building models applicable to hadron systems at intermediate energies. To do this I will first describe a class of models designed to incorporate nucleon-nucleon interactions, pion production, absorption and scattering into a single dynamical framework without dressing the nucleons with pion clouds. The second major topic concerns electromagnetic interactions. In the previous lecture I specifically excluded long-rang forces and zero-mass particles. Since many of the experimental data in hadron physics involve electromagnetic interactions this limitation is a major defect which must be addressed

  15. Psycho-neuro-endocrine-immune mechanisms of action of yoga in type II diabetes.

    Science.gov (United States)

    Singh, Vijay Pratap; Khandelwal, Bidita; Sherpa, Namgyal T

    2015-01-01

    Yoga has been found to benefit all the components of health viz. physical, mental, social and spiritual well being by incorporating a wide variety of practices. Pathophysiology of Type II DM and co-morbidities in Type II DM has been correlated with stress mechanisms. Stress suppresses body's immune system and neuro-humoral actions thereby aff ecting normal psychological state. It would not be wrong to state that correlation of diabetes with stress, anxiety and other psychological factors are bidirectional and lead to difficulty in understanding the interrelated mechanisms. Type II DM cannot be understood in isolation with psychological factors such as stress, anxiety and depression, neuro-endocrine and immunological factors. There is no review which tries to understand these mechanisms exclusively. The present literature review aims to understand interrelated Psycho-Neuro-Endocrine and Immunological mechanisms of action of Yoga in Type II Diabetes Mellitus. Published literature concerning mechanisms of action of Yoga in Type II DM emphasizing psycho-neuro-endocrine or immunological relations was retrieved from Pubmed using key words yoga, Type II diabetes mellitus, psychological, neural, endocrine, immune and mechanism of action. Those studies which explained the psycho-neuroendocrine and immune mechanisms of action of yoga were included and rest were excluded. Although primary aim of this study is to explain these mechanisms in Type II DM, some studies in non-diabetic population which had a similar pathway of stress mechanism was included because many insightful studies were available in that area. Search was conducted using terms yoga OR yogic AND diabetes OR diabetic IN title OR abstract for English articles. Of the 89 articles, we excluded non-English articles (22), editorials (20) and letters to editor (10). 37 studies were considered for this review. The postulated mechanism of action of yoga is through parasympathetic activation and the associated anti

  16. Mechanisms of Hg(II) uptake and methylation in methylating bacteria

    Energy Technology Data Exchange (ETDEWEB)

    Morel, Francois M. M. [Princeton Univ., NJ (United States). Geosciences

    2016-10-14

    The goal of this project was to understand the critical factors which control the availability and transport of Hg(II) into cells, a first step in the production of the neurotoxin, methylmercury. Specifically, this research focused on understanding the mechanism of bacterial mercury uptake and how mercury speciation affects the specificity and kinetics of mercury transport. Our research has shown that Hg(II) uptake in three different iron and sulfate-reducing proteobacteria occurs by the following mechanism (1) : Hg(II) uptake is an active transport process requiring energy, (2) it is dependent upon the structure of the Hg binding ligand, and (3) it is mediated by a heavy metal transporter such as one which transports the essential metal, Zn(II). In order to determine whether this mechanism extends to more diverse phylogenetic groups, we have begun examining Hg(II) uptake and bioavailability in two representative Hg methylating strains within the Firmicutes. These organisms have remarkably different membrane structures distinct from the Proteobacteria. Our results show low uptake rates in these two species of Firmicutes relative to the previously characterized Proteobacteria. This may explain the low methylation rates and yields observed in these organisms. Most surprisingly, however, these organisms appear to take up Hg(II) passively, as the addition of a protonophore failed to reduce Hg(II) uptake in these organisms. This is quite different to what has been observed previously for the Proteobacteria and suggests a different mechanism for Hg(II) uptake in the Firmicutes. We are continuing to understand and describe Hg(II) uptake in these organisms. A manuscript is expected to be submitted on this research in June 2016.

  17. Insights into the Reaction Mechanism of Aromatic Ring Cleavage by Homogentisate Dioxygenase: A Quantum Mechanical/Molecular Mechanical Study.

    Science.gov (United States)

    Qi, Yue; Lu, Jiarui; Lai, Wenzhen

    2016-05-26

    To elucidate the reaction mechanism of the ring cleavage of homogentisate by homogentisate dioxygenase, quantum mechanical/molecular mechanical (QM/MM) calculations were carried out by using two systems in different protonation states of the substrate C2 hydroxyl group. When the substrate C2 hydroxyl group is ionized (the ionized pathway), the superoxo attack on the substrate is the rate-limiting step in the catalytic cycle, with a barrier of 15.9 kcal/mol. Glu396 was found to play an important role in stabilizing the bridge species and its O-O cleavage product by donating a proton via a hydrogen-bonded water molecule. When the substrate C2 hydroxyl group is not ionized (the nonionized pathway), the O-O bond cleavage of the bridge species is the rate-limiting step, with a barrier of 15.3 kcal/mol. The QM/MM-optimized geometries for the dioxygen and alkylperoxo complexes using the nonionized model (for the C2 hydroxyl group) are in agreement with the experimental crystal structures, suggesting that the C2 hydroxyl group is more likely to be nonionized.

  18. The mechanisms behind decreased internalization of angiotensin II type 1 receptor.

    Science.gov (United States)

    Bian, Jingwei; Zhang, Suli; Yi, Ming; Yue, Mingming; Liu, Huirong

    2018-04-01

    The internalization of angiotensin II type 1 receptor (AT 1 R) plays an important role in maintaining cardiovascular homeostasis. Decreased receptor internalization is closely related to cardiovascular diseases induced by the abnormal activation of AT 1 R, such as hypertension. However, the mechanism behind reduced AT 1 R internalization is not fully understood. This review focuses on four parts of the receptor internalization process (the combination of agonists and receptors, receptor phosphorylation, endocytosis, and recycling) and summarizes the possible mechanisms by which AT 1 R internalization is reduced based on these four parts of the process. (1) The agonist has a large molecular weight or a stronger ability to hydrolyze phosphatidylinositol 4,5-bisphosphate (PtdIns (4,5) P 2 ), which can increase the consumption of PtdIns (4,5) P 2 . (2) AT 1 R phosphorylation is weakened because of an abnormal function of phosphorylated kinase or changes in phospho-barcoding and GPCR-β-arrestin complex conformation. (3) The abnormal formation of vesicles or AT 1 R heterodimers with fewer endocytic receptors results in less AT 1 R endocytosis. (4) The enhanced activity and upregulated expression of small GTP-binding protein 4 (Rab4) and 11 (Rab11), which regulate receptor recycling, and phosphatidylinositol 3-kinase increase AT 1 R recycling. In addition, lower expression of AT 1 R-associated protein (ATRAP) or higher expression of AT 1 R-associated protein 1 (ARAP1) can reduce receptor internalization. Copyright © 2018 Elsevier Inc. All rights reserved.

  19. Combined quantum mechanical and molecular mechanical reaction pathway calculation for aromatic hydroxylation by p-hydroxybenzoate-3-hydroxylase

    NARCIS (Netherlands)

    Ridder, L.; Mulholland, A.; Rietjens, I.M.C.M.; Vervoort, J.

    1999-01-01

    The reaction pathway for the aromatic 3-hydroxylation of p-hydroxybenzoate by the reactive C4a-hydroperoxyflavin cofactor intermediate in p-hydroxybenzoate hydroxylase (PHBH) has been investigated by a combined quantum mechanical and molecular mechanical (QM/MM) method. A structural model for the

  20. Fundamentals of physics II electromagnetism, optics, and quantum mechanics

    CERN Document Server

    Shankar, R

    2016-01-01

    R. Shankar, a well-known physicist and contagiously enthusiastic educator, was among the first to offer a course through the innovative Open Yale Course program. His popular online video lectures on introductory physics have been viewed over a million times. In this second book based on his online Yale course, Shankar explains essential concepts, including electromagnetism, optics, and quantum mechanics. The book begins at the simplest level, develops the basics, and reinforces fundamentals, ensuring a solid foundation in the principles and methods of physics. It provides an ideal introduction for college-level students of physics, chemistry, and engineering; for motivated AP Physics students; and for general readers interested in advances in the sciences.

  1. [Molecular Biology on the Mechanisms of Autism Spectrum Disorder for Clinical Psychiatrists].

    Science.gov (United States)

    Makinodan, Manabu

    2015-01-01

    While, in general, a certain number of clinical psychiatrists might not be familiar with molecular biology, the mechanisms of mental illnesses have been uncovered by molecular biology for decades. Among mental illnesses, even biological psychiatrists and neuroscientists have paid less attention to the biological treatment of autism spectrum disorder (ASD) than Alzheimer's disease and schizophrenia since ASD has been regarded as a developmental disorder that was seemingly untreatable. However, multifaceted methods of molecular biology have revealed the mechanisms that would lead to the medication of ASD. In this article, how molecular biology dissects the pathobiology of ASD is described in order to announce the possibilities of biological treatment for clinical psychiatrists.

  2. Molecular Mechanisms of Ion-Specific Effects on Proteins

    Czech Academy of Sciences Publication Activity Database

    Rembert, K. B.; Paterová, Jana; Heyda, Jan; Hilty, Ch.; Jungwirth, Pavel; Cremer, P. S.

    2012-01-01

    Roč. 134, č. 24 (2012), s. 10039-10046 ISSN 0002-7863 R&D Projects: GA ČR GA203/08/0114 Institutional research plan: CEZ:AV0Z40550506 Keywords : ions * proteins * molecular dynamics * NMR Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 10.677, year: 2012

  3. Molecular mechanisms of insulin resistance | Pillay | South African ...

    African Journals Online (AJOL)

    This review discusses recent advances in understanding of the structure and function of the insulin receptor and insulin action, and how these relate to the clinical aspects of insulin resistance associated with non-insulin-dependent diabetes and other disorders. Improved understanding of the molecular basis of insulin ...

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

    Science.gov (United States)

    Ojeda-May, Pedro; Pu, Jingzhi

    2015-11-07

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

  5. Mechanical testing of hydraulic fluids II; Mechanische Pruefung von Hydraulikfluessigkeiten II

    Energy Technology Data Exchange (ETDEWEB)

    Kessler, M.; Feldmann, D.G.; Laukart, V.

    2001-09-01

    Since May 1996 the Institute for Mechanical Engineering Design 1 of Technical University of Hamburg-Harburg is working on the topic of ''Mechanical Testing of Hydraulic fluids''. The first project lasting 2 1/2 years was completed in 1999, the results are published as the DGMK report 514. Within these project a testing principle for the ''mechanical testing'' of hydraulic fluids has been derived, a prototype of a test rig was designed and set in operation at the authors' institute. This DGMK-report 514-1 describes the results of the second project, which investigates the operating behaviour of the test-rig more in detail. Several test-runs with a total number of 11 different hydraulic fluids show the dependence of the different lubricating behaviour of the tested fluids and their friction and wear behaviour during the tests in a reproducible way. The aim of the project was to derive a testing principle including the design of a suitable test-rig for the mechanical testing of hydraulic fluids. Based on the described results it can be stated that with the developed test it is possible to test the lubricity of hydraulic fluids reproducible and in correlation to field experiences within a relatively short time, so the target was reached. (orig.)

  6. I: Hydrodynamic-focusing microreactor II: Mechanically interlocked molecules for functional materials

    Science.gov (United States)

    Coti, Karla Karina

    I: Microreactors, a class of microfluidics, offer numerous benefits -- such as small sample requirement, short analysis times and automations -- and have been used to study reactions of chemical and biological reagents. In order to understand the relationship between fast mixing, product regioselectivity, as well as the ability to separate, in time and space, the nanoparticle (NP) formation stages, a microreactor capable of fast and controllable mixing was developed (Chapter 1) based on multi-lamination and hydrodynamic-focusing. By taking advantage of the fast and controllable mixing properties of this novel microreactor one can control the time when chemical reactions commence inside the microchannels. These properties of the microreactor can be exploited to improve the product regioselectivity of a diazo-coupling reaction to attain a product distribution of monoazo to diazo product of ˜1:99, a selectivity unprecedented in both conventional, macroscopic reactors and other microfluidic systems. Additionally, the ability to separate different stages during the NP formation process inside the microreactor, allowed us to study the aggregation of polypyrrole NPs. II: Supramolecular actuators and molecular interlocked molecules, such as catenanes and rotaxanes, have attracted considerable attention because of their sophisticated topology and their application in functional molecular devices. The blending of supramolecular and mechanostereochemistry with mesoporous silica NPs has proven to be a powerful combination, leading to the development of a new class of materials -- mechanized silica nanoparticles ( Chapter 2). These new hybrid materials are designed to release their content in response to an external stimuli and their development is being driven by the need to improve current drug delivery technologies. In an effort to explore how the stimuli-controlled mechanical movement of switchable, bistable [2]rotaxanes -- based on a cyclobis(paraquat-p-phenylene) ring

  7. Statistical mechanics in the context of special relativity. II.

    Science.gov (United States)

    Kaniadakis, G

    2005-09-01

    The special relativity laws emerge as one-parameter (light speed) generalizations of the corresponding laws of classical physics. These generalizations, imposed by the Lorentz transformations, affect both the definition of the various physical observables (e.g., momentum, energy, etc.), as well as the mathematical apparatus of the theory. Here, following the general lines of [Phys. Rev. E 66, 056125 (2002)], we show that the Lorentz transformations impose also a proper one-parameter generalization of the classical Boltzmann-Gibbs-Shannon entropy. The obtained relativistic entropy permits us to construct a coherent and self-consistent relativistic statistical theory, preserving the main features of the ordinary statistical theory, which is recovered in the classical limit. The predicted distribution function is a one-parameter continuous deformation of the classical Maxwell-Boltzmann distribution and has a simple analytic form, showing power law tails in accordance with the experimental evidence. Furthermore, this statistical mechanics can be obtained as the stationary case of a generalized kinetic theory governed by an evolution equation obeying the H theorem and reproducing the Boltzmann equation of the ordinary kinetics in the classical limit.

  8. Cyclopentane combustion. Part II. Ignition delay measurements and mechanism validation

    KAUST Repository

    Rachidi, Mariam El

    2017-06-12

    This study reports cyclopentane ignition delay measurements over a wide range of conditions. The measurements were obtained using two shock tubes and a rapid compression machine, and were used to test a detailed low- and high-temperature mechanism of cyclopentane oxidation that was presented in part I of this study (Al Rashidi et al., 2017). The ignition delay times of cyclopentane/air mixtures were measured over the temperature range of 650–1350K at pressures of 20 and 40atm and equivalence ratios of 0.5, 1.0 and 2.0. The ignition delay times simulated using the detailed chemical kinetic model of cyclopentane oxidation show very good agreement with the experimental measurements, as well as with the cyclopentane ignition and flame speed data available in the literature. The agreement is significantly improved compared to previous models developed and investigated at higher temperatures. Reaction path and sensitivity analyses were performed to provide insights into the ignition-controlling chemistry at low, intermediate and high temperatures. The results obtained in this study confirm that cycloalkanes are less reactive than their non-cyclic counterparts. Moreover, cyclopentane, a high octane number and high octane sensitivity fuel, exhibits minimal low-temperature chemistry and is considerably less reactive than cyclohexane. This study presents the first experimental low-temperature ignition delay data of cyclopentane, a potential fuel-blending component of particular interest due to its desirable antiknock characteristics.

  9. Cyclopentane combustion. Part II. Ignition delay measurements and mechanism validation

    KAUST Repository

    Rachidi, Mariam El; Má rmol, Juan C.; Banyon, Colin; Sajid, Muhammad Bilal; Mehl, Marco; Pitz, William J.; Mohamed, Samah; Alfazazi, Adamu; Lu, Tianfeng; Curran, Henry J.; Farooq, Aamir; Sarathy, Mani

    2017-01-01

    This study reports cyclopentane ignition delay measurements over a wide range of conditions. The measurements were obtained using two shock tubes and a rapid compression machine, and were used to test a detailed low- and high-temperature mechanism of cyclopentane oxidation that was presented in part I of this study (Al Rashidi et al., 2017). The ignition delay times of cyclopentane/air mixtures were measured over the temperature range of 650–1350K at pressures of 20 and 40atm and equivalence ratios of 0.5, 1.0 and 2.0. The ignition delay times simulated using the detailed chemical kinetic model of cyclopentane oxidation show very good agreement with the experimental measurements, as well as with the cyclopentane ignition and flame speed data available in the literature. The agreement is significantly improved compared to previous models developed and investigated at higher temperatures. Reaction path and sensitivity analyses were performed to provide insights into the ignition-controlling chemistry at low, intermediate and high temperatures. The results obtained in this study confirm that cycloalkanes are less reactive than their non-cyclic counterparts. Moreover, cyclopentane, a high octane number and high octane sensitivity fuel, exhibits minimal low-temperature chemistry and is considerably less reactive than cyclohexane. This study presents the first experimental low-temperature ignition delay data of cyclopentane, a potential fuel-blending component of particular interest due to its desirable antiknock characteristics.

  10. Molecular assembly of recombinant chicken type II collagen in the yeast Pichia pastoris.

    Science.gov (United States)

    Xi, Caixia; Liu, Nan; Liang, Fei; Zhao, Xiao; Long, Juan; Yuan, Fang; Yun, Song; Sun, Yuying; Xi, Yongzhi

    2018-01-09

    Effective treatment of rheumatoid arthritis can be mediated by native chicken type II collagen (nCCII), recombinant peptide containing nCCII tolerogenic epitopes (CTEs), or a therapeutic DNA vaccine encoding the full-length CCOL2A1 cDNA. As recombinant CCII (rCCII) might avoid potential pathogenic virus contamination during nCCII preparation or chromosomal integration and oncogene activation associated with DNA vaccines, here we evaluated the importance of propeptide and telopeptide domains on rCCII triple helix molecular assembly. We constructed pC- and pN-procollagen (without N- or Cpropeptides, respectively) as well as CTEs located in the triple helical domain lacking both propeptides and telopeptides, and expressed these in yeast Pichia pastoris host strain GS115 (his4, Mut + ) simultaneously with recombinant chicken prolyl-4-hydroxylase α and β subunits. Both pC- and pN-procollagen monomers accumulated inside P. pastoris cells, whereas CTE was assembled into homotrimers with stable conformation and secreted into the supernatants, suggesting that the large molecular weight pC-or pN-procollagens were retained within the endoplasmic reticulum whereas the smaller CTEs proceeded through the secretory pathway. Furthermore, resulting recombinant chicken type II collagen pCα1(II) can induced collagen-induced arthritis (CIA) rat model, which seems to be as effective as the current standard nCCII. Notably, protease digestion assays showed that rCCII could assemble in the absence of C- and N-propeptides or telopeptides. These findings provide new insights into the minimal structural requirements for rCCII expression and folding.

  11. Capillary crystallization and molecular-replacement solution of haemoglobin II from the clam Lucina pectinata

    International Nuclear Information System (INIS)

    Gavira, José A.; Jesus, Walleska de; Camara-Artigas, Ana; López-Garriga, Juan; García-Ruiz, Juan M.

    2006-01-01

    The haemoglobin II from the clam L. pectinata has been crystallized using counter-diffusion in single capillary in the presence of agarose to improve crystal quality. Initial phases have been obtained by molecular replacement. Haemoglobin II is one of three haemoglobins present in the cytoplasm of the Lucina pectinata mollusc that inhabits the Caribbean coast. Using HBII purified from its natural source, crystallization screening was performed using the counter-diffusion method with capillaries of 0.2 mm inner diameter. Crystals of HbII suitable for data collection and structure determination were grown in the presence of agarose at 0.1%(w/v) in order to improve their quality. The crystals belong to the tetragonal space group P4 2 2 1 2, with unit-cell parameters a = b = 73.92, c = 152.35 Å, and diffracted X-rays to a resolution of better than 2.0 Å. The asymmetric unit is a homodimer with a corresponding Matthews coefficient (V M ) of 3.15 Å 3 Da −1 and a solvent content of 61% by volume

  12. Molecular organization of the 5S rDNA gene type II in elasmobranchs.

    Science.gov (United States)

    Castro, Sergio I; Hleap, Jose S; Cárdenas, Heiber; Blouin, Christian

    2016-01-01

    The 5S rDNA gene is a non-coding RNA that can be found in 2 copies (type I and type II) in bony and cartilaginous fish. Previous studies have pointed out that type II gene is a paralog derived from type I. We analyzed the molecular organization of 5S rDNA type II in elasmobranchs. Although the structure of the 5S rDNA is supposed to be highly conserved, our results show that the secondary structure in this group possesses some variability and is different than the consensus secondary structure. One of these differences in Selachii is an internal loop at nucleotides 7 and 112. These mutations observed in the transcribed region suggest an independent origin of the gene among Batoids and Selachii. All promoters were highly conserved with the exception of BoxA, possibly due to its affinity to polymerase III. This latter enzyme recognizes a dT4 sequence as stop signal, however in Rajiformes this signal was doubled in length to dT8. This could be an adaptation toward a higher efficiency in the termination process. Our results suggest that there is no TATA box in elasmobranchs in the NTS region. We also provide some evidence suggesting that the complexity of the microsatellites present in the NTS region play an important role in the 5S rRNA gene since it is significantly correlated with the length of the NTS.

  13. Molecular Mechanisms of Cutaneous Inflammatory Disorder: Atopic Dermatitis

    Science.gov (United States)

    Kim, Jung Eun; Kim, Jong Sic; Cho, Dae Ho; Park, Hyun Jeong

    2016-01-01

    Atopic dermatitis (AD) is a multifactorial inflammatory skin disease resulting from interactions between genetic susceptibility and environmental factors. The pathogenesis of AD is poorly understood, and the treatment of recalcitrant AD is still challenging. There is accumulating evidence for new gene polymorphisms related to the epidermal barrier function and innate and adaptive immunity in patients with AD. Newly-found T cells and dendritic cell subsets, cytokines, chemokines and signaling pathways have extended our understanding of the molecular pathomechanism underlying AD. Genetic changes caused by environmental factors have been shown to contribute to the pathogenesis of AD. We herein present a review of the genetics, epigenetics, barrier dysfunction and immunological abnormalities in AD with a focus on updated molecular biology. PMID:27483258

  14. Molecular modeling of polycarbonate materials: Glass transition and mechanical properties

    Science.gov (United States)

    Palczynski, Karol; Wilke, Andreas; Paeschke, Manfred; Dzubiella, Joachim

    2017-09-01

    Linking the experimentally accessible macroscopic properties of thermoplastic polymers to their microscopic static and dynamic properties is a key requirement for targeted material design. Classical molecular dynamics simulations enable us to study the structural and dynamic behavior of molecules on microscopic scales, and statistical physics provides a framework for relating these properties to the macroscopic properties. We take a first step toward creating an automated workflow for the theoretical prediction of thermoplastic material properties by developing an expeditious method for parameterizing a simple yet surprisingly powerful coarse-grained bisphenol-A polycarbonate model which goes beyond previous coarse-grained models and successfully reproduces the thermal expansion behavior, the glass transition temperature as a function of the molecular weight, and several elastic properties.

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

    Czech Academy of Sciences Publication Activity Database

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

    2015-01-01

    Roč. 7, č. 19 (2015), s. 8793-8802 ISSN 2040-3364 R&D Projects: GA ČR(CZ) GAP207/10/2207 Institutional support: RVO:61388963 Keywords : helicene molecular junctions * quantum interference * stereoselective syntheses * nonlinear optical properties Subject RIV: CC - Organic Chemistry Impact factor: 7.760, year: 2015 http://pubs.rsc.org/en/content/articlepdf/2015/nr/c5nr01297j

  16. Molecular and Metabolic Mechanisms of Carbon Sequestration in Marine Thrombolites

    Science.gov (United States)

    Mobberley, Jennifer

    2013-01-01

    The overall goal of my dissertation project has been to examine the molecular processes underlying carbon sequestration in lithifying microbial ecosystems, known as thrombolitic mats, and assess their feasibility for use in bioregenerative life support systems. The results of my research and education efforts funded by the Graduate Student Researchers Program can be summarized in four peer-reviewed research publication, one educational publication, two papers in preparation, and six research presentations at local and national science meetings (see below for specific details).

  17. Effects of ionizing radiation and the molecular and cellular mechanisms

    International Nuclear Information System (INIS)

    1982-01-01

    This symposium with its 60 contributions presents a survey of the current state of the art in molecular radiation biophysics and radiobiology in the FRG. Many contributions show the trend of applying findings in these fields to cancer research. The various sessions have been devoted to: 1) Radiation chemistry of biomolecules; 2) DNA damage and repair; 3) Repair of DNA damage; 4) Cell proliferation and cell inactivation; 5) Cancerogenesis, mutation and chromosomal damage; 6) Effects of heavy ions. (AJ) [de

  18. Mechanical design of EFW Exo II: A hybrid exoskeleton for elbow-forearm-wrist rehabilitation.

    Science.gov (United States)

    Bian, Hui; Chen, Ziye; Wang, Hao; Zhao, Tieshi

    2017-07-01

    The use of rehabilitation exoskeleton has become an important means for the treatment of stroke patients. A hybrid exoskeleton named EFW Exo II is developed for the motor function rehabilitation of elbow, forearm and wrist. The EFW Exo II is based on a parallel 2-URR/RRS mechanism and a serial R mechanism. It could fit both left and right arms for the symmetrical and open structure, and the distance between the elbow and wrist could automatically adjust for different forearm length. Details of the mechanical design are introduced. Brushless DC servo motors with planetary gear reducer are used as the actuators of the exoskeleton. Gear drive and belt drive are used for power transmission. A three dimensional force sensor is mounted in the handle to regulate the interaction between the exoskeleton and patient. The EFW Exo II can realize rehabilitation exercise for each joint and the ranges of motion meet the rehabilitation demands of daily living.

  19. Polarizable Atomic Multipole-based Molecular Mechanics for Organic Molecules.

    Science.gov (United States)

    Ren, Pengyu; Wu, Chuanjie; Ponder, Jay W

    2011-10-11

    An empirical potential based on permanent atomic multipoles and atomic induced dipoles is reported for alkanes, alcohols, amines, sulfides, aldehydes, carboxylic acids, amides, aromatics and other small organic molecules. Permanent atomic multipole moments through quadrupole moments have been derived from gas phase ab initio molecular orbital calculations. The van der Waals parameters are obtained by fitting to gas phase homodimer QM energies and structures, as well as experimental densities and heats of vaporization of neat liquids. As a validation, the hydrogen bonding energies and structures of gas phase heterodimers with water are evaluated using the resulting potential. For 32 homo- and heterodimers, the association energy agrees with ab initio results to within 0.4 kcal/mol. The RMS deviation of hydrogen bond distance from QM optimized geometry is less than 0.06 Å. In addition, liquid self-diffusion and static dielectric constants computed from molecular dynamics simulation are consistent with experimental values. The force field is also used to compute the solvation free energy of 27 compounds not included in the parameterization process, with a RMS error of 0.69 kcal/mol. The results obtained in this study suggest the AMOEBA force field performs well across different environments and phases. The key algorithms involved in the electrostatic model and a protocol for developing parameters are detailed to facilitate extension to additional molecular systems.

  20. The influence of certain molecular descriptors of fecal elimination of angiotensin II receptor antagonists

    Directory of Open Access Journals (Sweden)

    Trbojević-Stanković Jasna B.

    2015-01-01

    Full Text Available Angiotensin II receptor antagonists (ARBs modulate the function of the renin-angiotensin-aldosterone system and are commonly prescribed antihypertensive drugs, especially in patients with renal failure. In this study, the relationship between several molecular properties of seven ARBs (candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan and their fecal elimination data obtained from the literature were investigated. The ARB molecular descriptors were calculated using three software packages. Simple linear regression analysis showed the best 2 correlation between fecal elimination data and lipophilicity descriptor, ClogP values (R2 = 0.725. Multiple linear regression was applied to examine the correlation of ARBs’ fecal elimination data with their lipophilicity and one additional, calculated descriptor. The best correlation (R2 = 0.909 with an acceptable probability value, P <0.05 was established between the ARB fecal elimination data and their lipophilicity and aqueous solubility data. Applying computed molecular descriptors for evaluating drug elimination is of great importance in drug research.

  1. Nucleon molecular orbitals and the transition mechanism between molecular orbitals in nucleus-nucleus collisions

    International Nuclear Information System (INIS)

    Imanishi, B.; Misono, S.; von Oertzen, W.; Voit, H.

    1988-08-01

    The molecular orbitals of the nucleon(s) in nucleus-nucleus collisions are dynamically defined as a linear combination of nucleon single-particle orbits (LCNO) in a rotating frame by using the coupled-reaction-channel (CRC) theory. Nucleon molecular orbitals and the promotions of nucleon, - especially due to the Landau-Zener radial coupling are discussed with the method above mentioned. (author)

  2. Molecular programs induced by heat acclimation confer neuroprotection against TBI and hypoxic insults via cross-tolerance mechanisms

    Directory of Open Access Journals (Sweden)

    Michal eHorowitz

    2015-07-01

    Full Text Available Neuroprotection following prolonged exposure to high ambient temperatures (heat acclimation HA develops via altered molecular programs such as cross-tolerance (Heat Acclimation -Neuroprotection Cross-Tolerance -HANCT. The mechanisms underlying cross-tolerance depend on enhanced on-demand protective pathways evolving during acclimation. The protection achieved is long lasting and limits the need for de novo recruitment of cytoprotective pathways upon exposure to novel stressors. Using mouse and rat acclimated phenotypes, we will focus on the impact of heat acclimation on Angiotensin II-AT2 receptors in neurogenesis and on HIF-1 as key mediators in spontaneous recovery and HANCT after traumatic brain injury (TBI. The neuroprotective consequences of heat acclimation on NMDA and AMPA receptors will be discussed using the global hypoxia model. A behavioral-molecular link will be crystallized. The differences between HANCT and consensus preconditioning will be reviewed.

  3. [Adsorption kinetics and mechanism of lead (II) on polyamine-functionalized mesoporous activated carbon].

    Science.gov (United States)

    Li, Kun-Quan; Wang, Yan-Jin; Yang, Mei-Rong; Zhu, Zhi-Qiang; Zheng, Zheng

    2014-08-01

    Bagasse mesoporous carbon was prepared by microwave assisted H3 PO4 activation. Amido and imido groups were modified with ethanediamine on the channels' surface of mesoporous carbon through nitric oxidation and amide reaction. The influence of Pb(II) concentration, adsorption time on Pb(II) adsorption on the ethanediamine-modified mesoporous carbon (AC-EDA) was investigated. The adsorption kinetics and mechanism were also discussed. The results showed that AC-EDA had a great performance for Pb(II) adsorption, and more than 70% of Pb(II) was adsorbed in 5 minutes. The adsorption amount of Pb(II) on the carbon increased with the increase of solution pH in acidic conditions. It was found that AC-EDA had different binding energies on different adsorption sites for Pb(II) separation. The Pb(II) adsorption process on AC-EDA was controlled by intra-particle diffusion in the first 3 min, and then film diffusion played the important pole on the adsorption. The adsorption amount increased with the increase of temperature, indicating the adsorption was an endothermic reaction. The high adsorption energy (> 11 kJ x mol(-1)) implied that the) adsorption was a chemical adsorption. The XPS of AC-EDA before and after Pb(II) adsorption showed that the polyamine group was involved in the adsorption, and should be a main factor of the high efficient adsorption.

  4. Quantum Mechanics and Molecular Mechanics Study of the Catalytic Mechanism of Human AMSH-LP Domain Deubiquitinating Enzymes.

    Science.gov (United States)

    Zhu, Wenyou; Liu, Yongjun; Ling, Baoping

    2015-08-25

    Deubiquitinating enzymes (DUBs) catalyze the cleavage of the isopeptide bond in polyubiquitin chains to control and regulate the deubiquitination process in all known eukaryotic cells. The human AMSH-LP DUB domain specifically cleaves the isopeptide bonds in the Lys63-linked polyubiquitin chains. In this article, the catalytic mechanism of AMSH-LP has been studied using a combined quantum mechanics and molecular mechanics method. Two possible hydrolysis processes (Path 1 and Path 2) have been considered. Our calculation results reveal that the activation of Zn(2+)-coordinated water molecule is the essential step for the hydrolysis of isopeptide bond. In Path 1, the generated hydroxyl first attacks the carbonyl group of Gly76, and then the amino group of Lys63 is protonated, which is calculated to be the rate limiting step with an energy barrier of 13.1 kcal/mol. The energy barrier of the rate limiting step and the structures of intermediate and product are in agreement with the experimental results. In Path 2, the protonation of amino group of Lys63 is prior to the nucleophilic attack of activated hydroxyl. The two proton transfer processes in Path 2 correspond to comparable overall barriers (33.4 and 36.1 kcal/mol), which are very high for an enzymatic reaction. Thus, Path 2 can be ruled out. During the reaction, Glu292 acts as a proton transfer mediator, and Ser357 mainly plays a role in stabilizing the negative charge of Gly76. Besides acting as a Lewis acid, Zn(2+) also influences the reaction by coordinating to the reaction substrates (W1 and Gly76).

  5. THE SECOND SURVEY OF THE MOLECULAR CLOUDS IN THE LARGE MAGELLANIC CLOUD BY NANTEN. II. STAR FORMATION

    International Nuclear Information System (INIS)

    Kawamura, Akiko; Mizuno, Yoji; Minamidani, Tetsuhiro; Mizuno, Norikazu; Onishi, Toshikazu; Fukui, Yasuo; Fillipovic, Miroslav D.; Staveley-Smith, Lister; Kim, Sungeun; Mizuno, Akira

    2009-01-01

    We studied star formation activities in the molecular clouds in the Large Magellanic Cloud. We have utilized the second catalog of 272 molecular clouds obtained by NANTEN to compare the cloud distribution with signatures of massive star formation including stellar clusters, and optical and radio H II regions. We find that the molecular clouds are classified into three types according to the activities of massive star formation: Type I shows no signature of massive star formation; Type II is associated with relatively small H II region(s); and Type III with both H II region(s) and young stellar cluster(s). The radio continuum sources were used to confirm that Type I giant molecular clouds (GMCs) do not host optically hidden H II regions. These signatures of massive star formation show a good spatial correlation with the molecular clouds in the sense that they are located within ∼100 pc of the molecular clouds. Among possible ideas to explain the GMC types, we favor that the types indicate an evolutionary sequence; i.e., the youngest phase is Type I, followed by Type II, and the last phase is Type III, where the most active star formation takes place leading to cloud dispersal. The number of the three types of GMCs should be proportional to the timescale of each evolutionary stage if a steady state of massive star and cluster formation is a good approximation. By adopting the timescale of the youngest stellar clusters, 10 Myr, we roughly estimate the timescales of Types I, II, and III to be 6 Myr, 13 Myr, and 7 Myr, respectively, corresponding to a lifetime of 20-30 Myr for the GMCs with a mass above the completeness limit, 5 x 10 4 M sun .

  6. Molecular mechanism of crystallization impacting calcium phosphate cements

    Energy Technology Data Exchange (ETDEWEB)

    Giocondi, J L; El-Dasher, B S; Nancollas, G H; Orme, C A

    2009-05-31

    In summary, SPM data has shown that (1) Mg inhibits growth on all steps but relatively high Mg/Ca ratios are needed. Extracting the mechanism of interaction requires more modeling of the kinetic data, but step morphology is consistent with incorporation. (2) Citrate has several effects depending on the citrate/Ca ratio. At the lowest concentrations, citrate increases the step free energy without altering the step kinetics; at higher concentrations, the polar step is slowed. (3) Oxalate also slows the polar step but additionally stabilizes a new facet, with a [100]{sub Cc} step. (4) Etidronate has the greatest kinetic impact of the molecules studied. At 7{micro}M concentrations, the polar step slows by 60% and a new polar step appears. However, at the same time the [10-1]{sub Cc} increases by 67%. It should be noted that all of these molecules complex calcium and can effect kinetics by altering the solution supersaturation or the Ca to HPO{sub 4}{sup 2-} ratio. For the SPM data shown, this effect was corrected for to distinguish the effect of the molecule at the crystal surface from the effect of the molecule on the solution speciation. The goal of this paper is to draw connections between fundamental studies of atomic step motion and potential strategies for materials processing. It is not our intent to promote the utility of SPM for investigating processes in cement dynamics. The conditions are spectacularly different in many ways. The data shown in this paper are fairly close to equilibrium (S=1.6) whereas the nucleation of cements is initiated at supersaturation ratios in the thousands to millions. Of course, after the initial nucleation phase, the growth will occur at more modest supersaturations and as the cement evolves towards equilibrium certainly some of the growth will occur in regimes such as shown here. In addition to the difference in supersaturation, cements tend to have lower additive to calcium ratios. As an example, the additive to Ca ratio is

  7. Molecular mechanisms of plant competition: neighbour detection and response strategies

    NARCIS (Netherlands)

    Pierik, R.; Mommer, L.; Voesenek, L.A.C.J.

    2013-01-01

    Plant competition determines the diversity and species abundance of natural communities as well as potential yields in agricultural systems. Understanding the mechanisms of plant competition is instrumental to understanding plant performance in true vegetations. In this review, we will address

  8. Molecular Mechanisms of Insulin Secretion and Insulin Action.

    Science.gov (United States)

    Flatt, Peter R.; Bailey, Clifford J.

    1991-01-01

    Information and current ideas on the factors regulating insulin secretion, the mechanisms underlying the secretion and biological actions of insulin, and the main characteristics of diabetes mellitus are presented. (Author)

  9. Analyzing the molecular mechanism of lipoprotein localization in Brucella

    CSIR Research Space (South Africa)

    Goolab, S

    2015-10-01

    Full Text Available doi: 10.3389/fmicb.2015.01189 Edited by: Lee Mark Wetzler, Boston University School of Medicine, USA Reviewed by: Moriya Tsuji, Aaron Diamond AIDS Research Center, USA Thomas A. Ficht, Texas A&M University, USA *Correspondence: Shivani Goolab...-associated lipoproteins; POTRA, polypeptide-transport-associated; PRR, pattern-recognition receptors; RGD, Arg- Gly- Asp; Sec, system, general secretory; Tat system, twin-arginine translocation; T1SS, type I secretion system; T2SS, type II secretion system; T3SS, type III...

  10. Molecular Mechanisms of Inhibition of Streptococcus Species by Phytochemicals

    Directory of Open Access Journals (Sweden)

    Soheila Abachi

    2016-02-01

    Full Text Available This review paper summarizes the antibacterial effects of phytochemicals of various medicinal plants against pathogenic and cariogenic streptococcal species. The information suggests that these phytochemicals have potential as alternatives to the classical antibiotics currently used for the treatment of streptococcal infections. The phytochemicals demonstrate direct bactericidal or bacteriostatic effects, such as: (i prevention of bacterial adherence to mucosal surfaces of the pharynx, skin, and teeth surface; (ii inhibition of glycolytic enzymes and pH drop; (iii reduction of biofilm and plaque formation; and (iv cell surface hydrophobicity. Collectively, findings from numerous studies suggest that phytochemicals could be used as drugs for elimination of infections with minimal side effects.

  11. Examining the mechanical equilibrium of microscopic stresses in molecular simulations

    OpenAIRE

    Torres Sánchez, Alejandro; Vanegas, Juan Manuel; Arroyo Balaguer, Marino

    2015-01-01

    The microscopic stress field provides a unique connection between atomistic simulations and mechanics at the nanoscale. However, its definition remains ambiguous. Rather than a mere theoretical preoccupation, we show that this fact acutely manifests itself in local stress calculations of defective graphene, lipid bilayers, and fibrous proteins. We find that popular definitions of the microscopic stress violate the continuum statements of mechanical equilibrium, and we propose an unambiguous a...

  12. Radiation transport in dense interstellar dust clouds. II. Infrared emission from molecular clouds associated with H II regions

    International Nuclear Information System (INIS)

    Leung, C.M.

    1976-01-01

    Theoretical models are constructed to study the distribution of grain temperature (T/sub d/) and infrared emission from molecular clouds associated with H II regions (with embedded O: B stars). The effects of the following parameters on the temperature structure and the emergent spectrum are studied: grain type (graphite, silicate, and core-mantle grains), optical depth, density inhomogeneity, cloud size, anisotropic scattering, radiation field anisotropy, and characteristics of central heat source. T/sub d/ varies from approximately-greater-than100 K to approximately-less-than20 K throughout the major portion of a cloud, and dielectric grains attain lower temperatures. Due to an inward increase in T/sub d/, the radiation field is strongly forward-peaking, thereby producing a pronounced limb-darkening in the surface brightness. Important features of the computed emission spectra from typical models are compared with available observations, and the importance of beam dilution is emphasized. Theoretical surface brightnesses at selected infrared wavelengths are also presented. The outward radiation pressure on the dust grains is found to exceed the self-gravitational force of the gas over a large portion of a cloud, thus possibly causing the gas in the inner region to expand. Assumptions commonly used in the analysis of infrared observations are examined. Finally, observational methods of deriving the temperature structure (from color and brightness temperatures in the far-infrared), density distribution (from surface brightness at lambdaapproximately-greater-than1 mm), and optical depth (from multiaperture photometry) for the dust component in simple sources are discussed

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

    NARCIS (Netherlands)

    Denning, Denise; Roos, Wouter H

    2016-01-01

    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

  14. Molecular water oxidation mechanisms followed by transition metals: state of the art.

    Science.gov (United States)

    Sala, Xavier; Maji, Somnath; Bofill, Roger; García-Antón, Jordi; Escriche, Lluís; Llobet, Antoni

    2014-02-18

    One clean alternative to fossil fuels would be to split water using sunlight. However, to achieve this goal, researchers still need to fully understand and control several key chemical reactions. One of them is the catalytic oxidation of water to molecular oxygen, which also occurs at the oxygen evolving center of photosystem II in green plants and algae. Despite its importance for biology and renewable energy, the mechanism of this reaction is not fully understood. Transition metal water oxidation catalysts in homogeneous media offer a superb platform for researchers to investigate and extract the crucial information to describe the different steps involved in this complex reaction accurately. The mechanistic information extracted at a molecular level allows researchers to understand both the factors that govern this reaction and the ones that derail the system to cause decomposition. As a result, rugged and efficient water oxidation catalysts with potential technological applications can be developed. In this Account, we discuss the current mechanistic understanding of the water oxidation reaction catalyzed by transition metals in the homogeneous phase, based on work developed in our laboratories and complemented by research from other groups. Rather than reviewing all of the catalysts described to date, we focus systematically on the several key elements and their rationale from molecules studied in homogeneous media. We organize these catalysts based on how the crucial oxygen-oxygen bond step takes place, whether via a water nucleophilic attack or via the interaction of two M-O units, rather than based on the nuclearity of the water oxidation catalysts. Furthermore we have used DFT methodology to characterize key intermediates and transition states. The combination of both theory and experiments has allowed us to get a complete view of the water oxidation cycle for the different catalysts studied. Finally, we also describe the various deactivation pathways for

  15. Genetic factors and molecular mechanisms in dry eye disease.

    Science.gov (United States)

    Lee, Ling; Garrett, Qian; Flanagan, Judith; Chakrabarti, Subhabrata; Papas, Eric

    2018-04-01

    Dry eye disease (DED) is a complex condition with a multifactorial etiology that can be difficult to manage successfully. While external factors are modifiable, treatment success is limited if genetic factors contribute to the disease. The purpose of this review is to compile research describing normal and abnormal ocular surface function on a molecular level, appraise genetic studies involving DED or DED-associated diseases, and introduce the basic methods used for conducting genetic epidemiology studies. Copyright © 2018 Elsevier Inc. All rights reserved.

  16. Stability mechanisms of a thermophilic laccase probed by molecular dynamics

    DEFF Research Database (Denmark)

    Christensen, Niels Johan; Kepp, Kasper Planeta

    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...... 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....

  17. Nuclear Magnetic Shielding Constants from Quantum Mechanical/Molecular Mechanical Calculations Using Polarizable Embedding: Role of the Embedding Potential

    DEFF Research Database (Denmark)

    Steinmann, Casper; Olsen, Jógvan Magnus Haugaard; Kongsted, Jacob

    2014-01-01

    We present NMR shielding constants obtained through quantum mechanical/molecular mechanical (QM/MM) embedding calculations. Contrary to previous reports, we show that a relatively small QM region is sufficient, provided that a high-quality embedding potential is used. The calculated averaged NMR...... shielding constants of both acrolein and acetone solvated in water are based on a number of snapshots extracted from classical molecular dynamics simulations. We focus on the carbonyl chromophore in both molecules, which shows large solvation effects, and we study the convergence of shielding constants...

  18. Cytological, molecular mechanisms and temperature stress regulating production of diploid male gametes in Dianthus caryophyllus L.

    Science.gov (United States)

    Zhou, Xuhong; Mo, Xijun; Gui, Min; Wu, Xuewei; Jiang, Yalian; Ma, Lulin; Shi, Ziming; Luo, Ying; Tang, Wenru

    2015-12-01

    In plant evolution, because of its key role in sexual polyploidization or whole genome duplication events, diploid gamete formation is considered as an important component in diversification and speciation. Environmental stress often triggers unreduced gamete production. However, the molecular, cellular mechanisms and adverse temperature regulating diplogamete production in carnation remain poorly understood. Here, we investigate the cytological basis for 2n male gamete formation and describe the isolation and characterization of the first gene, DcPS1 (Dianthus Caryophyllus Parallel Spindle 1). In addition, we analyze influence of temperature stress on diploid gamete formation and transcript levels of DcPS1. Cytological evidence indicated that 2n male gamete formation is attributable to abnormal spindle orientation at male meiosis II. DcPS1 protein is conserved throughout the plant kingdom and carries domains suggestive of a regulatory function. DcPS1 expression analysis show DcPS1 gene probably have a role in 2n pollen formation. Unreduced pollen formation in various cultivation was sensitive to high or low temperature which was probably regulated by the level of DcPS1 transcripts. In a broader perspective, these findings can have potential applications in fundamental polyploidization research and plant breeding programs. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  19. Prediction of Sliding Friction Coefficient Based on a Novel Hybrid Molecular-Mechanical Model.

    Science.gov (United States)

    Zhang, Xiaogang; Zhang, Yali; Wang, Jianmei; Sheng, Chenxing; Li, Zhixiong

    2018-08-01

    Sliding friction is a complex phenomenon which arises from the mechanical and molecular interactions of asperities when examined in a microscale. To reveal and further understand the effects of micro scaled mechanical and molecular components of friction coefficient on overall frictional behavior, a hybrid molecular-mechanical model is developed to investigate the effects of main factors, including different loads and surface roughness values, on the sliding friction coefficient in a boundary lubrication condition. Numerical modelling was conducted using a deterministic contact model and based on the molecular-mechanical theory of friction. In the contact model, with given external loads and surface topographies, the pressure distribution, real contact area, and elastic/plastic deformation of each single asperity contact were calculated. Then asperity friction coefficient was predicted by the sum of mechanical and molecular components of friction coefficient. The mechanical component was mainly determined by the contact width and elastic/plastic deformation, and the molecular component was estimated as a function of the contact area and interfacial shear stress. Numerical results were compared with experimental results and a good agreement was obtained. The model was then used to predict friction coefficients in different operating and surface conditions. Numerical results explain why applied load has a minimum effect on the friction coefficients. They also provide insight into the effect of surface roughness on the mechanical and molecular components of friction coefficients. It is revealed that the mechanical component dominates the friction coefficient when the surface roughness is large (Rq > 0.2 μm), while the friction coefficient is mainly determined by the molecular component when the surface is relatively smooth (Rq < 0.2 μm). Furthermore, optimal roughness values for minimizing the friction coefficient are recommended.

  20. Molecular mechanisms of the sleep wake cycle : therapeutic applications to insomnia

    OpenAIRE

    Grima, Melanie; Hunter, Therese; Zhang, Yimeng

    2017-01-01

    The aim of this review is to explore the molecular mechanism and genetic components of the sleepwake cycle and insomnia. Moreover, we wanted to review the correlation between primary insomnia and its comorbidities. With this aim, a systematic review of recent evidence of the molecular and genetic mechanisms involved in the causation of primary insomnia, along with associations between primary insomnia and other diseases were conducted. Primary insomnia is a complex disorder which accounts for...

  1. Molecular mechanics work station for protein conformational studies

    International Nuclear Information System (INIS)

    Fine, R.; Levinthal, C.; Schoenborn, B.; Dimmier, G.; Rankowitz, C.

    1984-01-01

    Interest in computational problems in Biology has intensified over the last few years, partly due to the development of techniques for the rapid cloning, sequencing, and mutagenesis of genes from organisims ranging from E. coli to Man. The central dogma of molecular biology; that DNA codes for mRNA which codes for protein, has been understood in a linear programming sense since the genetic code was cracked. But what is not understood at present is how a protein, once assembled as a long sequence of amino acids, folds back on itself to produce a three-dimensional structure which is unique to that protein and which dictates its chemical and biological activity. This folding process is purely physics, and involves the time evolution of a system of several thousand atoms which interact with each other and with atoms from the surrounding solvent. Molecular dynamics simulations on smaller molecules suggest that approaches which treat the protein as a classical ensemble of atoms interacting with each other via an empirical Hamiltonian can yield the kind of predictive results one would like when applied to proteins

  2. Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects.

    Science.gov (United States)

    Sun, Wei-Lun; Quizon, Pamela M; Zhu, Jun

    2016-01-01

    Addiction to psychostimulants has been considered as a chronic psychiatric disorder characterized by craving and compulsive drug seeking and use. Over the past two decades, accumulating evidence has demonstrated that repeated drug exposure causes long-lasting neurochemical and cellular changes that result in enduring neuroadaptation in brain circuitry and underlie compulsive drug consumption and relapse. Through intercellular signaling cascades, drugs of abuse induce remodeling in the rewarding circuitry that contributes to the neuroplasticity of learning and memory associated with addiction. Here, we review the role of the extracellular signal-regulated kinase (ERK), a member of the mitogen-activated protein kinase, and its related intracellular signaling pathways in drug-induced neuroadaptive changes that are associated with drug-mediated psychomotor activity, rewarding properties and relapse of drug seeking behaviors. We also discuss the neurobiological and behavioral effects of pharmacological and genetic interferences with ERK-associated molecular cascades in response to abused substances. Understanding the dynamic modulation of ERK signaling in response to drugs may provide novel molecular targets for therapeutic strategies to drug addiction. Copyright © 2016. Published by Elsevier Inc.

  3. Molecular Mechanisms Modulating the Phenotype of Macrophages and Microglia

    Directory of Open Access Journals (Sweden)

    Stephanie A. Amici

    2017-11-01

    Full Text Available Macrophages and microglia play crucial roles during central nervous system development, homeostasis and acute events such as infection or injury. The diverse functions of tissue macrophages and microglia are mirrored by equally diverse phenotypes. A model of inflammatory/M1 versus a resolution phase/M2 macrophages has been widely used. However, the complexity of macrophage function can only be achieved by the existence of varied, plastic and tridimensional macrophage phenotypes. Understanding how tissue macrophages integrate environmental signals via molecular programs to define pathogen/injury inflammatory responses provides an opportunity to better understand the multilayered nature of macrophages, as well as target and modulate cellular programs to control excessive inflammation. This is particularly important in MS and other neuroinflammatory diseases, where chronic inflammatory macrophage and microglial responses may contribute to pathology. Here, we perform a comprehensive review of our current understanding of how molecular pathways modulate tissue macrophage phenotype, covering both classic pathways and the emerging role of microRNAs, receptor-tyrosine kinases and metabolism in macrophage phenotype. In addition, we discuss pathway parallels in microglia, novel markers helpful in the identification of peripheral macrophages versus microglia and markers linked to their phenotype.

  4. Molecular mechanisms involved in Bacillus subtilis biofilm formation

    Science.gov (United States)

    Mielich-Süss, Benjamin; Lopez, Daniel

    2014-01-01

    Summary Biofilms are the predominant lifestyle of bacteria in natural environments, and they severely impact our societies in many different fashions. Therefore, biofilm formation is a topic of growing interest in microbiology, and different bacterial models are currently studied to better understand the molecular strategies that bacteria undergo to build biofilms. Among those, biofilms of the soil-dwelling bacterium Bacillus subtilis are commonly used for this purpose. Bacillus subtilis biofilms show remarkable architectural features that are a consequence of sophisticated programs of cellular specialization and cell-cell communication within the community. Many laboratories are trying to unravel the biological role of the morphological features of biofilms, as well as exploring the molecular basis underlying cellular differentiation. In this review, we present a general perspective of the current state of knowledge of biofilm formation in B. subtilis. In particular, a special emphasis is placed on summarizing the most recent discoveries in the field and integrating them into the general view of these truly sophisticated microbial communities. PMID:24909922

  5. Evidence for systems-level molecular mechanisms of tumorigenesis

    Directory of Open Access Journals (Sweden)

    Capellá Gabriel

    2007-06-01

    Full Text Available Abstract Background Cancer arises from the consecutive acquisition of genetic alterations. Increasing evidence suggests that as a consequence of these alterations, molecular interactions are reprogrammed in the context of highly connected and regulated cellular networks. Coordinated reprogramming would allow the cell to acquire the capabilities for malignant growth. Results Here, we determine the coordinated function of cancer gene products (i.e., proteins encoded by differentially expressed genes in tumors relative to healthy tissue counterparts, hereafter referred to as "CGPs" defined as their topological properties and organization in the interactome network. We show that CGPs are central to information exchange and propagation and that they are specifically organized to promote tumorigenesis. Centrality is identified by both local (degree and global (betweenness and closeness measures, and systematically appears in down-regulated CGPs. Up-regulated CGPs do not consistently exhibit centrality, but both types of cancer products determine the overall integrity of the network structure. In addition to centrality, down-regulated CGPs show topological association that correlates with common biological processes and pathways involved in tumorigenesis. Conclusion Given the current limited coverage of the human interactome, this study proposes that tumorigenesis takes place in a specific and organized way at the molecular systems-level and suggests a model that comprises the precise down-regulation of groups of topologically-associated proteins involved in particular functions, orchestrated with the up-regulation of specific proteins.

  6. Molecular mechanics of DNA bricks: in situ structure, mechanical properties and ionic conductivity

    International Nuclear Information System (INIS)

    Slone, Scott Michael; Li, Chen-Yu; Aksimentiev, Aleksei; Yoo, Jejoong

    2016-01-01

    The DNA bricks method exploits self-assembly of short DNA fragments to produce custom three-dimensional objects with subnanometer precision. In contrast to DNA origami, the DNA brick method permits a variety of different structures to be realized using the same library of DNA strands. As a consequence of their design, however, assembled DNA brick structures have fewer interhelical connections in comparison to equivalent DNA origami structures. Although the overall shape of the DNA brick objects has been characterized and found to conform to the features of the target designs, the microscopic properties of DNA brick objects remain yet to be determined. Here, we use the all-atom molecular dynamics method to directly compare the structure, mechanical properties and ionic conductivity of DNA brick and DNA origami structures different only by internal connectivity of their consistituent DNA strands. In comparison to equivalent DNA origami structures, the DNA brick structures are found to be less rigid and less dense and have a larger cross-section area normal to the DNA helix direction. At the microscopic level, the junction in the DNA brick structures are found to be right-handed, similar to the structure of individual Holliday junctions (HJ) in solution, which contrasts with the left-handed structure of HJ in DNA origami. Subject to external electric field, a DNA brick plate is more leaky to ions than an equivalent DNA origami plate because of its lower density and larger cross-section area. Overall, our results indicate that the structures produced by the DNA brick method are fairly similar in their overall appearance to those created by the DNA origami method but are more compliant when subject to external forces, which likely is a consequence of their single crossover design. (paper)

  7. DMPD: Molecular mechanisms of macrophage activation and deactivation bylipopolysaccharide: roles of the receptor complex. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 14609719 Molecular mechanisms of macrophage activation and deactivation bylipopolys...acol Ther. 2003 Nov;100(2):171-94. (.png) (.svg) (.html) (.csml) Show Molecular mechanisms of macrophage act...medID 14609719 Title Molecular mechanisms of macrophage activation and deactivation bylipopolysaccharide: ro

  8. Cellular and Molecular Mechanisms in Vascular Smooth Muscle Cells by which Total Saponin Extracted from Tribulus Terrestris Protects Against Artherosclerosis

    Directory of Open Access Journals (Sweden)

    Mengquan Li

    2013-11-01

    Full Text Available Background/Aims: Total saponin extracted from Tribulus terrestris (TSETT has been reported to protect against atherosclerosis. We here investigate the cellular and molecular mechanisms of TSETT underlying protection against atherosclerosis. Methods: Cell proliferation was measured with Methyl thiazolyl tetrazolium (MTT; Intracellular H2O2 was measured with DCFH-DA, a fluorescent dye; Intracellular free Ca2+ was measured with a confocal laser scanning microscopy; Genes expression was measured with gene array and real-time quantitative polymerase chain reaction (RT-PCR; Phosphorylation of extracellular signal-regulated kinase 1/2 (phospho-ERK1/2 was measured with cell-based enzyme-linked immunosorbent assay (ELISA and western blotting. Results: TSETT significantly suppressed the increase in cells proliferation induced by angiotensin II, significantly suppressed the increase in the intracellular production of H2O2 induced by angiotensin II, significantly inhibited the increase in intracellular free Ca2+ induced by H2O2, significantly inhibited the increase in phospho-ERK1/2 induced by angiotensin II; significantly inhibited the increase in mRNA expression of c-fos, c-jun and pkc-α induced by angiotensin II. Conclusion: These findings provide a new insight into the antiatherosclerotic properties of TSETT and provide a pharmacological basis for the clinical application of TSETT in anti-atherosclerosis.

  9. Cellular and molecular mechanisms in vascular smooth muscle cells by which total saponin extracted from Tribulus terrestris protects against artherosclerosis.

    Science.gov (United States)

    Li, Mengquan; Guan, Yue; Liu, Jiaqi; Zhai, Fengguo; Zhang, Xiuping; Guan, Lixin

    2013-01-01

    Total saponin extracted from Tribulus terrestris (TSETT) has been reported to protect against atherosclerosis. We here investigate the cellular and molecular mechanisms of TSETT underlying protection against atherosclerosis. Cell proliferation was measured with Methyl thiazolyl tetrazolium (MTT); Intracellular H2O2 was measured with DCFH-DA, a fluorescent dye; Intracellular free Ca(2+) was measured with a confocal laser scanning microscopy; Genes expression was measured with gene array and real-time quantitative polymerase chain reaction (RT-PCR); Phosphorylation of extracellular signal-regulated kinase 1/2 (phospho-ERK1/2) was measured with cell-based enzyme-linked immunosorbent assay (ELISA) and western blotting. TSETT significantly suppressed the increase in cells proliferation induced by angiotensin II, significantly suppressed the increase in the intracellular production of H2O2 induced by angiotensin II, significantly inhibited the increase in intracellular free Ca(2+) induced by H2O2, significantly inhibited the increase in phospho-ERK1/2 induced by angiotensin II; significantly inhibited the increase in mRNA expression of c-fos, c-jun and pkc-α induced by angiotensin II. These findings provide a new insight into the antiatherosclerotic properties of TSETT and provide a pharmacological basis for the clinical application of TSETT in anti-atherosclerosis. © 2013 S. Karger AG, Basel.

  10. Molecular Mechanisms of Disease Pathogenesis Differ in Krabbe Disease Variants

    DEFF Research Database (Denmark)

    Spratley, Samantha J; Hill, Chris H; Viuff, Agnete H

    2016-01-01

    different mutations have been identified in GALC that cause Krabbe disease but the mechanisms by which they cause disease remain unclear. We have generated monoclonal antibodies against full-length human GALC and used these to monitor the trafficking and processing of GALC variants in cell-based assays...

  11. Molecular mechanisms of toxicity of important food-borne phytotoxins

    NARCIS (Netherlands)

    Rietjens, I.M.C.M.; Martena, M.J.; Boersma, M.G.; Spiegelenberg, W.; Alink, G.M.

    2005-01-01

    At present, there is an increasing interest for plant ingredients and their use in drugs, for teas, or in food supplements. The present review describes the nature and mechanism of action of the phytochemicals presently receiving increased attention in the field of food toxicology. This relates to

  12. Molecular Mechanisms Linking Exercise to Cancer Prevention and Treatment

    DEFF Research Database (Denmark)

    Hojman, Pernille; Gehl, Julie; Christensen, Jesper F.

    2018-01-01

    The benefits of exercise training for cancer patients are becoming increasingly evident. Physical exercise has been shown to reduce cancer incidence and inhibit tumor growth. Here we provide the status of the current molecular understanding of the effect of exercise on cancer. We propose...... that exercise has a role in controlling cancer progression through a direct effect on tumor-intrinsic factors, interplay with whole-body exercise effects, alleviation of cancer-related adverse events, and improvement of anti-cancer treatment efficacy. These findings have wide-ranging societal implications......, as this understanding may lead to changes in cancer treatment strategies. Hojman et al. discuss the role of exercise in controlling cancer progression through direct effects on tumor-intrinsic factors, interplay with whole-body exercise effects, alleviation of cancer-related adverse events, and improvement of cancer...

  13. Molecular mechanism of sarcopenia and cachexia: recent research advances.

    Science.gov (United States)

    Sakuma, Kunihiro; Aoi, Wataru; Yamaguchi, Akihiko

    2017-06-01

    Skeletal muscle provides a fundamental basis for human function, enabling locomotion and respiration. Muscle loss occurs as a consequence of several chronic diseases (cachexia) and normal aging (sarcopenia). Although many negative regulators (atrogin-1, muscle ring finger-1, nuclear factor-kappaB (NF-κB), myostatin, etc.) have been proposed to enhance protein degradation during both sarcopenia and cachexia, the adaptation of these mediators markedly differs within both conditions. Sarcopenia and cachectic muscles have been demonstrated to be abundant in myostatin-linked molecules. The ubiquitin-proteasome system (UPS) is activated during rapid atrophy model (cancer cachexia), but few mediators of the UPS change during sarcopenia. NF-κB signaling is activated in cachectic, but not in sarcopenic, muscle. Recent studies have indicated the age-related defect of autophagy signaling in skeletal muscle, whereas autophagic activation occurs in cachectic muscle. This review provides recent research advances dealing with molecular mediators modulating muscle mass in both sarcopenia and cachexia.

  14. Nucleocytoplasmic Shuttling of Cytoskeletal Proteins: Molecular Mechanism and Biological Significance

    Directory of Open Access Journals (Sweden)

    Masahiro Kumeta

    2012-01-01

    Full Text Available Various nuclear functional complexes contain cytoskeletal proteins as regulatory subunits; for example, nuclear actin participates in transcriptional complexes, and actin-related proteins are integral to chromatin remodeling complexes. Nuclear complexes such as these are involved in both basal and adaptive nuclear functions. In addition to nuclear import via classical nuclear transport pathways or passive diffusion, some large cytoskeletal proteins spontaneously migrate into the nucleus in a karyopherin-independent manner. The balance of nucleocytoplasmic distribution of such proteins can be altered by several factors, such as import versus export, or capture and release by complexes. The resulting accumulation or depletion of the nuclear populations thereby enhances or attenuates their nuclear functions. We propose that such molecular dynamics constitute a form of cytoskeleton-modulated regulation of nuclear functions which is mediated by the translocation of cytoskeletal components in and out of the nucleus.

  15. Regulation of Caenorhabditis elegans vitellogenesis by DAF-2/IIS through separable transcriptional and posttranscriptional mechanisms.

    Science.gov (United States)

    DePina, Ana S; Iser, Wendy B; Park, Sung-Soo; Maudsley, Stuart; Wilson, Mark A; Wolkow, Catherine A

    2011-07-12

    Evolutionary theories of aging propose that longevity evolves as a competition between reproduction and somatic maintenance for a finite pool of resources. Reproduction is thought to shorten lifespan by depleting resources from processes promoting somatic maintenance. Maternal yolk production, vitellogenesis, represents a significant maternal cost for reproduction and is suppressed under genetic and environmental conditions that extend lifespan. However, little is known about the pathways regulating vitellogenesis in response to prolongevity cues. In order to identify mechanisms that suppress vitellogenesis under prolongevity conditions, we studied factors regulating vitellogenesis in C. elegans nematodes. In C. elegans, vitellogenesis is depressed in the absence of insulin-like signaling (IIS). We found that the C. elegans daf-2/IIS pathway regulates vitellogenesis through two mechanisms. vit-2 transcript levels in daf-2 mutants were indirectly regulated through a germline-dependent signal, and could be rescued by introduction of daf-2(+) sperm. However, yolk protein (YP) levels in daf-2 mutants were also regulated by germline-independent posttranscriptional mechanisms. C. elegans vitellogenesis is regulated transcriptionally and posttranscriptionally in response to environmental and reproductive cues. The daf-2 pathway suppressed vitellogenesis through transcriptional mechanisms reflecting reproductive phenotypes, as well as distinct posttranscriptional mechanisms. This study reveals that pleiotropic effects of IIS pathway mutations can converge on a common downstream target, vitellogenesis, as a mechanism to modulate longevity.

  16. Regulation of Caenorhabditis elegans vitellogenesis by DAF-2/IIS through separable transcriptional and posttranscriptional mechanisms

    Directory of Open Access Journals (Sweden)

    Wilson Mark A

    2011-07-01

    Full Text Available Abstract Background Evolutionary theories of aging propose that longevity evolves as a competition between reproduction and somatic maintenance for a finite pool of resources. Reproduction is thought to shorten lifespan by depleting resources from processes promoting somatic maintenance. Maternal yolk production, vitellogenesis, represents a significant maternal cost for reproduction and is suppressed under genetic and environmental conditions that extend lifespan. However, little is known about the pathways regulating vitellogenesis in response to prolongevity cues. Results In order to identify mechanisms that suppress vitellogenesis under prolongevity conditions, we studied factors regulating vitellogenesis in C. elegans nematodes. In C. elegans, vitellogenesis is depressed in the absence of insulin-like signaling (IIS. We found that the C. elegans daf-2/IIS pathway regulates vitellogenesis through two mechanisms. vit-2 transcript levels in daf-2 mutants were indirectly regulated through a germline-dependent signal, and could be rescued by introduction of daf-2(+ sperm. However, yolk protein (YP levels in daf-2 mutants were also regulated by germline-independent posttranscriptional mechanisms. Conclusions C. elegans vitellogenesis is regulated transcriptionally and posttranscriptionally in response to environmental and reproductive cues. The daf-2 pathway suppressed vitellogenesis through transcriptional mechanisms reflecting reproductive phenotypes, as well as distinct posttranscriptional mechanisms. This study reveals that pleiotropic effects of IIS pathway mutations can converge on a common downstream target, vitellogenesis, as a mechanism to modulate longevity.

  17. The molecular environment of the pillar-like features in the H II region G46.5-0.2

    Science.gov (United States)

    Paron, S.; Celis Peña, M.; Ortega, M. E.; Fariña, C.; Petriella, A.; Rubio, M.; Ashley, R. P.

    2017-10-01

    At the interface of H II regions and molecular gas, peculiar structures appear, some of them with pillar-like shapes. Understanding their origin is important for characterizing triggered star formation and the impact of massive stars on the interstellar medium. In order to study the molecular environment and influence of radiation on two pillar-like features related to the H II region G46.5-0.2, we performed molecular line observations with the Atacama Submillimeter Telescope Experiment and spectroscopic optical observations with the Isaac Newton Telescope. From the optical observations, we identified the star that is exciting the H II region as spectral type O4-6. The molecular data allowed us to study the structure of the pillars and an HCO+ cloud lying between them. In this HCO+ cloud, which has no well-defined 12CO counterpart, we found direct evidence of star formation: two molecular outflows and two associated near-IR nebulosities. The outflow axis orientation is perpendicular to the direction of the radiation flow from the H II region. Several Class I sources are also embedded in this HCO+ cloud, showing that it is usual that young stellar objects (YSOs) form large associations occupying a cavity bounded by pillars. On the other hand, it was confirmed that the radiation-driven implosion (RDI) process is not occurring in one of the pillar tips.

  18. WISDOM Project - II. Molecular gas measurement of the supermassive black hole mass in NGC 4697

    Science.gov (United States)

    Davis, Timothy A.; Bureau, Martin; Onishi, Kyoko; Cappellari, Michele; Iguchi, Satoru; Sarzi, Marc

    2017-07-01

    As part of the mm-Wave Interferometric Survey of Dark Object Masses (WISDOM) project, we present an estimate of the mass of the supermassive black hole (SMBH) in the nearby fast-rotating early-type galaxy NGC 4697. This estimate is based on Atacama Large Millimeter/submillimeter Array (ALMA) cycle-3 observations of the 12CO(2-1) emission line with a linear resolution of 29 pc (0.53 arcsec). We find that NGC 4697 hosts a small relaxed central molecular gas disc with a mass of 1.6 × 107 M⊙, co-spatial with the obscuring dust disc visible in optical Hubble Space Telescope imaging. We also resolve thermal 1 mm continuum emission from the dust in this disc. NGC 4697 is found to have a very low molecular gas velocity dispersion, σgas = 1.65^{+0.68}_{-0.65} km s-1. This seems to be partially because the giant molecular cloud mass function is not fully sampled, but other mechanisms such as chemical differentiation in a hard radiation field or morphological quenching also seem to be required. We detect a Keplerian increase of the rotation of the molecular gas in the very centre of NGC 4697, and use forward modelling of the ALMA data cube in a Bayesian framework with the KINematic Molecular Simulation (kinms) code to estimate an SMBH mass of (1.3_{-0.17}^{+0.18}) × 108 M⊙ and an I-band mass-to-light ratio of 2.14_{-0.05}^{+0.04} M⊙/L⊙ (at the 99 per cent confidence level). Our estimate of the SMBH mass is entirely consistent with previous measurements from stellar kinematics. This increases confidence in the growing number of SMBH mass estimates being obtained in the ALMA era.

  19. Anisotropic mechanical properties of graphene sheets from molecular dynamics

    International Nuclear Information System (INIS)

    Ni Zhonghua; Bu Hao; Zou Min; Yi Hong; Bi Kedong; Chen Yunfei

    2010-01-01

    Anisotropic mechanical properties are observed for a sheet of graphene along different load directions. The anisotropic mechanical properties are attributed to the hexagonal structure of the unit cells of the graphene. Under the same tensile loads, the edge bonds bear larger load in the longitudinal mode (LM) than in the transverse mode (TM), which causes fracture sooner in LM than in TM. The Young's modulus and the third order elastic modulus for the LM are slightly larger than that for the TM. Simulation also demonstrates that, for both LM and TM, the loading and unloading stress-strain response curves overlap as long as the graphene is unloaded before the fracture point. This confirms that graphene sustains complete elastic and reversible deformation in the elongation process.

  20. Molecular mechanisms of DNA repair inhibition by caffeine

    Energy Technology Data Exchange (ETDEWEB)

    Selby, C.P.; Sancar, A. (Univ. of North Carolina School of Medicine, Chapel Hill (USA))

    1990-05-01

    Caffeine potentiates the mutagenic and lethal effects of genotoxic agents. It is thought that this is due, at least in some organisms, to inhibition of DNA repair. However, direct evidence for inhibition of repair enzymes has been lacking. Using purified Escherichia coli DNA photolyase and (A)BC excinuclease, we show that the drug inhibits photoreactivation and nucleotide excision repair by two different mechanisms. Caffeine inhibits photoreactivation by interfering with the specific binding of photolyase to damaged DNA, and it inhibits nucleotide excision repair by promoting nonspecific binding of the damage-recognition subunit, UvrA, of (A)BC excinuclease. A number of other intercalators, including acriflavin and ethidium bromide, appear to inhibit the excinuclease by a similar mechanism--that is, by trapping the UvrA subunit in nonproductive complexes on undamaged DNA.

  1. Molecular Mechanisms Regulating Temperature Compensation of the Circadian Clock.

    Science.gov (United States)

    Narasimamurthy, Rajesh; Virshup, David M

    2017-01-01

    An approximately 24-h biological timekeeping mechanism called the circadian clock is present in virtually all light-sensitive organisms from cyanobacteria to humans. The clock system regulates our sleep-wake cycle, feeding-fasting, hormonal secretion, body temperature, and many other physiological functions. Signals from the master circadian oscillator entrain peripheral clocks using a variety of neural and hormonal signals. Even centrally controlled internal temperature fluctuations can entrain the peripheral circadian clocks. But, unlike other chemical reactions, the output of the clock system remains nearly constant with fluctuations in ambient temperature, a phenomenon known as temperature compensation. In this brief review, we focus on recent advances in our understanding of the posttranslational modifications, especially a phosphoswitch mechanism controlling the stability of PER2 and its implications for the regulation of temperature compensation.

  2. Molecular Mechanisms Regulating Temperature Compensation of the Circadian Clock

    Directory of Open Access Journals (Sweden)

    David M. Virshup

    2017-04-01

    Full Text Available An approximately 24-h biological timekeeping mechanism called the circadian clock is present in virtually all light-sensitive organisms from cyanobacteria to humans. The clock system regulates our sleep–wake cycle, feeding–fasting, hormonal secretion, body temperature, and many other physiological functions. Signals from the master circadian oscillator entrain peripheral clocks using a variety of neural and hormonal signals. Even centrally controlled internal temperature fluctuations can entrain the peripheral circadian clocks. But, unlike other chemical reactions, the output of the clock system remains nearly constant with fluctuations in ambient temperature, a phenomenon known as temperature compensation. In this brief review, we focus on recent advances in our understanding of the posttranslational modifications, especially a phosphoswitch mechanism controlling the stability of PER2 and its implications for the regulation of temperature compensation.

  3. Molecular Mechanisms of Antipsychotic Drug-Induced Diabetes

    Directory of Open Access Journals (Sweden)

    Jiezhong Chen

    2017-11-01

    Full Text Available Antipsychotic drugs (APDs are widely prescribed to control various mental disorders. As mental disorders are chronic diseases, these drugs are often used over a life-time. However, APDs can cause serious glucometabolic side-effects including type 2 diabetes and hyperglycaemic emergency, leading to medication non-compliance. At present, there is no effective approach to overcome these side-effects. Understanding the mechanisms for APD-induced diabetes should be helpful in prevention and treatment of these side-effects of APDs and thus improve the clinical outcomes of APDs. In this review, the potential mechanisms for APD-induced diabetes are summarized so that novel approaches can be considered to relieve APD-induced diabetes. APD-induced diabetes could be mediated by multiple mechanisms: (1 APDs can inhibit the insulin signaling pathway in the target cells such as muscle cells, hepatocytes and adipocytes to cause insulin resistance; (2 APD-induced obesity can result in high levels of free fatty acids (FFA and inflammation, which can also cause insulin resistance. (3 APDs can cause direct damage to β-cells, leading to dysfunction and apoptosis of β-cells. A recent theory considers that both β-cell damage and insulin resistance are necessary factors for the development of diabetes. In high-fat diet-induced diabetes, the compensatory ability of β-cells is gradually damaged, while APDs cause direct β-cell damage, accounting for the severe form of APD-induced diabetes. Based on these mechanisms, effective prevention of APD-induced diabetes may need an integrated approach to combat various effects of APDs on multiple pathways.

  4. Molecular and Cell Mechanisms of Singlet Oxygen Effect on Biosystems

    OpenAIRE

    Martusevich А.А.; Peretyagin S.P.; Martusevich А.К.

    2012-01-01

    There has been considered a poorly studied form of activated oxygen — singlet oxygen. Its physicochemical properties (electron configuration of a molecule, reactive capacity, features) are analyzed, and enzymic and nonenzymic ways of singlet oxygen generation in body are specified. There are shown in detail biological effects of the compound as a regulator of cell activity including that determining the mechanism of apoptosis initiation. The relation of singlet oxygen and photodynamic effect ...

  5. Molecular Mechanisms Regulating Temperature Compensation of the Circadian Clock

    OpenAIRE

    David M. Virshup; Rajesh Narasimamurthy

    2017-01-01

    An approximately 24-h biological timekeeping mechanism called the circadian clock is present in virtually all light-sensitive organisms from cyanobacteria to humans. The clock system regulates our sleep–wake cycle, feeding–fasting, hormonal secretion, body temperature, and many other physiological functions. Signals from the master circadian oscillator entrain peripheral clocks using a variety of neural and hormonal signals. Even centrally controlled internal temperature fluctuations can entr...

  6. Carboplatin: molecular mechanisms of action associated with chemoresistance

    Directory of Open Access Journals (Sweden)

    Graziele Fonseca de Sousa

    2014-12-01

    Full Text Available Carboplatin is a derivative of cisplatin; it has a similar mechanism of action, but differs in terms of structure and toxicity. It was approved by the FDA in the 1980s and since then it has been widely used in the treatment of several tumor types. This agent is characterized by its ability to generate lesions in DNA through the formation of adducts with platinum, thereby inhibiting replication and transcription and leading to cell death. However, its use can lead to serious inconvenience arising from the development of resistance that some patients acquire during treatment, limiting the scope of its full potential. Currently, the biochemical mechanisms related to resistance are not precisely known. Therefore, knowledge of pathways associated with resistance caused by carboplatin exposure may provide valuable clues for more efficient rational drug design in platinum-based therapy and the development of new therapeutic strategies. In this narrative review, we discuss some of the known mechanisms of resistance to platinum-based drugs, especially carboplatin.

  7. Insights of asphaltene aggregation mechanism from molecular dynamics simulation

    Directory of Open Access Journals (Sweden)

    Jennifer De León

    2015-01-01

    Full Text Available Se estudió el proceso de agregación de asfaltenos utilizando té cnicas de dinámica molecular. Se utilizaron cuatro estructuras diferentes. Las primeras tres moléculas tienen una estructura continental, con núcleos aromáticos condensador, mientras que la cuarta pose e una estructura tipo archipiélago, con pequeños grupos de anillos ar omáticos conectados con cadenas saturadas. Las moléculas fueron construidas de manera atomística, en la cual cada átomo se desc ribe individualmente. Se calcula ron las fuerzas de interacción a 300 K y 200 atm; las fuerzas de Van der W aals y las interacciones elect rostáticas fueron evaluadas separadamente. Se calculó el paráme tro de solubilidad para las cuatro molécu las. Se encontró que las inte racciones de Van der Waals asoc iadas a los anillos aromáticos y las fuerzas electrostáticas ocasionadas princ ipalmente por la presencia de heteroátomos como oxígeno, azufr e y nitrógeno, son igualmente r elevantes en la agregación de moléculas de asfalteno. Para todas las molé culas se encontró que los sistemas de asfaltenos tienen menor e nergía en estado de agregación que en estado monomérico. Para las estruct uras continentales, la presencia de largas cadenas obstruye el proceso de formación de agregados. Para las estructuras tipo archipiélago, la flexibilidad de las moléculas facilita la agregación con ot ras estructuras. La presencia de heteroátomos ocasiona una fuerza repulsiva que dificulta la agregación. El volumen molecular y la energía de c ohesión también son sensibles a la confi guración geométrica y la compos ición de las especies, lo cual afecta el parámetro de solubilidad.

  8. Report of National Cancer Institute symposium: comparison of mechanisms of carcinogenesis by radiation and chemical agents. I. Common molecular mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Borg, D.C.

    1984-01-01

    Some aspects of molecular mechanisms common to radiation and chemical carcinogenesis are discussed, particularly the DNA damage done by these agents. Emphasis is placed on epidemiological considerations and on dose-response models used in risk assessment to extrapolate from experimental data obtained at high doses to the effects from long-term, low-level exposures. 3 references, 6 figures. (ACR)

  9. Report of National Cancer Institute symposium: comparison of mechanisms of carcinogenesis by radiation and chemical agents. I. Common molecular mechanisms

    International Nuclear Information System (INIS)

    Borg, D.C.

    1984-01-01

    Some aspects of molecular mechanisms common to radiation and chemical carcinogenesis are discussed, particularly the DNA damage done by these agents. Emphasis is placed on epidemiological considerations and on dose-response models used in risk assessment to extrapolate from experimental data obtained at high doses to the effects from long-term, low-level exposures. 3 references, 6 figures

  10. Ab initio study of structural and mechanical property of solid molecular hydrogens

    Science.gov (United States)

    Ye, Yingting; Yang, Li; Yang, Tianle; Nie, Jinlan; Peng, Shuming; Long, Xinggui; Zu, Xiaotao; Du, Jincheng

    2015-06-01

    Ab initio calculations based on density functional theory (DFT) were performed to investigate the structural and the elastic properties of solid molecular hydrogens (H2). The influence of molecular axes of H2 on structural relative stabilities of hexagonal close-packed (hcp) and face-centered cubic (fcc) structured hydrogen molecular crystals were systematically investigated. Our results indicate that for hcp structures, disordered hydrogen molecule structure is more stable, while for fcc structures, Pa3 hydrogen molecular crystal is most stable. The cohesive energy of fcc H2 crystal was found to be lower than hcp. The mechanical properties of fcc and hcp hydrogen molecular crystals were obtained, with results consistent with previous theoretical calculations. In addition, the effects of zero point energy (ZPE) and van der Waals (vdW) correction on the cohesive energy and the stability of hydrogen molecular crystals were systematically studied and discussed.

  11. Metabolic actions of FGF21: molecular mechanisms and therapeutic implications

    Directory of Open Access Journals (Sweden)

    Xuan Ge

    2012-08-01

    Full Text Available Fibroblast growth factor 21 (FGF21 is an atypical member of the FGF family that functions as an endocrine factor. In obese animals, elevation of plasma FGF21 levels by either pharmacological or genetic approaches reduces body weight, decreases hyperglycemia and hyperlipidemia, alleviates fatty liver and increases insulin sensitivity. FGF21 exerts its pleiotropic metabolic effects through its actions on multiple targets, including adipose tissue, liver, brain and pancreas. The expression of FGF21 is under the control of both peroxisome proliferator-activated receptor gamma (PPARγ and peroxisome proliferator-activated receptor alpha (PPARα. A growing body of evidence suggests that the metabolic benefits of these two nuclear receptors are mediated in part by induction of FGF21. In humans, plasma levels of FGF21 are elevated in obese subjects and patients with type 2 diabetes, but are reduced in patients with autoimmune diabetes. This review summarizes recent advances in understanding the physiological roles of FGF21 and the molecular pathways underlying its actions, and also discusses the future prospective of developing FGF21 or its agonists as therapeutic agents for obesity-related medical complications.

  12. Lipoprotein(a: Cellular Effects and Molecular Mechanisms

    Directory of Open Access Journals (Sweden)

    Kirsten Riches

    2012-01-01

    Full Text Available Lipoprotein(a (Lp(a is an independent risk factor for the development of cardiovascular disease (CVD. Indeed, individuals with plasma concentrations >20 mg/dL carry a 2-fold increased risk of developing CVD, accounting for ~25% of the population. Circulating levels of Lp(a are remarkably resistant to common lipid lowering therapies, and there are currently no robust treatments available for reduction of Lp(a apart from plasma apheresis, which is costly and labour intensive. The Lp(a molecule is composed of two parts, an LDL/apoB-100 core and a unique glycoprotein, apolipoprotein(a (apo(a, both of which can interact with components of the coagulation cascade, inflammatory pathways, and cells of the blood vessel wall (smooth muscle cells (SMC and endothelial cells (EC. Therefore, it is of key importance to determine the molecular pathways by which Lp(a exerts its influence on the vascular system in order to design therapeutics to target its cellular effects. This paper will summarise the role of Lp(a in modulating cell behaviour in all aspects of the vascular system including platelets, monocytes, SMC, and EC.

  13. Molecular mechanisms involved in the production of chromosomal aberrations. I

    International Nuclear Information System (INIS)

    Natarajan, A.T.; Obe, G.

    1978-01-01

    Chinese hamster ovary cells (CHO) were X-irradiated in G2 stage of the cell cycle and immediately treated, in the presence of inactivated Sendai virus, with Neurospora endonuclease (E.C. 3.1.4.), an enzyme which is specific for cleaving single-stranded DNA. With this treatment, the frequencies of all types of chromosome aberrations increased when compared to X-irradiated controls. These results are interpreted as due to the conversion of some of the X-ray induced single-stranded DNA breaks into double-strand breaks by this enzyme. Similar enhancement due to this enzyme was found following treatment with methyl methanesulfonate (MMS) and bleomycin, but not following UV and mitomycin C. Addition of Micrococcus endonuclease and Neurospora endonuclease to the cells did not alter the frequencies of aberrations induced by UV. The introduction of enzymes with specific DNA-repair function offers possibilities to probe into the molecular events involved in the formation of structural chromosome aberrations induced by different classes of physical and chemical mutagens. (Auth.)

  14. Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: A mechanism by which angiotensin II antagonizes cGMP signaling

    Science.gov (United States)

    Kim, Dongsoo; Aizawa, Toru; Wei, Heng; Pi, Xinchun; Rybalkin, Sergei D.; Berk, Bradford C.; Yan, Chen

    2014-01-01

    Angiotensin II (Ang II) and nitric oxide (NO)/natriuretic peptide (NP) signaling pathways mutually regulate each other. Imbalance of Ang II and NO/NP has been implicated in the pathophysiology of many vascular diseases. cGMP functions as a key mediator in the interaction between Ang II and NO/NP. Cyclic nucleotide phosphodiesterase 5A (PDE5A) is important in modulating cGMP signaling by hydrolyzing cGMP in vascular smooth muscle cells (VSMC). Therefore, we examined whether Ang II negatively modulates intracellular cGMP signaling in VSMC by regulating PDE5A. Ang II rapidly and transiently increased PDE5A mRNA levels in rat aortic VSMC. Upregulation of PDE5A mRNA was associated with a time-dependent increase of both PDE5 protein expression and activity. Increased PDE5A mRNA level was transcription-dependent and mediated by the Ang II type 1 receptor. Ang II-mediated activation of extracellular signal-regulated kinases 1/2 (ERK1/2) was essential for Ang II-induced PDE5A upregulation. Pretreatment of VSMC with Ang II inhibited C-type NP (CNP) stimulated cGMP signaling, such as cGMP dependent protein kinase (PKG)-mediated phosphorylation of vasodilator-stimulated-phosphoprotein (VASP). Ang II-mediated inhibition of PKG was blocked when PDE5 activity was decreased by selective PDE5 inhibitors, suggesting that upregulation of PDE5A expression is an important mechanism for Ang II to attenuate cGMP signaling. PDE5A may also play a critical role in the growth promoting effects of Ang II because inhibition of PDE5A activity significantly decreased Ang II-stimulated VSMC growth. These observations establish a new mechanism by which Ang II antagonizes cGMP signaling and stimulates VSMC growth. PMID:15623434

  15. [Review: plant polyphenols modulate lipid metabolism and related molecular mechanism].

    Science.gov (United States)

    Dai, Yan-li; Zou, Yu-xiao; Liu, Fan; Li, Hong-zhi

    2015-11-01

    Lipid metabolism disorder is an important risk factor to obesity, hyperlipidemia and type 2 diabetes as well as other chronic metabolic disease. It is also a key target in preventing metabolic syndrome, chronic disease prevention. Plant polyphenol plays an important role in maintaining or improving lipid profile in a variety of ways. including regulating cholesterol absorption, inhibiting synthesis and secretion of triglyceride, and lowering plasma low density lipoprotein oxidation, etc. The purpose of this article is to review the lipid regulation effects of plant polyphenols and its related mechanisms.

  16. Molecular mechanisms in DM1 - a focus on foci

    DEFF Research Database (Denmark)

    Pettersson, Olof Joakim; Aagaard, Lars; Jensen, Thomas G.

    2015-01-01

    -expanded RNA remains in the nuclear compartment, while in dividing cells such as fibroblasts a considerable fraction of the mutant RNA reaches the cytoplasm, consistent with findings that both nuclear and cytoplasmic events are mis-regulated in DM1. Recent evidence suggests that the nuclear aggregates......, or ribonuclear foci, are more dynamic than previously anticipated and regulated by several proteins, including RNA helicases. In this review, we focus on the homeostasis of DMPK mRNA foci and discuss how their dynamic regulation may affect disease-causing mechanisms in DM1...

  17. Radiative and mechanical feedback into the molecular gas of NGC 253

    NARCIS (Netherlands)

    Rosenberg, M. J. F.; Kazandjian, M. V.; van der Werf, P. P.; Israel, F. P.; Meijerink, R.; Weiß, A.; Requena-Torres, M. A.; Güsten, R.

    Starburst galaxies are galaxies or regions of galaxies undergoing intense periods of star formation. Understanding the heating and cooling mechanisms in these galaxies can give us insight to the driving mechanisms that fuel the starburst. Molecular emission lines play a crucial role in the cooling

  18. Molecular Mechanisms Underlying the Epileptogenesis and Seizure Progression in Tuberous Sclerosis Complex 1 Deficient Mouse Models

    Science.gov (United States)

    2016-10-01

    dysregulation in epileptogenesis in the developing brain? 2) What are the molecular mechanisms downstream of mTOR hyperactivation that trigger epileptogenesis...underlying epilepsy. Hopefully, a knowledge of these mechanisms will aid in a rational development of therapies. KEYWORDS Tuberous Sclerosis, Epilepsy

  19. Exploiting large-pore metal-organic frameworks for separations through entropic molecular mechanisms

    NARCIS (Netherlands)

    Torres-Knoop, A.; Dubbeldam, D.

    2015-01-01

    We review the molecular mechanisms behind adsorption and the separations of mixtures in metal-organic frameworks and zeolites. Separation mechanisms can be based on differences in the affinity of the adsorbate with the framework and on entropic effects. To develop next-generation adsorbents, the

  20. Molecular Mechanism for Various Pharmacological Activities of NSAIDS

    Directory of Open Access Journals (Sweden)

    Tohru Mizushima

    2010-05-01

    Full Text Available The anti-inflammatory action of non-steroidal anti-inflammatory drugs (NSAIDs is mediated through their inhibitory effects on cyclooxygenase (COX activity. On the other hand, NSAID use is often associated with gastrointestinal complications. The inhibition of COX by NSAIDs is not the sole explanation for the gastrointestinal side effects of NSAIDs. Furthermore, recent epidemiological studies have revealed that prolonged NSAID use reduces the risk of cancer and Alzheimer’s disease (AD and a COX-independent unknown mechanism is suggested to be involved in these activities of NSAIDs. In this article, I review our recent work on the COX-independent mechanism involved in NSAID-induced gastric lesions and anti-tumor and anti-AD activities of NSAIDs. Using DNA microarray analysis, we found that NSAIDs affect expression of various genes in a COX-independent manner. We found that membrane permeabilization activity of NSAIDs and resulting NSAID-induced apoptosis are involved in NSAID-induced gastric lesions. On the other hand, induction of expression of tight junction-related genes and endoplasmic reticulum chaperones were suggested to be involved in anti-tumor and anti-AD, respectively, activities of NSAIDs. These results suggest that NSAIDs affect expression of various genes in a COX-independent manner, which is involved in various pharmacological activities of NSAIDs.

  1. Molecular Mechanisms of Cannabis Signaling in the Brain.

    Science.gov (United States)

    Ronan, Patrick J; Wongngamnit, Narin; Beresford, Thomas P

    2016-01-01

    Cannabis has been cultivated and used by humans for thousands of years. Research for decades was focused on understanding the mechanisms of an illegal/addictive drug. This led to the discovery of the vast endocannabinoid system. Research has now shifted to understanding fundamental biological questions related to one of the most widespread signaling systems in both the brain and the body. Our understanding of cannabinoid signaling has advanced significantly in the last two decades. In this review, we discuss the state of knowledge on mechanisms of Cannabis signaling in the brain and the modulation of key brain neurotransmitter systems involved in both brain reward/addiction and psychiatric disorders. It is highly probable that various cannabinoids will be found to be efficacious in the treatment of a number of psychiatric disorders. However, while there is clearly much potential, marijuana has not been properly vetted by the medical-scientific evaluation process and there are clearly a range of potentially adverse side-effects-including addiction. We are at crossroads for research on endocannabinoid function and therapeutics (including the use of exogenous treatments such as Cannabis). With over 100 cannabinoid constituents, the majority of which have not been studied, there is much Cannabis research yet to be done. With more states legalizing both the medicinal and recreational use of marijuana the rigorous scientific investigation into cannabinoid signaling is imperative. Copyright © 2016. Published by Elsevier Inc.

  2. Molecular Mechanisms That Contribute to Bone Marrow Pain

    Directory of Open Access Journals (Sweden)

    Jason J. Ivanusic

    2017-09-01

    Full Text Available Pain associated a bony pathology puts a significant burden on individuals, society, and the health-care systems worldwide. Pathology that involves the bone marrow activates sensory nerve terminal endings of peripheral bone marrow nociceptors, and is the likely trigger for pain. This review presents our current understanding of how bone marrow nociceptors are influenced by noxious stimuli presented in pathology associated with bone marrow. A number of ion channels and receptors are emerging as important modulators of the activity of peripheral bone marrow nociceptors. Nerve growth factor (NGF sequestration has been trialed for the management of inflammatory bone pain (osteoarthritis, and there is significant evidence for interaction of NGF with bone marrow nociceptors. Activation of transient receptor potential cation channel subfamily V member 1 sensitizes bone marrow nociceptors and could contribute to increased sensitivity of patients to noxious stimuli in various bony pathologies. Acid-sensing ion channels sense changes to tissue pH in the bone marrow microenvironment and could be targeted to treat pathology that involves acidosis of the bone marrow. Piezo2 is a mechanically gated ion channel that has recently been reported to be expressed by most myelinated bone marrow nociceptors and might be a target for treatments directed against mechanically induced bone pain. These ion channels and receptors could be useful targets for the development of peripherally acting drugs to treat pain of bony origin.

  3. Molecular Mechanism of Terbinafine Resistance in Saccharomyces cerevisiae

    Science.gov (United States)

    Leber, Regina; Fuchsbichler, Sandra; Klobučníková, Vlasta; Schweighofer, Natascha; Pitters, Eva; Wohlfarter, Kathrin; Lederer, Mojca; Landl, Karina; Ruckenstuhl, Christoph; Hapala, Ivan; Turnowsky, Friederike

    2003-01-01

    Ten mutants of the yeast Saccharomyces cerevisiae resistant to the antimycotic terbinafine were isolated after chemical or UV mutagenesis. Molecular analysis of these mutants revealed single base pair exchanges in the ERG1 gene coding for squalene epoxidase, the target of terbinafine. The mutants did not show cross-resistance to any of the substrates of various pleiotropic drug resistance efflux pumps tested. The ERG1 mRNA levels in the mutants did not differ from those in the wild-type parent strains. Terbinafine resistance was transmitted with the mutated alleles in gene replacement experiments, proving that single amino acid substitutions in the Erg1 protein were sufficient to confer the resistance phenotype. The amino acid changes caused by the point mutations were clustered in two regions of the Erg1 protein. Seven mutants carried the amino acid substitutions F402L (one mutant), F420L (one mutant), and P430S (five mutants) in the C-terminal part of the protein; and three mutants carried an L251F exchange in the central part of the protein. Interestingly, all exchanges identified involved amino acids which are conserved in the squalene epoxidases of yeasts and mammals. Two mutations that were generated by PCR mutagenesis of the ERG1 gene and that conferred terbinafine resistance mapped in the same regions of the Erg1 protein, with one resulting in an L251F exchange and the other resulting in an F433S exchange. The results strongly indicate that these regions are responsible for the interaction of yeast squalene epoxidase with terbinafine. PMID:14638499

  4. Molecular mechanisms of thyroid tumorigenesis; Molekulare Mechanismen der Schilddruesentumorgenese

    Energy Technology Data Exchange (ETDEWEB)

    Krause, K.; Fuehrer, D. [Universitaetsklinikum Leipzig (Germany). Abt. fuer Endokrinolgoie, Diabetologie und Nephrologie

    2008-09-15

    Thyroid nodules are the most frequent endocrine disorder and occur in approximately 30% of the German population. Thyroid nodular disease constitutes a very heterogeneous entity. A striking diversity of possible functional and morphological features of a thyroid tumour derived from the same thyroid ancestor cell, is a hallmark of thyroid tumorigenesis and is due to specific genetic alterations. Defects in known candidate genes can be found in up to 70% of differentiated thyroid carcinomas and determine the respective cancer phenotype. Papillary thyroid cancers (PTC) harbour BRAF (or much less frequently RAS) mutations in sporadically occurring tumours, while radiation-induced PTC display chromosomal rearrangements such as RET, TRK, APR9 / BRAF. These genetic events results in constitutive MAPKinase activation. Follicular thyroid cancers (FTC) harbour RAS mutations or PAX8/ PPAR{gamma} rearrangements, both of which, however have also been identified in follicular adenoma. In addition, recent studies show, that activation of PI3K/AKT signalling occurs with high frequency in follicular thyroid tumours. Undifferentiated (anaplastic) thyroid cancers (ATC) display genetic features of FTC or PTC, in addition to aberant activation of multiple tyrosinkinase pathways (overexpression or mutations in PI3K and MAPK pathways). This underscores the concept of a sequential evolution of ATC from differentiated thyroid cancer, a process widely conceived to be triggered by p53 inactivation. In contrast, the molecular pathogenesis of benign thyroid tumours, in particular cold thyroid nodules is less known, except for toxic thyroid nodules, which arise from constitutive activation of cAMP signalling, predominantly through TSHR mutations. (orig.)

  5. Mechanism of selective recruitment of RNA polymerases II and III to snRNA gene promoters.

    Science.gov (United States)

    Dergai, Oleksandr; Cousin, Pascal; Gouge, Jerome; Satia, Karishma; Praz, Viviane; Kuhlman, Tracy; Lhôte, Philippe; Vannini, Alessandro; Hernandez, Nouria

    2018-05-01

    RNA polymerase II (Pol II) small nuclear RNA (snRNA) promoters and type 3 Pol III promoters have highly similar structures; both contain an interchangeable enhancer and "proximal sequence element" (PSE), which recruits the SNAP complex (SNAPc). The main distinguishing feature is the presence, in the type 3 promoters only, of a TATA box, which determines Pol III specificity. To understand the mechanism by which the absence or presence of a TATA box results in specific Pol recruitment, we examined how SNAPc and general transcription factors required for Pol II or Pol III transcription of SNAPc-dependent genes (i.e., TATA-box-binding protein [TBP], TFIIB, and TFIIA for Pol II transcription and TBP and BRF2 for Pol III transcription) assemble to ensure specific Pol recruitment. TFIIB and BRF2 could each, in a mutually exclusive fashion, be recruited to SNAPc. In contrast, TBP-TFIIB and TBP-BRF2 complexes were not recruited unless a TATA box was present, which allowed selective and efficient recruitment of the TBP-BRF2 complex. Thus, TBP both prevented BRF2 recruitment to Pol II promoters and enhanced BRF2 recruitment to Pol III promoters. On Pol II promoters, TBP recruitment was separate from TFIIB recruitment and enhanced by TFIIA. Our results provide a model for specific Pol recruitment at SNAPc-dependent promoters. © 2018 Dergai et al.; Published by Cold Spring Harbor Laboratory Press.

  6. Molecular Mechanism of preQ(1) Riboswitch Action: A Molecular Dynamics Study

    Czech Academy of Sciences Publication Activity Database

    Banáš, Pavel; Sklenovský, P.; Wedekind, J.E.; Šponer, Jiří; Otyepka, Michal

    2012-01-01

    Roč. 116, č. 42 (2012), s. 12721-12734 ISSN 1520-6106 R&D Projects: GA ČR(CZ) GD203/09/H046; GA ČR(CZ) GA203/09/1476; GA ČR(CZ) GAP208/12/1878; GA ČR(CZ) GBP305/12/G034 Grant - others:GA ČR(CZ) GBP208/12/G016 Program:GB Institutional support: RVO:68081707 Keywords : HEPATITIS -DELTA VIRUS * PARTICLE MESH EWALD * SAM-II RIBOSWITCH Subject RIV: BO - Biophysics; BO - Biophysics (BFU-R) Impact factor: 3.607, year: 2012

  7. NAD+ in Aging: Molecular Mechanisms and Translational Implications.

    Science.gov (United States)

    Fang, Evandro F; Lautrup, Sofie; Hou, Yujun; Demarest, Tyler G; Croteau, Deborah L; Mattson, Mark P; Bohr, Vilhelm A

    2017-10-01

    The coenzyme NAD + is critical in cellular bioenergetics and adaptive stress responses. Its depletion has emerged as a fundamental feature of aging that may predispose to a wide range of chronic diseases. Maintenance of NAD + levels is important for cells with high energy demands and for proficient neuronal function. NAD + depletion is detected in major neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, cardiovascular disease and muscle atrophy. Emerging evidence suggests that NAD + decrements occur in various tissues during aging, and that physiological and pharmacological interventions bolstering cellular NAD + levels might retard aspects of aging and forestall some age-related diseases. Here, we discuss aspects of NAD + biosynthesis, together with putative mechanisms of NAD + action against aging, including recent preclinical and clinical trials. Published by Elsevier Ltd.

  8. Excited hydrogen bonds in the molecular mechanism of muscle contraction.

    Science.gov (United States)

    Bespalova, S V; Tolpygo, K B

    1991-11-21

    The mechanism of muscle contraction is considered. The hydrolysis of an ATP molecule is assumed to produce the excitation of hydrogen bonds A--H...B between electronegative atoms A and B, which are contained in the myosin head and actin filament. This excitation energy epsilon f depends on the interatomic distance AB = R and generates the tractive force f = -delta epsilon f/delta R, that makes atoms AB approach each other. The swing of the myosin head results in macroscopic mutual displacement of actin and myosin polymers. The motion of the actin filament under the action of this force is studied. The conditions under which a considerable portion of the excitation energy converts into the potential tension energy of the actin filament are analysed, and the probability of higher muscle efficiency existence is discussed.

  9. Dissecting the molecular mechanisms of intraflagellar transport in Chlamydomonas

    DEFF Research Database (Denmark)

    Pedersen, L. B.; Geimer, S.; Rosenbaum, J. L.

    2006-01-01

    Background The assembly and maintenance of eukaryotic cilia and flagella are mediated by intraflagellar transport (IFT), a bidirectional microtubule (MT)-based transport system. The IFT system consists of anterograde (kinesin-2) and retrograde (cDynein1b) motor complexes and IFT particles...... comprising two complexes, A and B. In the current model for IFT, kinesin-2 carries cDynein1b, IFT particles, and axonemal precursors from the flagellar base to the tip, and cDynein1b transports kinesin-2, IFT particles, and axonemal turnover products from the tip back to the base. Most of the components...... of the IFT system have been identified and characterized, but the mechanisms by which these different components are coordinated and regulated at the flagellar base and tip are unclear. Results Using a variety of Chlamydomonas mutants, we confirm that cDynein1b requires kinesin-2 for transport toward the tip...

  10. Mammalian life histories: their evolution and molecular-genetic mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Sacher, G.A.

    1978-01-01

    Survival curves for various species of mammals are discussed and a table is presented to show recorded maximum life spans of about 30 species of mammals. The range of longevities is from one year for shrews and moles up to more than 80 years for the fin whale. The constitutional correlates of longevity are discussed with regard to body size, brain weight,metabolic rates, and body temperature. It is concluded that longevity evolved as a positive trait, associated with the evolution of large body size and brain size. Life table data for man, the thorough-bred horse, beagle dogs, and the laboratory rodents, Mus musculus and Peromyscus leucopus are discussed. The data show a pattern of exponential increase of death rate with age. A laboratory model using Mus musculus and Peromyscus leucopus for the study of the longevity-assurance mechanisms is described. (HLW)

  11. Molecular and Cellular Mechanisms of Shigella flexneri Dissemination.

    Science.gov (United States)

    Agaisse, Hervé

    2016-01-01

    The intracellular pathogen Shigella flexneri is the causative agent of bacillary dysentery in humans. The disease is characterized by bacterial invasion of intestinal cells, dissemination within the colonic epithelium through direct spread from cell to cell, and massive inflammation of the intestinal mucosa. Here, we review the mechanisms supporting S. flexneri dissemination. The dissemination process primarily relies on actin assembly at the bacterial pole, which propels the pathogen throughout the cytosol of primary infected cells. Polar actin assembly is supported by polar expression of the bacterial autotransporter family member IcsA, which recruits the N-WASP/ARP2/3 actin assembly machinery. As motile bacteria encounter cell-cell contacts, they form plasma membrane protrusions that project into adjacent cells. In addition to the ARP2/3-dependent actin assembly machinery, protrusion formation relies on formins and myosins. The resolution of protrusions into vacuoles occurs through the collapse of the protrusion neck, leading to the formation of an intermediate membrane-bound compartment termed vacuole-like protrusions (VLPs). VLP formation requires tyrosine kinase and phosphoinositide signaling in protrusions, which relies on the integrity of the bacterial type 3 secretion system (T3SS). The T3SS is also required for escaping double membrane vacuoles through the activity of the T3SS translocases IpaB and IpaC, and the effector proteins VirA and IcsB. Numerous factors supporting envelope biogenesis contribute to IcsA exposure and maintenance at the bacterial pole, including LPS synthesis, membrane proteases, and periplasmic chaperones. Although less characterized, the assembly and function of the T3SS in the context of bacterial dissemination also relies on factors supporting envelope biogenesis. Finally, the dissemination process requires the adaptation of the pathogen to various cellular compartments through transcriptional and post-transcriptional mechanisms.

  12. Analyzing the molecular mechanism of lipoprotein localization in Brucella.

    Science.gov (United States)

    Goolab, Shivani; Roth, Robyn L; van Heerden, Henriette; Crampton, Michael C

    2015-01-01

    Bacterial lipoproteins possess diverse structure and functionality, ranging from bacterial physiology to pathogenic processes. As such many lipoproteins, originating from Brucella are exploited as potential vaccines to countermeasure brucellosis infection in the host. These membrane proteins are translocated from the cytoplasm to the cell membrane where they are anchored peripherally by a multifaceted targeting mechanism. Although much research has focused on the identification and classification of Brucella lipoproteins and their potential use as vaccine candidates for the treatment of Brucellosis, the underlying route for the translocation of these lipoproteins to the outer surface of the Brucella (and other pathogens) outer membrane (OM) remains mostly unknown. This is partly due to the complexity of the organism and evasive tactics used to escape the host immune system, the variation in biological structure and activity of lipoproteins, combined with the complex nature of the translocation machinery. The biosynthetic pathway of Brucella lipoproteins involves a distinct secretion system aiding translocation from the cytoplasm, where they are modified by lipidation, sorted by the lipoprotein localization machinery pathway and thereafter equipped for export to the OM. Surface localized lipoproteins in Brucella may employ a lipoprotein flippase or the β-barrel assembly complex for translocation. This review provides an overview of the characterized Brucella OM proteins that form part of the OM, including a handful of other characterized bacterial lipoproteins and their mechanisms of translocation. Lipoprotein localization pathways in gram negative bacteria will be used as a model to identify gaps in Brucella lipoprotein localization and infer a potential pathway. Of particular interest are the dual topology lipoproteins identified in Escherichia coli and Haemophilus influenza. The localization and topology of these lipoproteins from other gram negative bacteria

  13. Analyzing the molecular mechanism of lipoprotein localization in Brucella

    Science.gov (United States)

    Goolab, Shivani; Roth, Robyn L.; van Heerden, Henriette; Crampton, Michael C.

    2015-01-01

    Bacterial lipoproteins possess diverse structure and functionality, ranging from bacterial physiology to pathogenic processes. As such many lipoproteins, originating from Brucella are exploited as potential vaccines to countermeasure brucellosis infection in the host. These membrane proteins are translocated from the cytoplasm to the cell membrane where they are anchored peripherally by a multifaceted targeting mechanism. Although much research has focused on the identification and classification of Brucella lipoproteins and their potential use as vaccine candidates for the treatment of Brucellosis, the underlying route for the translocation of these lipoproteins to the outer surface of the Brucella (and other pathogens) outer membrane (OM) remains mostly unknown. This is partly due to the complexity of the organism and evasive tactics used to escape the host immune system, the variation in biological structure and activity of lipoproteins, combined with the complex nature of the translocation machinery. The biosynthetic pathway of Brucella lipoproteins involves a distinct secretion system aiding translocation from the cytoplasm, where they are modified by lipidation, sorted by the lipoprotein localization machinery pathway and thereafter equipped for export to the OM. Surface localized lipoproteins in Brucella may employ a lipoprotein flippase or the β-barrel assembly complex for translocation. This review provides an overview of the characterized Brucella OM proteins that form part of the OM, including a handful of other characterized bacterial lipoproteins and their mechanisms of translocation. Lipoprotein localization pathways in gram negative bacteria will be used as a model to identify gaps in Brucella lipoprotein localization and infer a potential pathway. Of particular interest are the dual topology lipoproteins identified in Escherichia coli and Haemophilus influenza. The localization and topology of these lipoproteins from other gram negative bacteria

  14. Molecular and Cellular mechanisms of Shigella flexneri dissemination

    Directory of Open Access Journals (Sweden)

    Herve eAgaisse

    2016-03-01

    Full Text Available The intracellular pathogen Shigella flexneri is the causative agent of bacillary dysentery in humans. The disease is characterized by bacterial invasion of intestinal cells, dissemination within the colonic epithelium through direct spread from cell to cell, and massive inflammation of the intestinal mucosa. Here, we review the mechanisms supporting S. flexneri dissemination. The dissemination process primarily relies on actin assembly at the bacterial pole, which propels the pathogen throughout the cytosol of primary infected cells. Polar actin assembly is supported by polar expression of the bacterial autotransporter family member IcsA, which recruits the N-WASP/ARP2/3 actin assembly machinery. As motile bacteria encounter cell-cell contacts, they form plasma membrane protrusions that project into adjacent cells. In addition to the ARP2/3-dependent actin assembly machinery, protrusion formation relies on formins and myosins. The resolution of protrusions into vacuoles occurs through the collapse of the protrusion neck, leading to the formation of an intermediate membrane-bound compartment termed vacuole-like protrusions (VLPs. VLP formation requires tyrosine kinase and phosphoinositide signaling in protrusions, which relies on the integrity of the bacterial type 3 secretion system (T3SS. The T3SS is also required for escaping double membrane vacuoles through the activity of the T3SS translocases IpaB and IpaC, and the effector proteins VirA and IcsB. Numerous factors supporting envelope biogenesis contribute to IcsA exposure and maintenance at the bacterial pole, including LPS synthesis, membrane proteases, and periplasmic chaperones. Although less characterized, the assembly and function of the T3SS in the context of bacterial dissemination also relies on factors supporting envelope biogenesis. Finally, the dissemination process requires the adaptation of the pathogen to various cellular compartments through transcriptional and post

  15. Behavior and mechanism of Ni(II) uptake on MnO2 by a combination of macroscopic and EXAFS investigation

    International Nuclear Information System (INIS)

    Guodong Sheng; Jiang Sheng; Shitong Yang; Ju Hu; Xiangke Wang

    2011-01-01

    The effects of pH, ionic strength, competing ions and initial metal concentrations on the uptake behavior and mechanism of radioactive Ni(II) onto MnO 2 was investigated using a combination of classical macroscopic methods and the extended X-ray absorption fine structure (EXAFS) spectroscopy technique. The results indicated that the uptake of Ni(II) on MnO 2 is obviously dependent on pH but independent of ionic strength, which suggested that the uptake of Ni(II) onto MnO 2 is attributed to an inner-sphere surface complex rather than an outer-sphere surface complex. EXAFS analysis shows that the hydrated Ni(II) is adsorbed through six-fold coordination with an average Ni-O interatomic distance of 2.04 ± 0.01 A. It can be inferred from the EXAFS analysis that the inner-sphere surface complex of Ni(II) onto MnO 2 is involved in both edge-sharing and corner-sharing linkages. Both the macroscopic uptake data and the molecular level evidence of Ni(II) surface speciation at the MnO 2 -water interfaces should be factored into better prediction of the bioavailability and mobility of Ni(II) in soil and water environment. (author)

  16. Mechanisms of two-color laser-induced field-free molecular orientation.

    Science.gov (United States)

    Spanner, Michael; Patchkovskii, Serguei; Frumker, Eugene; Corkum, Paul

    2012-09-14

    Two mechanisms of two-color (ω+2ω) laser-induced field-free molecular orientation, based on the hyperpolarizability and ionization depletion, are explored and compared. The CO molecule is used as a computational example. While the hyperpolarizability mechanism generates small amounts of orientation at intensities below the ionization threshold, ionization depletion quickly becomes the dominant mechanism as soon as ionizing intensities are reached. Only the ionization mechanism leads to substantial orientation (e.g., on the order of ≳0.1). For intensities typical of laser-induced molecular alignment and orientation experiments, the two mechanisms lead to robust, characteristic timings of the field-free orientation wave-packet revivals relative to the alignment revivals and the revival time. The revival timings can be used to detect the active orientation mechanism experimentally.

  17. Mechanisms of energy transfer and conversion in plant Light-Harvesting Complex II

    Energy Technology Data Exchange (ETDEWEB)

    Barros, Tiago Ferreira de

    2009-09-24

    subject of this thesis. From the results obtained during this doctoral work, five main conclusions can be drawn concerning the mechanism of qE: 1. Substitution of Vio by Zea in LHC-II is not sufficient for efficient dissipation of excess excitation energy. 2. Aggregation quenching of LHC-II does not require Vio, Neo nor a specific Chl pair. 3. With one exception, the pigment structure in LHC-II is rigid. 4. The two X-ray structures of LHC-II show the same energy transmitting state of the complex. 5. Crystalline LHC-II resembles the complex in the thylakoid membrane. Models of the aggregation quenching mechanism in vitro and the qE mechanism in vivo are presented as a corollary of this doctoral work. LHC-II aggregation quenching in vitro is attributed to the formation of energy sinks on the periphery of LHC-II through random interaction with other trimers, free pigments or impurities. A similar but unrelated process is proposed to occur in the thylakoid membrane, by which excess excitation energy is dissipated upon specific interaction between LHC-II and a PsbS monomer carrying Zea. At the end of this thesis, an innovative experimental model for the analysis of all key aspects of qE is proposed in order to finally solve the qE enigma, one of the last unresolved problems in photosynthesis research. (orig.)

  18. Quantum Mechanics/Molecular Mechanics Modeling of Drug Metabolism: Mexiletine N-Hydroxylation by Cytochrome P450 1A2.

    Science.gov (United States)

    Lonsdale, Richard; Fort, Rachel M; Rydberg, Patrik; Harvey, Jeremy N; Mulholland, Adrian J

    2016-06-20

    The mechanism of cytochrome P450(CYP)-catalyzed hydroxylation of primary amines is currently unclear and is relevant to drug metabolism; previous small model calculations have suggested two possible mechanisms: direct N-oxidation and H-abstraction/rebound. We have modeled the N-hydroxylation of (R)-mexiletine in CYP1A2 with hybrid quantum mechanics/molecular mechanics (QM/MM) methods, providing a more detailed and realistic model. Multiple reaction barriers have been calculated at the QM(B3LYP-D)/MM(CHARMM27) level for the direct N-oxidation and H-abstraction/rebound mechanisms. Our calculated barriers indicate that the direct N-oxidation mechanism is preferred and proceeds via the doublet spin state of Compound I. Molecular dynamics simulations indicate that the presence of an ordered water molecule in the active site assists in the binding of mexiletine in the active site, but this is not a prerequisite for reaction via either mechanism. Several active site residues play a role in the binding of mexiletine in the active site, including Thr124 and Phe226. This work reveals key details of the N-hydroxylation of mexiletine and further demonstrates that mechanistic studies using QM/MM methods are useful for understanding drug metabolism.

  19. Computational revelation of binding mechanisms of inhibitors to endocellular protein tyrosine phosphatase 1B using molecular dynamics simulations.

    Science.gov (United States)

    Yan, Fangfang; Liu, Xinguo; Zhang, Shaolong; Su, Jing; Zhang, Qinggang; Chen, Jianzhong

    2017-11-06

    Endocellular protein tyrosine phosphatase 1B (PTP1B) is one of the most promising target for designing and developing drugs to cure type-II diabetes and obesity. Molecular dynamics (MD) simulations combined with molecular mechanics generalized Born surface area (MM-GBSA) and solvated interaction energy methods were applied to study binding differences of three inhibitors (ID: 901, 941, and 968) to PTP1B, the calculated results show that the inhibitor 901 has the strongest binding ability to PTP1B among the current inhibitors. Principal component (PC) analysis was also carried out to investigate the conformational change of PTP1B, and the results indicate that the associations of inhibitors with PTP1B generate a significant effect on the motion of the WPD-loop. Free energy decomposition method was applied to study the contributions of individual residues to inhibitor bindings, it is found that three inhibitors can generate hydrogen bonding interactions and hydrophobic interactions with different residues of PTP1B, which provide important forces for associations of inhibitors with PTP1B. This research is expected to give a meaningfully theoretical guidance to design and develop of effective drugs curing type-II diabetes and obesity.

  20. A molecular mechanism of mitotic centrosome assembly in Drosophila

    Science.gov (United States)

    Conduit, Paul T; Richens, Jennifer H; Wainman, Alan; Holder, James; Vicente, Catarina C; Pratt, Metta B; Dix, Carly I; Novak, Zsofia A; Dobbie, Ian M; Schermelleh, Lothar; Raff, Jordan W

    2014-01-01

    Centrosomes comprise a pair of centrioles surrounded by pericentriolar material (PCM). The PCM expands dramatically as cells enter mitosis, but it is unclear how this occurs. In this study, we show that the centriole protein Asl initiates the recruitment of DSpd-2 and Cnn to mother centrioles; both proteins then assemble into co-dependent scaffold-like structures that spread outwards from the mother centriole and recruit most, if not all, other PCM components. In the absence of either DSpd-2 or Cnn, mitotic PCM assembly is diminished; in the absence of both proteins, it appears to be abolished. We show that DSpd-2 helps incorporate Cnn into the PCM and that Cnn then helps maintain DSpd-2 within the PCM, creating a positive feedback loop that promotes robust PCM expansion around the mother centriole during mitosis. These observations suggest a surprisingly simple mechanism of mitotic PCM assembly in flies. DOI: http://dx.doi.org/10.7554/eLife.03399.001 PMID:25149451

  1. Molecular mechanism of biophylaxis for adverse factor in working environment

    International Nuclear Information System (INIS)

    Koizumi, Shinji

    2000-01-01

    It has been known that there exist some specific proteins in the pathway by which adverse environmental components are transferred to genes mediating the biophylaxis mechanism. Therefore, it seemed that information exchange might be made through interaction between such proteins and unknown proteins, and this step would be the key step of biophylaxis. In this study, construction of a recombinant protein was attempted to develop a detection method for such protein-protein interaction using radioisotopes. First, vectors that can express ZRF protein with S-tag at the N-terminal end in E.coli were constructed (pZRF29, pZRF30) and E.coli transfected with the vector was cultured to collect the recombinant protein. Thus obtained recombinant ZRF protein was analyzed by polyacrylamide gel electrophoresis and detection was made by Coomassie staining. Using the two vectors, ZRF protein was produced. The protein could be obtained at much higher efficiency in the present system than the previous system. However, the expression level of β-galactosidase as the control was still higher than that of the ZRF protein. This would be due to the higher stability of β- galactosidase, suggesting that further improvement might be obtainable by stabilizing the ZRF protein at the time of expression. It was thought necessary to choose the optimum conditions of the system in respects of cell culture and induction of the recombinant protein as well as protein extraction. (M.N.)

  2. An Updated Review of the Molecular Mechanisms in Drug Hypersensitivity

    Directory of Open Access Journals (Sweden)

    Chun-Bing Chen

    2018-01-01

    Full Text Available Drug hypersensitivity may manifest ranging from milder skin reactions (e.g., maculopapular exanthema and urticaria to severe systemic reactions, such as anaphylaxis, drug reactions with eosinophilia and systemic symptoms (DRESS/drug-induced hypersensitivity syndrome (DIHS, or Stevens–Johnson syndrome (SJS/toxic epidermal necrolysis (TEN. Current pharmacogenomic studies have made important strides in the prevention of some drug hypersensitivity through the identification of relevant genetic variants, particularly for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs. The associations identified by these studies are usually drug, phenotype, and ethnic specific. The drug presentation models that explain how small drug antigens might interact with HLA and T cell receptor (TCR molecules in drug hypersensitivity include the hapten theory, the p-i concept, the altered peptide repertoire model, and the altered TCR repertoire model. The broad spectrum of clinical manifestations of drug hypersensitivity involving different drugs, as well as the various pathomechanisms involved, makes the diagnosis and management of it more challenging. This review highlights recent advances in our understanding of the predisposing factors, immune mechanisms, pathogenesis, diagnostic tools, and therapeutic approaches for drug hypersensitivity.

  3. Testosterone deficiency syndrome: cellular and molecular mechanism of action.

    Science.gov (United States)

    Carruthers, Malcolm

    2013-02-01

    There is virtually no correlation between what are generally accepted to be the symptoms of deficient androgen in men and levels of androgens as measured in the laboratory. Now that androgen deficiency is being shown to play a part in conditions as diverse as metabolic syndrome, diabetes, and coronary heart disease, a hypothesis is needed to explain this apparent discrepancy between measured androgen levels and our understanding of the symptoms of androgen deficiency. When the possible mechanisms for androgen actions are considered, one explanation emerges that androgen may act much like insulin in persons with type 2 diabetes mellitus: the degree of androgen resistance may be variable depending on the organs or systems considered. Therefore, the symptoms can result from altered or damaged synthesis of androgen synthesis or regulation, elevated androgen binding, a reduction in tissue response, or decreased as a result of polymorphism and aging. Genomic transcription and translation may also be affected. As with diabetes, in adult male androgen deficiency, it is suggested that the definition of androgen deficiency should be based on individual physiology, with the requirements of the individual at a particular stage of life setting the baseline against which any deficiency of androgens or androgen metabolites, either absolute or relative, is determined. This approach will affect the terminology, etiology, diagnosis, and treatment of androgen deficiency.

  4. Molecular mechanisms of severe acute respiratory syndrome (SARS

    Directory of Open Access Journals (Sweden)

    Zabel Peter

    2005-01-01

    Full Text Available Abstract Severe acute respiratory syndrome (SARS is a new infectious disease caused by a novel coronavirus that leads to deleterious pulmonary pathological features. Due to its high morbidity and mortality and widespread occurrence, SARS has evolved as an important respiratory disease which may be encountered everywhere in the world. The virus was identified as the causative agent of SARS due to the efforts of a WHO-led laboratory network. The potential mutability of the SARS-CoV genome may lead to new SARS outbreaks and several regions of the viral genomes open reading frames have been identified which may contribute to the severe virulence of the virus. With regard to the pathogenesis of SARS, several mechanisms involving both direct effects on target cells and indirect effects via the immune system may exist. Vaccination would offer the most attractive approach to prevent new epidemics of SARS, but the development of vaccines is difficult due to missing data on the role of immune system-virus interactions and the potential mutability of the virus. Even in a situation of no new infections, SARS remains a major health hazard, as new epidemics may arise. Therefore, further experimental and clinical research is required to control the disease.

  5. Neural, Cellular and Molecular Mechanisms of Active Forgetting

    Science.gov (United States)

    Medina, Jorge H.

    2018-01-01

    The neurobiology of memory formation attracts much attention in the last five decades. Conversely, the rules that govern and the mechanisms underlying forgetting are less understood. In addition to retroactive interference, retrieval-induced forgetting and passive decay of time, it has been recently demonstrated that the nervous system has a diversity of active and inherent processes involved in forgetting. In Drosophila, some operate mainly at an early stage of memory formation and involves dopamine (DA) neurons, specific postsynaptic DA receptor subtypes, Rac1 activation and induces rapid active forgetting. In mammals, others regulate forgetting and persistence of seemingly consolidated memories and implicate the activity of DA receptor subtypes and AMPA receptors in the hippocampus (HP) and related structures to activate parallel signaling pathways controlling active time-dependent forgetting. Most of them may involve plastic changes in synaptic and extrasynaptic receptors including specific removal of GluA2 AMPA receptors. Forgetting at longer timescales might also include changes in adult neurogenesis in the dentate gyrus (DG) of the HP. Therefore, based on relevance or value considerations neuronal circuits may regulate in a time-dependent manner what is formed, stored, and maintained and what is forgotten. PMID:29467630

  6. Multidrug-Resistant Candida: Epidemiology, Molecular Mechanisms, and Treatment.

    Science.gov (United States)

    Arendrup, Maiken Cavling; Patterson, Thomas F

    2017-08-15

    Invasive Candida infections remain an important cause of morbidity and mortality, especially in hospitalized and immunocompromised or critically ill patients. A limited number of antifungal agents from only a few drug classes are available to treat patients with these serious infections. Resistance can be either intrinsic or acquired. Resistance mechanisms are not exchanged between Candida; thus, acquired resistance either emerges in response to an antifungal selection pressure in the individual patient or, more rarely, occur due to horizontal transmission of resistant strains between patients. Although multidrug resistance is uncommon, increasing reports of multidrug resistance to the azoles, echinocandins, and polyenes have occurred in several Candida species, most notably Candida glabrata and more recently Candida auris. Drivers are overall antifungal use, subtherapeutic drug levels at sites of infection/colonization, drug sequestration in the biofilm matrix, and, in the setting of outbreaks, suboptimal infection control. Moreover, recent research suggests that DNA mismatch repair gene mutations may facilitate acquisition of resistance mutations in C. glabrata specifically. Diagnosis of antifungal-resistant Candida infections is critical to the successful management of patients with these infections. Reduction of unnecessary use of antifungals via antifungal stewardship is critical to limit multidrug resistance emergence. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  7. Molecular mechanisms of responses to radiation through protein kinase C

    International Nuclear Information System (INIS)

    Nakajima, Tetsuo

    2005-01-01

    Described are the activation and cascade of the protein kinase C (PKC) which mediating the control of radiation-induced apoptosis. PKC is a family of c-, n- and a-subtypes and plays a major role in responding to the radiation exposure for DNA repair, cell cycle arrest and apoptosis. The author has conducted studies of mouse thymic lymphoma cells which have a property to respond even to low dose radiation, and has showed that, in the highly radiosensitive cell strain, 3SBH5 where apoptosis occurs in 50 and 90% post 0.5 and 2 Gy exposure, respectively, cPKC works as a surviving signal without intracellular movement after irradiation. In contrast, PKC has been alternatively shown to participate in apoptosis induction, showing that different enzyme species in the subtypes work specifically depending on passing time. Comparison with the radio-resistant cell strain, XR223, has revealed that the difference in the localization controls of PKCδ in the cell determines the radiosensitivity, however, the control mechanism is found to be separate from Atm pathway by which PKCδ is usually regulated. Recent studies have revealed that PKC performs the intracellular cross-talk in various phosphorylation cascades. Studies of PKC can be toward their uses for radiation effect assessment, radiotherapy and medicare for urgent exposure. (S.I.)

  8. Molecular mechanisms of acrolein toxicity: relevance to human disease.

    Science.gov (United States)

    Moghe, Akshata; Ghare, Smita; Lamoreau, Bryan; Mohammad, Mohammad; Barve, Shirish; McClain, Craig; Joshi-Barve, Swati

    2015-02-01

    Acrolein, a highly reactive unsaturated aldehyde, is a ubiquitous environmental pollutant and its potential as a serious environmental health threat is beginning to be recognized. Humans are exposed to acrolein per oral (food and water), respiratory (cigarette smoke, automobile exhaust, and biocide use) and dermal routes, in addition to endogenous generation (metabolism and lipid peroxidation). Acrolein has been suggested to play a role in several disease states including spinal cord injury, multiple sclerosis, Alzheimer's disease, cardiovascular disease, diabetes mellitus, and neuro-, hepato-, and nephro-toxicity. On the cellular level, acrolein exposure has diverse toxic effects, including DNA and protein adduction, oxidative stress, mitochondrial disruption, membrane damage, endoplasmic reticulum stress, and immune dysfunction. This review addresses our current understanding of each pathogenic mechanism of acrolein toxicity, with emphasis on the known and anticipated contribution to clinical disease, and potential therapies. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  9. Molecular mechanisms of toxicity of important food-borne phytotoxins.

    Science.gov (United States)

    Rietjens, Ivonne M C M; Martena, Martijn J; Boersma, Marelle G; Spiegelenberg, Wim; Alink, Gerrit M

    2005-02-01

    At present, there is an increasing interest for plant ingredients and their use in drugs, for teas, or in food supplements. The present review describes the nature and mechanism of action of the phytochemicals presently receiving increased attention in the field of food toxicology. This relates to compounds including aristolochic acids, pyrrolizidine alkaloids, beta-carotene, coumarin, the alkenylbenzenes safrole, methyleugenol and estragole, ephedrine alkaloids and synephrine, kavalactones, anisatin, St. John's wort ingredients, cyanogenic glycosides, solanine and chaconine, thujone, and glycyrrhizinic acid. It can be concluded that several of these phytotoxins cause concern, because of their bioactivation to reactive alkylating intermediates that are able to react with cellular macromolecules causing cellular toxicity, and, upon their reaction with DNA, genotoxicity resulting in tumors. Another group of the phytotoxins presented is active without the requirement for bioactivation and, in most cases, these compounds appear to act as neurotoxins interacting with one of the neurotransmitter systems. Altogether, the examples presented illustrate that natural does not equal safe and that in modern society adverse health effects, upon either acute or chronic exposure to phytochemicals, can occur as a result of use of plant- or herb-based foods, teas, or other extracts.

  10. An Updated Review of the Molecular Mechanisms in Drug Hypersensitivity

    Science.gov (United States)

    Abe, Riichiro; Pan, Ren-You; Wang, Chuang-Wei

    2018-01-01

    Drug hypersensitivity may manifest ranging from milder skin reactions (e.g., maculopapular exanthema and urticaria) to severe systemic reactions, such as anaphylaxis, drug reactions with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS), or Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Current pharmacogenomic studies have made important strides in the prevention of some drug hypersensitivity through the identification of relevant genetic variants, particularly for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). The associations identified by these studies are usually drug, phenotype, and ethnic specific. The drug presentation models that explain how small drug antigens might interact with HLA and T cell receptor (TCR) molecules in drug hypersensitivity include the hapten theory, the p-i concept, the altered peptide repertoire model, and the altered TCR repertoire model. The broad spectrum of clinical manifestations of drug hypersensitivity involving different drugs, as well as the various pathomechanisms involved, makes the diagnosis and management of it more challenging. This review highlights recent advances in our understanding of the predisposing factors, immune mechanisms, pathogenesis, diagnostic tools, and therapeutic approaches for drug hypersensitivity. PMID:29651444

  11. Molecular mechanisms of root gravity sensing and signal transduction.

    Science.gov (United States)

    Strohm, Allison K; Baldwin, Katherine L; Masson, Patrick H

    2012-01-01

    Plants use gravity as a guide to direct their roots down into the soil to anchor themselves and to find resources needed for growth and development. In higher plants, the columella cells of the root tip form the primary site of gravity sensing, and in these cells the sedimentation of dense, starch-filled plastids (amyloplasts) triggers gravity signal transduction. This generates an auxin gradient across the root cap that is transmitted to the elongation zone where it promotes differential cell elongation, allowing the root to direct itself downward. It is still not well understood how amyloplast sedimentation leads to auxin redistribution. Models have been proposed to explain how mechanosensitive ion channels or ligand-receptor interactions could connect these events. Although their roles are still unclear, possible second messengers in this process include protons, Ca(2+), and inositol 1,4,5-triphosphate. Upon gravistimulation, the auxin efflux facilitators PIN3 and PIN7 relocalize to the lower side of the columella cells and mediate auxin redistribution. However, evidence for an auxin-independent secondary mechanism of gravity sensing and signal transduction suggests that this physiological process is quite complex. Furthermore, plants must integrate a variety of environmental cues, resulting in multifaceted relationships between gravitropism and other directional growth responses such as hydro-, photo-, and thigmotropism. Copyright © 2011 Wiley Periodicals, Inc.

  12. A Molecular Dynamics (MD and Quantum Mechanics/Molecular Mechanics (QM/MM Study on Ornithine Cyclodeaminase (OCD: A Tale of Two Iminiums

    Directory of Open Access Journals (Sweden)

    James W. Gauld

    2012-10-01

    Full Text Available Ornithine cyclodeaminase (OCD is an NAD+-dependent deaminase that is found in bacterial species such as Pseudomonas putida. Importantly, it catalyzes the direct conversion of the amino acid L-ornithine to L-proline. Using molecular dynamics (MD and a hybrid quantum mechanics/molecular mechanics (QM/MM method in the ONIOM formalism, the catalytic mechanism of OCD has been examined. The rate limiting step is calculated to be the initial step in the overall mechanism: hydride transfer from the L-ornithine’s Cα–H group to the NAD+ cofactor with concomitant formation of a Cα=NH2+ Schiff base with a barrier of 90.6 kJ mol−1. Importantly, no water is observed within the active site during the MD simulations suitably positioned to hydrolyze the Cα=NH2+ intermediate to form the corresponding carbonyl. Instead, the reaction proceeds via a non-hydrolytic mechanism involving direct nucleophilic attack of the δ-amine at the Cα-position. This is then followed by cleavage and loss of the α-NH2 group to give the Δ1-pyrroline-2-carboxylate that is subsequently reduced to L-proline.

  13. A Molecular Dynamics (MD) and Quantum Mechanics/Molecular Mechanics (QM/MM) Study on Ornithine Cyclodeaminase (OCD): A Tale of Two Iminiums

    Science.gov (United States)

    Ion, Bogdan F.; Bushnell, Eric A. C.; De Luna, Phil; Gauld, James W.

    2012-01-01

    Ornithine cyclodeaminase (OCD) is an NAD+-dependent deaminase that is found in bacterial species such as Pseudomonas putida. Importantly, it catalyzes the direct conversion of the amino acid L-ornithine to L-proline. Using molecular dynamics (MD) and a hybrid quantum mechanics/molecular mechanics (QM/MM) method in the ONIOM formalism, the catalytic mechanism of OCD has been examined. The rate limiting step is calculated to be the initial step in the overall mechanism: hydride transfer from the L-ornithine’s Cα–H group to the NAD+ cofactor with concomitant formation of a Cα=NH2 + Schiff base with a barrier of 90.6 kJ mol−1. Importantly, no water is observed within the active site during the MD simulations suitably positioned to hydrolyze the Cα=NH2 + intermediate to form the corresponding carbonyl. Instead, the reaction proceeds via a non-hydrolytic mechanism involving direct nucleophilic attack of the δ-amine at the Cα-position. This is then followed by cleavage and loss of the α-NH2 group to give the Δ1-pyrroline-2-carboxylate that is subsequently reduced to L-proline. PMID:23202934

  14. Molecular Diagnosis of 5α-Reductase Type II Deficiency in Brazilian Siblings with 46,XY Disorder of Sex Development

    Directory of Open Access Journals (Sweden)

    Maricilda Palandi de Mello

    2011-12-01

    Full Text Available The steroid 5α-reductase type II enzyme catalyzes the conversion of testosterone (T to dihydrotestosterone (DHT, and its deficiency leads to undervirilization in 46,XY individuals, due to an impairment of this conversion in genital tissues. Molecular analysis in the steroid 5α-reductase type II gene (SRD5A2 was performed in two 46,XY female siblings. SRD5A2 gene sequencing revealed that the patients were homozygous for p.Gln126Arg missense mutation, which results from the CGA > CAA nucleotide substitution. The molecular result confirmed clinical diagnosis of 46,XY disorder of sex development (DSD for the older sister and directed the investigation to other family members. Studies on SRD5A2 protein structure showed severe changes at NADPH binding region indicating that structural modeling analysis can be useful to evaluate the deleterious role of a mutation as causing 5α-reductase type II enzyme deficiency.

  15. Insight into the Mechanism of Hydrolysis of Meropenem by OXA-23 Serine-β-lactamase Gained by Quantum Mechanics/Molecular Mechanics Calculations.

    Science.gov (United States)

    Sgrignani, Jacopo; Grazioso, Giovanni; De Amici, Marco

    2016-09-13

    The fast and constant development of drug resistant bacteria represents a serious medical emergency. To overcome this problem, the development of drugs with new structures and modes of action is urgently needed. In this work, we investigated, at the atomistic level, the mechanisms of hydrolysis of Meropenem by OXA-23, a class D β-lactamase, combining unbiased classical molecular dynamics and umbrella sampling simulations with classical force field-based and quantum mechanics/molecular mechanics potentials. Our calculations provide a detailed structural and dynamic picture of the molecular steps leading to the formation of the Meropenem-OXA-23 covalent adduct, the subsequent hydrolysis, and the final release of the inactive antibiotic. In this mechanistic framework, the predicted activation energy is in good agreement with experimental kinetic measurements, validating the expected reaction path.

  16. Illustrating the Molecular Origin of Mechanical Stress in Ductile Deformation of Polymer Glasses

    Science.gov (United States)

    Li, Xiaoxiao; Liu, Jianning; Liu, Zhuonan; Tsige, Mesfin; Wang, Shi-Qing

    2018-02-01

    New experiments show that tensile stress vanishes shortly after preyield deformation of polymer glasses while tensile stress after postyield deformation stays high and relaxes on much longer time scales, thus hinting at a specific molecular origin of stress in ductile cold drawing: chain tension rather than intersegmental interactions. Molecular dynamics simulation based on a coarse-grained model for polystyrene confirms the conclusion that the chain network plays an essential role, causing the glassy state to yield and to respond with a high level of intrachain retractive stress. This identification sheds light on the future development regarding an improved theoretical account for molecular mechanics of polymer glasses and the molecular design of stronger polymeric materials to enhance their mechanical performance.

  17. Illustrating the Molecular Origin of Mechanical Stress in Ductile Deformation of Polymer Glasses.

    Science.gov (United States)

    Li, Xiaoxiao; Liu, Jianning; Liu, Zhuonan; Tsige, Mesfin; Wang, Shi-Qing

    2018-02-16

    New experiments show that tensile stress vanishes shortly after preyield deformation of polymer glasses while tensile stress after postyield deformation stays high and relaxes on much longer time scales, thus hinting at a specific molecular origin of stress in ductile cold drawing: chain tension rather than intersegmental interactions. Molecular dynamics simulation based on a coarse-grained model for polystyrene confirms the conclusion that the chain network plays an essential role, causing the glassy state to yield and to respond with a high level of intrachain retractive stress. This identification sheds light on the future development regarding an improved theoretical account for molecular mechanics of polymer glasses and the molecular design of stronger polymeric materials to enhance their mechanical performance.

  18. Molecular Mechanisms behind Free Radical Scavengers Function against Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Fereshteh Ahmadinejad

    2017-07-01

    Full Text Available Accumulating evidence shows that oxidative stress is involved in a wide variety of human diseases: rheumatoid arthritis, Alzheimer’s disease, Parkinson’s disease, cancers, etc. Here, we discuss the significance of oxidative conditions in different disease, with the focus on neurodegenerative disease including Parkinson’s disease, which is mainly caused by oxidative stress. Reactive oxygen and nitrogen species (ROS and RNS, respectively, collectively known as RONS, are produced by cellular enzymes such as myeloperoxidase, NADPH-oxidase (nicotinamide adenine dinucleotide phosphate-oxidase and nitric oxide synthase (NOS. Natural antioxidant systems are categorized into enzymatic and non-enzymatic antioxidant groups. The former includes a number of enzymes such as catalase and glutathione peroxidase, while the latter contains a number of antioxidants acquired from dietary sources including vitamin C, carotenoids, flavonoids and polyphenols. There are also scavengers used for therapeutic purposes, such as 3,4-dihydroxyphenylalanine (L-DOPA used routinely in the treatment of Parkinson’s disease (not as a free radical scavenger, and 3-methyl-1-phenyl-2-pyrazolin-5-one (Edaravone that acts as a free radical detoxifier frequently used in acute ischemic stroke. The cell surviving properties of L-DOPA and Edaravone against oxidative stress conditions rely on the alteration of a number of stress proteins such as Annexin A1, Peroxiredoxin-6 and PARK7/DJ-1 (Parkinson disease protein 7, also known as Protein deglycase DJ-1. Although they share the targets in reversing the cytotoxic effects of H2O2, they seem to have distinct mechanism of function. Exposure to L-DOPA may result in hypoxia condition and further induction of ORP150 (150-kDa oxygen-regulated protein with its concomitant cytoprotective effects but Edaravone seems to protect cells via direct induction of Peroxiredoxin-2 and inhibition of apoptosis.

  19. Molecular mechanisms of citrus flavanones on hepatic gluconeogenesis.

    Science.gov (United States)

    Constantin, Rodrigo Polimeni; Constantin, Renato Polimeni; Bracht, Adelar; Yamamoto, Nair Seiko; Ishii-Iwamoto, Emy Luiza; Constantin, Jorgete

    2014-01-01

    It is well known that hyperglycaemia is the initiating cause of tissue damage associated with type 2 diabetes mellitus and that enhanced hepatic gluconeogenesis may account for the increase in blood glucose levels. The purpose of this work was to investigate the possible actions and mechanisms of three related citrus flavanones, namely hesperidin, hesperetin and naringenin, on hepatic gluconeogenesis and related parameters using isolated perfused rat liver. Hesperetin and naringenin (but not hesperidin) inhibited gluconeogenesis from lactate plus pyruvate, alanine and dihydroxyacetone. The inhibitory effects of these flavanones on gluconeogenesis from lactate and pyruvate (hesperetin IC50 75.6 μM; naringenin IC50 85.5 μM) as well as from alanine were considerably more pronounced than those from dihydroxyacetone. The main cause of gluconeogenesis inhibition is the reduction of pyruvate carboxylation by hesperetin (IC50 134.2 μM) and naringenin (IC50 143.5 μM) via inhibition of pyruvate transport into the mitochondria. Secondary causes are likely inhibition of energy metabolism, diversion of glucose 6-phosphate for glucuronidation reactions and oxidation of NADH by flavanone phenoxyl radicals. The influence of the structural differences between hesperetin and naringenin on their metabolic effects was negligible. Analytical evidence indicated that the presence of a rutinoside moiety in hesperidin noticeably decreases its metabolic effects, confirming that hesperetin and naringenin interact with intracellular enzymes and mitochondrial or cellular membranes better than hesperidin. Thus, the inhibition of the gluconeogenic pathway by citrus flavanones, which was similar to that of the drug metformin, may represent an attractive novel treatment strategy for type 2 diabetes. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. Molecular cloning, characterization and localization of chicken type II procollagen gene.

    Science.gov (United States)

    Xi, Caixia; Liu, Nan; Liang, Fei; Guo, Siqi; Sun, Yuying; Yang, Fengtang; Xi, Yongzhi

    2006-01-17

    Chicken type II procollagen (ccol2a1) has become as an important oral tolerance protein for effective treatment of rheumatoid arthritis. However, its molecular identity remains unclear. Here, we reported the full-length cDNA and nearly complete genomic DNA encoding ccol2a1. We have determined the structural organization, evolutional characters, developmental expression and chromosomal mapping of the gene. The full-length cDNA sequence spans 4837 bp containing all the coding region of the ccol2a1 including 3' and 5' untranslation region. The deduced peptide of ccol2a1, composed of 1420 amino acids, can be divided into signal peptide, N-propeptide, N-telopeptide, triple helix, C-telopeptide and C-propeptide. The ccol2a1 genomic DNA sequence was determined to be 12,523 bp long containing 54 exons interrupted by 53 introns. Comparison of the ccol2a1 with its counterparts in human, mouse, canine, horse, rat, frog and newt revealed highly conserved sequence in the triple helix domain. Chromosomal mapping of ccol2a1 locates it on 4P2. While the ccol2a1 mRNA was expressed in multiple tissues, the protein was only detected in chondrogenic cartilage, vitreous body and cornea. The ccol2a1 was found to contain two isoforms detected by RT-PCR. The distribution of the ccol2a1 lacking exon 2wasfrequently detected in chondrogenic tissues, whereas the exon 2-containing isoform was more abundant in non-chondrogenic tissues. These results provide useful information for preparing recombinant chicken type II collagen and for a better understanding of normal cartilage development.