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...

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.

Molecular Mechanisms of Breast Cancer Metastasis and Potential Anti-metastatic Compounds.

Science.gov (United States)

Tungsukruthai, Sucharat; Petpiroon, Nalinrat; Chanvorachote, Pithi

2018-05-01

Throughout the world, breast cancer is among the major causes of cancer-related death and is the most common cancer found in women. The development of cancer molecular knowledge has surpassed the novel concept of cancer biology and unraveled principle targets for anticancer drug developments and treatment strategies. Metastatic breast cancer cells acquire their aggressive features through several mechanisms, including augmentation of survival, proliferation, tumorigenicity, and motility-related cellular pathways. Clearly, natural product-derived compounds have since long been recognized as an important source for anticancer drugs, several of which have been shown to have promising anti-metastasis activities by suppressing key molecular features supporting such cell aggressiveness. This review provides the essential details of breast cancer, the molecular-based insights into metastasis, as well as the effects and mechanisms of potential compounds for breast cancer therapeutic approaches. As the abilities of cancer cells to invade and metastasize are addressed as the hallmarks of cancer, compounds possessing anti-metastatic effects, together with their defined molecular drug action could benefit the development of new drugs as well as treatment strategies. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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.

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.

Bioinformatics analysis on molecular mechanism of rheum officinale in treatment of jaundice

Science.gov (United States)

Shan, Si; Tu, Jun; Nie, Peng; Yan, Xiaojun

2017-01-01

Objective: To study the molecular mechanism of Rheum officinale in the treatment of Jaundice by building molecular networks and comparing canonical pathways. Methods: Target proteins of Rheum officinale and related genes of Jaundice were searched from Pubchem and Gene databases online respectively. Molecular networks and canonical pathways comparison analyses were performed by Ingenuity Pathway Analysis (IPA). Results: The molecular networks of Rheum officinale and Jaundice were complex and multifunctional. The 40 target proteins of Rheum officinale and 33 Homo sapiens genes of Jaundice were found in databases. There were 19 common pathways both related networks. Rheum officinale could regulate endothelial differentiation, Interleukin-1B (IL-1B) and Tumor Necrosis Factor (TNF) in these pathways. Conclusions: Rheum officinale treat Jaundice by regulating many effective nodes of Apoptotic pathway and cellular immunity related pathways.

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.

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...

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.

Endocrine-disrupting Chemicals: Review of Toxicological Mechanisms Using Molecular Pathway Analysis

Science.gov (United States)

Yang, Oneyeol; Kim, Hye Lim; Weon, Jong-Il; Seo, Young Rok

2015-01-01

Endocrine disruptors are known to cause harmful effects to human through various exposure routes. These chemicals mainly appear to interfere with the endocrine or hormone systems. As importantly, numerous studies have demonstrated that the accumulation of endocrine disruptors can induce fatal disorders including obesity and cancer. Using diverse biological tools, the potential molecular mechanisms related with these diseases by exposure of endocrine disruptors. Recently, pathway analysis, a bioinformatics tool, is being widely used to predict the potential mechanism or biological network of certain chemicals. In this review, we initially summarize the major molecular mechanisms involved in the induction of the above mentioned diseases by endocrine disruptors. Additionally, we provide the potential markers and signaling mechanisms discovered via pathway analysis under exposure to representative endocrine disruptors, bisphenol, diethylhexylphthalate, and nonylphenol. The review emphasizes the importance of pathway analysis using bioinformatics to finding the specific mechanisms of toxic chemicals, including endocrine disruptors. PMID:25853100

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.)

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.)

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.

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.

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.

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.

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...

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.

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

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.

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

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...

[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.

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.

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.

Theoretical Characterization of the Spectral Density of the Water-Soluble Chlorophyll-Binding Protein from Combined Quantum Mechanics/Molecular Mechanics Molecular Dynamics Simulations.

Science.gov (United States)

Rosnik, Andreana M; Curutchet, Carles

2015-12-08

Over the past decade, both experimentalists and theorists have worked to develop methods to describe pigment-protein coupling in photosynthetic light-harvesting complexes in order to understand the molecular basis of quantum coherence effects observed in photosynthesis. Here we present an improved strategy based on the combination of quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations and excited-state calculations to predict the spectral density of electronic-vibrational coupling. We study the water-soluble chlorophyll-binding protein (WSCP) reconstituted with Chl a or Chl b pigments as the system of interest and compare our work with data obtained by Pieper and co-workers from differential fluorescence line-narrowing spectra (Pieper et al. J. Phys. Chem. B 2011, 115 (14), 4042-4052). Our results demonstrate that the use of QM/MM MD simulations where the nuclear positions are still propagated at the classical level leads to a striking improvement of the predicted spectral densities in the middle- and high-frequency regions, where they nearly reach quantitative accuracy. This demonstrates that the so-called "geometry mismatch" problem related to the use of low-quality structures in QM calculations, not the quantum features of pigments high-frequency motions, causes the failure of previous studies relying on similar protocols. Thus, this work paves the way toward quantitative predictions of pigment-protein coupling and the comprehension of quantum coherence effects in photosynthesis.

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.

Molecular and cellular insights into Zika virus-related neuropathies.

Science.gov (United States)

Zhou, Kai; Wang, Long; Yu, Di; Huang, Hesuyuan; Ji, Hong; Mo, Xuming

2017-06-01

Zika virus (ZIKV), a relatively elusive Aedes mosquito-transmitted flavivirus, had been brought into spotlight until recent widespread outbreaks accompanied by unexpectedly severe clinical neuropathies, including fetal microcephaly and Guillain-Barré syndrome (GBS) in the adult. In this review, we focus on the underlying cellular and molecular mechanisms by which vertically transmitted microorganisms reach the fetus and trigger neuropathies.

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.

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.

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.

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

Molecular Age-Related Changes in the Anterior Segment of the Eye

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Luis Fernando Hernandez-Zimbron

2017-01-01

Full Text Available Purpose. To examine the current knowledge about the age-related processes in the anterior segment of the eye at a biological, clinical, and molecular level. Methods. We reviewed the available published literature that addresses the aging process of the anterior segment of the eye and its associated molecular and physiological events. We performed a search on PubMed, CINAHL, and Embase using the MeSH terms “eye,” “anterior segment,” and “age.” We generated searches to account for synonyms of these keywords and MESH headings as follows: (1 “Eye” AND “ageing process” OR “anterior segment ageing” and (2 “Anterior segment” AND “ageing process” OR “anterior segment” AND “molecular changes” AND “age.” Results. Among the principal causes of age-dependent alterations in the anterior segment of the eye, we found the mutation of the TGF-β gene and loss of autophagy in addition to oxidative stress, which contributes to the pathogenesis of degenerative diseases. Conclusions. In this review, we summarize the current knowledge regarding some of the molecular mechanisms related to aging in the anterior segment of the eye. We also introduce and propose potential roles of autophagy, an important mechanism responsible for maintaining homeostasis and proteostasis under stress conditions in the anterior segment during aging.

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.

Molecular mechanics of silk nanostructures under varied mechanical loading.

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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.

Molecular modifications-mechanical behaviour relationships for gamma irradiated LLDPE/PA6 blends

International Nuclear Information System (INIS)

Valenza, A.; Spadaro, G.; Calderaro, E.

1994-01-01

The molecular modifications, due to γ radiation under vacuum, of linear low density polyethylene/polyamide 6 blends are presented and related to their mechanical behaviour. Solubility and melt viscosity tests indicate that in blends the polyethylene component undergoes mainly crosslinking phenomena, whereas the main effect on polyamide is chain branching. According to these molecular modifications, the most relevant effect is the increase of the tensile modulus for the polyethylene rich blends and the increase of the impact strength for the polyamide rich blends. (author)

Multiscale Quantum Mechanics/Molecular Mechanics Simulations with Neural Networks.

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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.

Molecular Mechanisms Responsible for Increased Vulnerability of the Ageing Oocyte to Oxidative Damage

Science.gov (United States)

Redgrove, Kate A.; McLaughlin, Eileen A.

2017-01-01

In their midthirties, women experience a decline in fertility, coupled to a pronounced increase in the risk of aneuploidy, miscarriage, and birth defects. Although the aetiology of such pathologies are complex, a causative relationship between the age-related decline in oocyte quality and oxidative stress (OS) is now well established. What remains less certain are the molecular mechanisms governing the increased vulnerability of the aged oocyte to oxidative damage. In this review, we explore the reduced capacity of the ageing oocyte to mitigate macromolecular damage arising from oxidative insults and highlight the dramatic consequences for oocyte quality and female fertility. Indeed, while oocytes are typically endowed with a comprehensive suite of molecular mechanisms to moderate oxidative damage and thus ensure the fidelity of the germline, there is increasing recognition that the efficacy of such protective mechanisms undergoes an age-related decline. For instance, impaired reactive oxygen species metabolism, decreased DNA repair, reduced sensitivity of the spindle assembly checkpoint, and decreased capacity for protein repair and degradation collectively render the aged oocyte acutely vulnerable to OS and limits their capacity to recover from exposure to such insults. We also highlight the inadequacies of our current armoury of assisted reproductive technologies to combat age-related female infertility, emphasising the need for further research into mechanisms underpinning the functional deterioration of the ageing oocyte. PMID:29312475

Molecular mechanisms in lithium-associated renal disease: a systematic review.

Science.gov (United States)

Rej, Soham; Pira, Shamira; Marshe, Victoria; Do, André; Elie, Dominique; Looper, Karl J; Herrmann, Nathan; Müller, Daniel J

2016-11-01

Lithium is an essential treatment in bipolar disorder and treatment-resistant depression; however, its use has been limited by concerns regarding its renal adverse effects. An improved understanding of potential molecular mechanisms can help develop prevention and treatment strategies for lithium-associated renal disease. We conducted a systematic literature search using MEDLINE, Embase, and PsychINFO including English-language original research articles published prior to November 2015 that specifically investigated lithium's effects on nephrogenic diabetes insipidus (NDI) and chronic kidney disease (CKD), using molecular markers. From a total of 3510 records, 71 pre-clinical studies and two relevant clinical studies were identified. Molecular alterations were reported in calcium signaling, inositol monophosphate, extracellular-regulated, prostaglandin, sodium/solute transport, G-protein-coupled receptors, nitric oxide, vasopressin/aquaporin, and inflammation-related pathways in lithium-associated renal disease. The majority of studies found that these mechanisms were implicated in NDI, while few studies had examined CKD. Future studies will have to focus on (1) validating the present findings in human subjects and (2) examining CKD, which is the most clinically relevant lithium-associated renal effect. This will improve our understanding of lithium's biological effects, as well as inform a personalized medicine approach, which could lead to safer lithium prescribing and less renal adverse events.

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

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.

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

STATINS AND MYOPATHY: MOLECULAR MECHANISMS

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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. 

Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

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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.

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.

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

Molecular toxicity mechanism of nanosilver

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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.

[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.

New insights into the molecular mechanism of intestinal fatty acid absorption.

Science.gov (United States)

Wang, Tony Y; Liu, Min; Portincasa, Piero; Wang, David Q-H

2013-11-01

Dietary fat is one of the most important energy sources of all the nutrients. Fatty acids, stored as triacylglycerols (also called triglycerides) in the body, are an important reservoir of stored energy and derived primarily from animal fats and vegetable oils. Although the molecular mechanisms for the transport of water-insoluble amphipathic fatty acids across cell membranes have been debated for many years, it is now believed that the dominant means for intestinal fatty acid uptake is via membrane-associated fatty acid-binding proteins, that is, fatty acid transporters on the apical membrane of enterocytes. These findings indicate that intestinal fatty acid absorption is a multistep process that is regulated by multiple genes at the enterocyte level, and intestinal fatty acid absorption efficiency could be determined by factors influencing intraluminal fatty acid molecules across the brush border membrane of enterocytes. To facilitate research on intestinal, hepatic and plasma triacylglycerol metabolism, it is imperative to establish standard protocols for precisely and accurately measuring the efficiency of intestinal fatty acid absorption in humans and animal models. In this review, we will discuss the chemical structure and nomenclature of fatty acids and summarize recent progress in investigating the molecular mechanisms underlying the intestinal absorption of fatty acids, with a particular emphasis on the physical chemistry of intestinal lipids and the molecular physiology of intestinal fatty acid transporters. A better understanding of the molecular mechanism of intestinal fatty acid absorption should lead to novel approaches to the treatment and the prevention of fatty acid-related metabolic diseases that are prevalent worldwide. © 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.

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

Features of Knowledge Building in Biology: Understanding Undergraduate Students’ Ideas about Molecular Mechanisms

Science.gov (United States)

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

2016-01-01

Research has suggested that teaching and learning in molecular and cellular biology (MCB) is difficult. We used a new lens to understand undergraduate reasoning about molecular mechanisms: the knowledge-integration approach to conceptual change. Knowledge integration is the dynamic process by which learners acquire new ideas, develop connections between ideas, and reorganize and restructure prior knowledge. Semistructured, clinical think-aloud interviews were conducted with introductory and upper-division MCB students. Interviews included a written conceptual assessment, a concept-mapping activity, and an opportunity to explain the biomechanisms of DNA replication, transcription, and translation. Student reasoning patterns were explored through mixed-method analyses. Results suggested that students must sort mechanistic entities into appropriate mental categories that reflect the nature of MCB mechanisms and that conflation between these categories is common. We also showed how connections between molecular mechanisms and their biological roles are part of building an integrated knowledge network as students develop expertise. We observed differences in the nature of connections between ideas related to different forms of reasoning. Finally, we provide a tentative model for MCB knowledge integration and suggest its implications for undergraduate learning. PMID:26931398

Molecular and Neuronal Plasticity Mechanisms in the Amygdala-Prefrontal Cortical Circuit: Implications for Opiate Addiction Memory Formation

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Laura G Rosen

2015-11-01

Full Text Available The persistence of associative memories linked to the rewarding properties of drugs of abuse is a core underlying feature of the addiction process. Opiate class drugs in particular, possess potent euphorigenic effects which, when linked to environmental cues, can produce drug-related ‘trigger’ memories that may persist for lengthy periods of time, even during abstinence, in both humans and other animals. Furthermore, the transitional switch from the drug-naïve, non-dependent state to states of dependence and withdrawal, represents a critical boundary between distinct neuronal and molecular substrates associated with opiate-reward memory formation. Identifying the functional molecular and neuronal mechanisms related to the acquisition, consolidation, recall and extinction phases of opiate-related reward memories is critical for understanding, and potentially reversing, addiction-related memory plasticity characteristic of compulsive drug-seeking behaviors. The mammalian prefrontal cortex (PFC and basolateral nucleus of the amygdala (BLA share important functional and anatomical connections that are involved importantly in the processing of associative memories linked to drug reward. In addition, both regions share interconnections with the mesolimbic pathway’s ventral tegmental area (VTA and nucleus accumbens (NAc and can modulate dopamine (DA transmission and neuronal activity associated with drug-related DAergic signaling dynamics. In this review, we will summarize research from both human and animal modelling studies highlighting the importance of neuronal and molecular plasticity mechanisms within this circuitry during critical phases of opiate addiction-related learning and memory processing. Specifically, we will focus on two molecular signaling pathways known to be involved in both drug-related neuroadaptations and in memory-related plasticity mechanisms; the extracellular-signal-regulated kinase system (ERK and the Ca2+/calmodulin

Computational exploration of single-protein mechanics by steered molecular dynamics

Energy Technology Data Exchange (ETDEWEB)

Sotomayor, Marcos [Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio (United States)

2015-12-31

Hair cell mechanotransduction happens in tens of microseconds, involves forces of a few picoNewtons, and is mediated by nanometer-scale molecular conformational changes. As proteins involved in this process become identified and their high resolution structures become available, multiple tools are being used to explore their “single-molecule responses” to force. Optical tweezers and atomic force microscopy offer exquisite force and extension resolution, but cannot reach the high loading rates expected for high frequency auditory stimuli. Molecular dynamics (MD) simulations can reach these fast time scales, and also provide a unique view of the molecular events underlying protein mechanics, but its predictions must be experimentally verified. Thus a combination of simulations and experiments might be appropriate to study the molecular mechanics of hearing. Here I review the basics of MD simulations and the different methods used to apply force and study protein mechanics in silico. Simulations of tip link proteins are used to illustrate the advantages and limitations of this method.

Molecular mechanisms underlying the emergence of bacterial pathogens: an ecological perspective.

Science.gov (United States)

Bartoli, Claudia; Roux, Fabrice; Lamichhane, Jay Ram

2016-02-01

The rapid emergence of new bacterial diseases negatively affects both human health and agricultural productivity. Although the molecular mechanisms underlying these disease emergences are shared between human- and plant-pathogenic bacteria, not much effort has been made to date to understand disease emergences caused by plant-pathogenic bacteria. In particular, there is a paucity of information in the literature on the role of environmental habitats in which plant-pathogenic bacteria evolve and on the stress factors to which these microbes are unceasingly exposed. In this microreview, we focus on three molecular mechanisms underlying pathogenicity in bacteria, namely mutations, genomic rearrangements and the acquisition of new DNA sequences through horizontal gene transfer (HGT). We briefly discuss the role of these mechanisms in bacterial disease emergence and elucidate how the environment can influence the occurrence and regulation of these molecular mechanisms by directly impacting disease emergence. The understanding of such molecular evolutionary mechanisms and their environmental drivers will represent an important step towards predicting bacterial disease emergence and developing sustainable management strategies for crops. © 2015 BSPP AND JOHN WILEY & SONS LTD.

An overview of potential molecular mechanisms involved in VSMC phenotypic modulation.

Science.gov (United States)

Zhang, Ming-Jie; Zhou, Yi; Chen, Lei; Wang, Yan-Qin; Wang, Xu; Pi, Yan; Gao, Chang-Yue; Li, Jing-Cheng; Zhang, Li-Li

2016-02-01

The fully differentiated medial vascular smooth muscle cells (VSMCs) of mature vessels keep quiescent and contractile. However, VSMC can exhibit the plasticity in phenotype switching from a differentiated and contractile phenotype to a dedifferentiated state in response to alterations in local environmental cues, which is called phenotypic modulation or switching. Distinguishing from its differentiated state expressing more smooth muscle (SM)-specific/selective proteins, the phenotypic modulation in VSMC is characterized by an increased rate of proliferation, migration, synthesis of extracellular matrix proteins and decreased expression of SM contractile proteins. Although it has been well demonstrated that phenotypic modulation of VSMC contributes to the occurrence and progression of many proliferative vascular diseases, little is known about the details of the molecular mechanisms of VSMC phenotypic modulation. Growing evidence suggests that variety of molecules including microRNAs, cytokines and biochemical factors, membrane receptors, ion channels, cytoskeleton and extracellular matrix play important roles in controlling VSMC phenotype. The focus of the present review is to provide an overview of potential molecular mechanisms involved in VSMC phenotypic modulation in recent years. To clarify VSMC differentiation and phenotypic modulation mechanisms will contribute to producing cell-based therapeutic interventions for aberrant VSMC differentiation-related diseases.

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.

Molecular Mechanisms of Neonatal Brain Injury

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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.

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

A coordinated molecular 'fishing' mechanism in heterodimeric kinesin

International Nuclear Information System (INIS)

Hou, Ruizheng; Wang, Zhisong

2010-01-01

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

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.

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.

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.)

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...

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

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

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.

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 ...

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

Integrated network analysis reveals potentially novel molecular mechanisms and therapeutic targets of refractory epilepsies.

Directory of Open Access Journals (Sweden)

Hongwei Chu

Full Text Available Epilepsy is a complex neurological disorder and a significant health problem. The pathogenesis of epilepsy remains obscure in a significant number of patients and the current treatment options are not adequate in about a third of individuals which were known as refractory epilepsies (RE. Network medicine provides an effective approach for studying the molecular mechanisms underlying complex diseases. Here we integrated 1876 disease-gene associations of RE and located those genes to human protein-protein interaction (PPI network to obtain 42 significant RE-associated disease modules. The functional analysis of these disease modules showed novel molecular pathological mechanisms of RE, such as the novel enriched pathways (e.g., "presynaptic nicotinic acetylcholine receptors", "signaling by insulin receptor". Further analysis on the relationships between current drug targets and the RE-related disease genes showed the rational mechanisms of most antiepileptic drugs. In addition, we detected ten potential novel drug targets (e.g., KCNA1, KCNA4-6, KCNC3, KCND2, KCNMA1, CAMK2G, CACNB4 and GRM1 located in three RE related disease modules, which might provide novel insights into the new drug discovery for RE therapy.

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.

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

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.

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.

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

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

Science.gov (United States)

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

2013-02-19

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

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

Analytical mechanics for relativity and quantum mechanics

CERN Document Server

Johns, Oliver Davis

2011-01-01

Analytical Mechanics for Relativity and Quantum Mechanics is an innovative and mathematically sound treatment of the foundations of analytical mechanics and the relation of classical mechanics to relativity and quantum theory. It is intended for use at the introductory graduate level. A distinguishing feature of the book is its integration of special relativity into teaching of classical mechanics. After a thorough review of the traditional theory, Part II of the book introduces extended Lagrangian and Hamiltonian methods that treat time as a transformable coordinate rather than the fixed parameter of Newtonian physics. Advanced topics such as covariant Langrangians and Hamiltonians, canonical transformations, and Hamilton-Jacobi methods are simplified by the use of this extended theory. And the definition of canonical transformation no longer excludes the Lorenz transformation of special relativity. This is also a book for those who study analytical mechanics to prepare for a critical exploration of quantum...

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)

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)

Perfect/complete scattering experiments. Probing quantum mechanics on atomic and molecular collisions and coincidences

International Nuclear Information System (INIS)

Lohmann, Bernd; Grum-Grzhimailo, Alexei N.; Kleinpoppen, Hans

2013-01-01

Derives parameters for electrons, photons, atoms, ions, molecules calculated from theory. Delivers the quantum mechanical knowledge of atomic and molecular physics. Presents state-of-the-art experiments in atomic and molecular physics and related theoretical approaches. The main goal of this book is to elucidate what kind of experiment must be performed in order to determine the full set of independent parameters which can be extracted and calculated from theory, where electrons, photons, atoms, ions, molecules, or molecular ions may serve as the interacting constituents of matter. The feasibility of such perfect' and-or 'complete' experiments, providing the complete quantum mechanical knowledge of the process, is associated with the enormous potential of modern research techniques, both, in experiment and theory. It is even difficult to overestimate the role of theory in setting of the complete experiment, starting with the fact that an experiment can be complete only within a certain theoretical framework, and ending with the direct prescription of what, and in what conditions should be measured to make the experiment 'complete'. The language of the related theory is the language of quantum mechanical amplitudes and their relative phases. This book captures the spirit of research in the direction of the complete experiment in atomic and molecular physics, considering some of the basic quantum processes: scattering, Auger decay and photo-ionization. It includes a description of the experimental methods used to realize, step by step, the complete experiment up to the level of the amplitudes and phases. The corresponding arsenal includes, beyond determining the total cross section, the observation of angle and spin resolved quantities, photon polarization and correlation parameters, measurements applying coincidence techniques, preparing initially polarized targets, and even more sophisticated methods. The 'complete' experiment is, until today, hardly to perform

Perfect/complete scattering experiments. Probing quantum mechanics on atomic and molecular collisions and coincidences

Energy Technology Data Exchange (ETDEWEB)

Lohmann, Bernd [Muenster Univ. (Germany). Inst. fuer Theoretische Physik 1; Grum-Grzhimailo, Alexei N. [Moscow State Univ. (Russian Federation). Skobeltsyn Inst. of Nuclear Physics; Kleinpoppen, Hans

2013-07-01

Derives parameters for electrons, photons, atoms, ions, molecules calculated from theory. Delivers the quantum mechanical knowledge of atomic and molecular physics. Presents state-of-the-art experiments in atomic and molecular physics and related theoretical approaches. The main goal of this book is to elucidate what kind of experiment must be performed in order to determine the full set of independent parameters which can be extracted and calculated from theory, where electrons, photons, atoms, ions, molecules, or molecular ions may serve as the interacting constituents of matter. The feasibility of such perfect' and-or 'complete' experiments, providing the complete quantum mechanical knowledge of the process, is associated with the enormous potential of modern research techniques, both, in experiment and theory. It is even difficult to overestimate the role of theory in setting of the complete experiment, starting with the fact that an experiment can be complete only within a certain theoretical framework, and ending with the direct prescription of what, and in what conditions should be measured to make the experiment 'complete'. The language of the related theory is the language of quantum mechanical amplitudes and their relative phases. This book captures the spirit of research in the direction of the complete experiment in atomic and molecular physics, considering some of the basic quantum processes: scattering, Auger decay and photo-ionization. It includes a description of the experimental methods used to realize, step by step, the complete experiment up to the level of the amplitudes and phases. The corresponding arsenal includes, beyond determining the total cross section, the observation of angle and spin resolved quantities, photon polarization and correlation parameters, measurements applying coincidence techniques, preparing initially polarized targets, and even more sophisticated methods. The 'complete' experiment is

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

Evidence-based efficacy of adaptogens in fatigue, and molecular mechanisms related to their stress-protective activity.

Science.gov (United States)

Panossian, Alexander; Wikman, Georg

2009-09-01

The aim of this review article is to assess the level of scientific evidence presented by clinical trials of adaptogens in fatigue, and to provide a rationale at the molecular level for verified effects. Strong scientific evidence is available for Rhodiola rosea SHR-5 extract, which improved attention, cognitive function and mental performance in fatigue and in chronic fatigue syndrome. Good scientific evidence has been documented in trails in which Schisandra chinensis and Eleutherococcus senticosus increased endurance and mental performance in patients with mild fatigue and weakness. Based on their efficacy in clinical studies, adaptogens can be defined as a pharmacological group of herbal preparations that increase tolerance to mental exhaustion and enhance attention and mental endurance in situations of decreased performance. The beneficial stress-protective effect of adaptogens is related to regulation of homeostasis via several mechanisms of action associated with the hypothalamic-pituitary-adrenal axis and the control of key mediators of stress response such as molecular chaperons (e.g. Hsp70), stress-activated c-Jun N-terminal protein kinase (JNK1), Forkhead Box O transcription factor DAF-16, cortisol and nitric oxide (NO). The key point of action of phytoadaptogens appears to be their up-regulating and stress-mimetic effects on the "stress-sensor" protein Hsp70, which plays an important role in cell survival and apoptosis. Hsp70 inhibits the expression of NO synthase II gene and interacts with glucocorticoid receptors directly and via the JNK pathway, thus affecting the levels of circulating cortisol and NO. Prevention of stress-induced increase in NO, and the associated decrease in ATP production, results in increased performance and endurance. Adaptogen-induced up-regulation of Hsp70 triggers stress-induced JNK-1 and DAF-16-mediated pathways regulating the resistance to stress and resulting in enhanced mental and physical performance and, possibly

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

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

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

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.

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.

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.

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.

Molecular Signature and Mechanisms of Hepatitis D Virus-Associated Hepatocellular Carcinoma.

Science.gov (United States)

Diaz, Giacomo; Engle, Ronald E; Tice, Ashley; Melis, Marta; Montenegro, Stephanie; Rodriguez-Canales, Jaime; Hanson, Jeffrey; Emmert-Buck, Michael R; Bock, Kevin W; Moore, Ian N; Zamboni, Fausto; Govindarajan, Sugantha; Kleiner, David; Farci, Patrizia

2018-06-01

There is limited data on the molecular mechanisms whereby hepatitis D virus (HDV) promotes liver cancer. Therefore, serum and liver specimens obtained at the time of liver transplantation from well-characterized patients with HDV-HCC (n-5) and with non-HCC HDV cirrhosis (n=7) were studied using an integrated genomic approach. Transcriptomic profiling was performed using laser capture-microdissected (LCM) malignant and non-malignant hepatocytes, tumorous and non-tumorous liver tissue from patients with HDV-HCC, and liver tissue from patients with non-HCC HDV cirrhosis. HDV-HCC was also compared with hepatitis B virus (HBV) HBV-HCC alone and hepatitis C virus (HCV) HCV-HCC. HDV malignant hepatocytes were characterized by an enrichment of up-regulated transcripts associated with pathways involved in cell cycle/DNA replication, damage and repair (sonic hedgehog, GADD45, DNA-damage-induced 14-3-3σ, cyclins and cell cycle regulation, cell cycle: G2/M DNA-damage checkpoint regulation, and hereditary breast cancer). Moreover, a large network of genes identified functionally relate to DNA repair, cell cycle, mitotic apparatus and cell division, including 4 cancer testis antigen genes, attesting to the critical role of genetic instability in this tumor. Besides being over-expressed, these genes were also strongly co-regulated. Gene co-regulation was high not only when compared to non-malignant hepatocytes, but also to malignant hepatocytes from HBV-HCC alone or HCV-HCC. Activation and co-regulation of genes critically associated with DNA replication, damage, and repair point to genetic instability as an important mechanism of HDV hepatocarcinogenesis. This specific HDV-HCC trait emerged also from the comparison of the molecular pathways identified for each hepatitis virus-associated HCC. Despite the dependence of HDV on HBV, these findings suggest that HDV and HBV promote carcinogenesis by distinct molecular mechanisms. This study identifies a molecular signature of HDV

Of Fighting Flies, Mice, and Men: Are Some of the Molecular and Neuronal Mechanisms of Aggression Universal in the Animal Kingdom?

Science.gov (United States)

Thomas, Amanda L; Davis, Shaun M; Dierick, Herman A

2015-08-01

Aggressive behavior is widespread in the animal kingdom, but the degree of molecular conservation between distantly related species is still unclear. Recent reports suggest that at least some of the molecular mechanisms underlying this complex behavior in flies show remarkable similarities with such mechanisms in mice and even humans. Surprisingly, some aspects of neuronal control of aggression also show remarkable similarity between these distantly related species. We will review these recent findings, address the evolutionary implications, and discuss the potential impact for our understanding of human diseases characterized by excessive aggression.

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.

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...

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…

[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.

The Progress of Mitophagy and Related Pathogenic Mechanisms of the Neurodegenerative Diseases and Tumor

Directory of Open Access Journals (Sweden)

Ying Song

2015-01-01

Full Text Available Mitochondrion, an organelle with two layers of membrane, is extremely vital to eukaryotic cell. Its major functions are energy center and apoptosis censor inside cell. The intactness of mitochondrial membrane is important to maintain its structure and function. Mitophagy is one kind of autophagy. In recent years, studies of mitochondria have shown that mitophagy is regulated by various factors and is an important regulation mechanism for organisms to maintain their normal state. In addition, abnormal mitophagy is closely related to several neurodegenerative diseases and tumor. However, the related signal pathway and its regulation mechanism still remain unclear. As a result, summarizing the progress of mitophagy and its related pathogenic mechanism not only helps to reveal the complicated molecular mechanism, but also helps to find a new target to treat the related diseases.

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...

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.

Promising Diabetes Therapy Based on the Molecular Mechanism for Glucose Toxicity: Usefulness of SGLT2 Inhibitors as well as Incretin-Related Drugs.

Science.gov (United States)

Kaneto, Hideaki; Obata, Atsushi; Shimoda, Masashi; Kimura, Tomohiko; Hirukawa, Hidenori; Okauchi, Seizo; Matsuoka, Taka-Aki; Kaku, Kohei

2016-01-01

Pancreatic β-cell dysfunction and insulin resistance are the main characteristics of type 2 diabetes. Chronic exposure of β-cells to hyperglycemia leads to the deterioration of β-cell function. Such phenomena are well known as pancreatic β-cell glucose toxicity. MafA, a strong transactivator of insulin gene, is particularly important for the maintenance of mature β-cell function, but its expression level is significantly reduced under diabetic conditions which is likely associated with β-cell failure. Reduction of incretin receptor expression level in β-cells in diabetes is also likely associated with β-cell failure. On the other hand, incretin-related drugs and sodium-glucose co-transporter 2 (SGLT2) inhibitors are promising diabetes therapy based on the mechanism for pancreatic β-cell glucose toxicity. Indeed, it was shown that incretin-related drugs exerted protective effects on β-cells through the augmentation of IRS-2 expression especially in the presence of pioglitazone. It was also shown that incretin-related drug and/or pioglitazone exerted more protective effects on β-cells at the early stage of diabetes compared to the advanced stage. SGLT2 inhibitors, new hypoglycemic agents, also exert beneficial effects for the protection of pancreatic β-cells as well as for the reduction of insulin resistance in various insulin target tissues. Taken together, it is important to select appropriate therapy based on the molecular mechanism for glucose toxicity.

Cis-to- Trans Isomerization of Azobenzene Derivatives Studied with Transition Path Sampling and Quantum Mechanical/Molecular Mechanical Molecular Dynamics.

Science.gov (United States)

Muždalo, Anja; Saalfrank, Peter; Vreede, Jocelyne; Santer, Mark

2018-04-10

Azobenzene-based molecular photoswitches are becoming increasingly important for the development of photoresponsive, functional soft-matter material systems. Upon illumination with light, fast interconversion between a more stable trans and a metastable cis configuration can be established resulting in pronounced changes in conformation, dipole moment or hydrophobicity. A rational design of functional photosensitive molecules with embedded azo moieties requires a thorough understanding of isomerization mechanisms and rates, especially the thermally activated relaxation. For small azo derivatives considered in the gas phase or simple solvents, Eyring's classical transition state theory (TST) approach yields useful predictions for trends in activation energies or corresponding half-life times of the cis isomer. However, TST or improved theories cannot easily be applied when the azo moiety is part of a larger molecular complex or embedded into a heterogeneous environment, where a multitude of possible reaction pathways may exist. In these cases, only the sampling of an ensemble of dynamic reactive trajectories (transition path sampling, TPS) with explicit models of the environment may reveal the nature of the processes involved. In the present work we show how a TPS approach can conveniently be implemented for the phenomenon of relaxation-isomerization of azobenzenes starting with the simple examples of pure azobenzene and a push-pull derivative immersed in a polar (DMSO) and apolar (toluene) solvent. The latter are represented explicitly at a molecular mechanical (MM) and the azo moiety at a quantum mechanical (QM) level. We demonstrate for the push-pull azobenzene that path sampling in combination with the chosen QM/MM scheme produces the expected change in isomerization pathway from inversion to rotation in going from a low to a high permittivity (explicit) solvent model. We discuss the potential of the simulation procedure presented for comparative calculation of

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.

Crosstalk between Apoptosis and Autophagy: Molecular Mechanisms and Therapeutic Strategies in Cancer

Directory of Open Access Journals (Sweden)

Abdelouahid El-Khattouti

2013-01-01

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

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

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.

Computation of Hydration Free Energies Using the Multiple Environment Single System Quantum Mechanical/Molecular Mechanical Method.

Science.gov (United States)

König, Gerhard; Mei, Ye; Pickard, Frank C; Simmonett, Andrew C; Miller, Benjamin T; Herbert, John M; Woodcock, H Lee; Brooks, Bernard R; Shao, Yihan

2016-01-12

A recently developed MESS-E-QM/MM method (multiple-environment single-system quantum mechanical molecular/mechanical calculations with a Roothaan-step extrapolation) is applied to the computation of hydration free energies for the blind SAMPL4 test set and for 12 small molecules. First, free energy simulations are performed with a classical molecular mechanics force field using fixed-geometry solute molecules and explicit TIP3P solvent, and then the non-Boltzmann-Bennett method is employed to compute the QM/MM correction (QM/MM-NBB) to the molecular mechanical hydration free energies. For the SAMPL4 set, MESS-E-QM/MM-NBB corrections to the hydration free energy can be obtained 2 or 3 orders of magnitude faster than fully converged QM/MM-NBB corrections, and, on average, the hydration free energies predicted with MESS-E-QM/MM-NBB fall within 0.10-0.20 kcal/mol of full-converged QM/MM-NBB results. Out of five density functionals (BLYP, B3LYP, PBE0, M06-2X, and ωB97X-D), the BLYP functional is found to be most compatible with the TIP3P solvent model and yields the most accurate hydration free energies against experimental values for solute molecules included in this study.

Molecular Mechanisms in Exercise-Induced Cardioprotection

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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.

Integrated Modules Analysis to Explore the Molecular Mechanisms of Phlegm-Stasis Cementation Syndrome with Ischemic Heart Disease

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Wei-Ming Xu

2018-01-01

Full Text Available Background: Ischemic heart disease (IHD has been the leading cause of death for several decades globally, IHD patients usually hold the symptoms of phlegm-stasis cementation syndrome (PSCS as significant complications. However, the underlying molecular mechanisms of PSCS complicated with IHD have not yet been fully elucidated.Materials and Methods: Network medicine methods were utilized to elucidate the underlying molecular mechanisms of IHD phenotypes. Firstly, high-quality IHD-associated genes from both human curated disease-gene association database and biomedical literatures were integrated. Secondly, the IHD disease modules were obtained by dissecting the protein-protein interaction (PPI topological modules in the String V9.1 database and the mapping of IHD-associated genes to the PPI topological modules. After that, molecular functional analyses (e.g., Gene Ontology and pathway enrichment analyses for these IHD disease modules were conducted. Finally, the PSCS syndrome modules were identified by mapping the PSCS related symptom-genes to the IHD disease modules, which were further validated by both pharmacological and physiological evidences derived from published literatures.Results: The total of 1,056 high-quality IHD-associated genes were integrated and evaluated. In addition, eight IHD disease modules (the PPI sub-networks significantly relevant to IHD were identified, in which two disease modules were relevant to PSCS syndrome (i.e., two PSCS syndrome modules. These two modules had enriched pathways on Toll-like receptor signaling pathway (hsa04620 and Renin-angiotensin system (hsa04614, with the molecular functions of angiotensin maturation (GO:0002003 and response to bacterium (GO:0009617, which had been validated by classical Chinese herbal formulas-related targets, IHD-related drug targets, and the phenotype features derived from human phenotype ontology (HPO and published biomedical literatures.Conclusion: A network medicine

Integrated Modules Analysis to Explore the Molecular Mechanisms of Phlegm-Stasis Cementation Syndrome with Ischemic Heart Disease.

Science.gov (United States)

Xu, Wei-Ming; Yang, Kuo; Jiang, Li-Jie; Hu, Jing-Qing; Zhou, Xue-Zhong

2018-01-01

Background: Ischemic heart disease (IHD) has been the leading cause of death for several decades globally, IHD patients usually hold the symptoms of phlegm-stasis cementation syndrome (PSCS) as significant complications. However, the underlying molecular mechanisms of PSCS complicated with IHD have not yet been fully elucidated. Materials and Methods: Network medicine methods were utilized to elucidate the underlying molecular mechanisms of IHD phenotypes. Firstly, high-quality IHD-associated genes from both human curated disease-gene association database and biomedical literatures were integrated. Secondly, the IHD disease modules were obtained by dissecting the protein-protein interaction (PPI) topological modules in the String V9.1 database and the mapping of IHD-associated genes to the PPI topological modules. After that, molecular functional analyses (e.g., Gene Ontology and pathway enrichment analyses) for these IHD disease modules were conducted. Finally, the PSCS syndrome modules were identified by mapping the PSCS related symptom-genes to the IHD disease modules, which were further validated by both pharmacological and physiological evidences derived from published literatures. Results: The total of 1,056 high-quality IHD-associated genes were integrated and evaluated. In addition, eight IHD disease modules (the PPI sub-networks significantly relevant to IHD) were identified, in which two disease modules were relevant to PSCS syndrome (i.e., two PSCS syndrome modules). These two modules had enriched pathways on Toll-like receptor signaling pathway (hsa04620) and Renin-angiotensin system (hsa04614), with the molecular functions of angiotensin maturation (GO:0002003) and response to bacterium (GO:0009617), which had been validated by classical Chinese herbal formulas-related targets, IHD-related drug targets, and the phenotype features derived from human phenotype ontology (HPO) and published biomedical literatures. Conclusion: A network medicine

Integrated Modules Analysis to Explore the Molecular Mechanisms of Phlegm-Stasis Cementation Syndrome with Ischemic Heart Disease

Science.gov (United States)

Xu, Wei-Ming; Yang, Kuo; Jiang, Li-Jie; Hu, Jing-Qing; Zhou, Xue-Zhong

2018-01-01

Background: Ischemic heart disease (IHD) has been the leading cause of death for several decades globally, IHD patients usually hold the symptoms of phlegm-stasis cementation syndrome (PSCS) as significant complications. However, the underlying molecular mechanisms of PSCS complicated with IHD have not yet been fully elucidated. Materials and Methods: Network medicine methods were utilized to elucidate the underlying molecular mechanisms of IHD phenotypes. Firstly, high-quality IHD-associated genes from both human curated disease-gene association database and biomedical literatures were integrated. Secondly, the IHD disease modules were obtained by dissecting the protein-protein interaction (PPI) topological modules in the String V9.1 database and the mapping of IHD-associated genes to the PPI topological modules. After that, molecular functional analyses (e.g., Gene Ontology and pathway enrichment analyses) for these IHD disease modules were conducted. Finally, the PSCS syndrome modules were identified by mapping the PSCS related symptom-genes to the IHD disease modules, which were further validated by both pharmacological and physiological evidences derived from published literatures. Results: The total of 1,056 high-quality IHD-associated genes were integrated and evaluated. In addition, eight IHD disease modules (the PPI sub-networks significantly relevant to IHD) were identified, in which two disease modules were relevant to PSCS syndrome (i.e., two PSCS syndrome modules). These two modules had enriched pathways on Toll-like receptor signaling pathway (hsa04620) and Renin-angiotensin system (hsa04614), with the molecular functions of angiotensin maturation (GO:0002003) and response to bacterium (GO:0009617), which had been validated by classical Chinese herbal formulas-related targets, IHD-related drug targets, and the phenotype features derived from human phenotype ontology (HPO) and published biomedical literatures. Conclusion: A network medicine

Molecular mechanisms underlying formation of long-term reward memories and extinction memories in the honeybee (Apis mellifera)

Science.gov (United States)

2014-01-01

The honeybee (Apis mellifera) has long served as an invertebrate model organism for reward learning and memory research. Its capacity for learning and memory formation is rooted in the ecological need to efficiently collect nectar and pollen during summer to ensure survival of the hive during winter. Foraging bees learn to associate a flower's characteristic features with a reward in a way that resembles olfactory appetitive classical conditioning, a learning paradigm that is used to study mechanisms underlying learning and memory formation in the honeybee. Due to a plethora of studies on appetitive classical conditioning and phenomena related to it, the honeybee is one of the best characterized invertebrate model organisms from a learning psychological point of view. Moreover, classical conditioning and associated behavioral phenomena are surprisingly similar in honeybees and vertebrates, suggesting a convergence of underlying neuronal processes, including the molecular mechanisms that contribute to them. Here I review current thinking on the molecular mechanisms underlying long-term memory (LTM) formation in honeybees following classical conditioning and extinction, demonstrating that an in-depth analysis of the molecular mechanisms of classical conditioning in honeybees might add to our understanding of associative learning in honeybees and vertebrates. PMID:25225299

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

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 ...

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

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.

Molecular-level mechanisms of vibrational frequency shifts in a polar liquid.

Science.gov (United States)

Morales, Christine M; Thompson, Ward H

2011-06-16

A molecular-level analysis of the origins of the vibrational frequency shifts of the CN stretching mode in neat liquid acetonitrile is presented. The frequency shifts and infrared spectrum are calculated using a perturbation theory approach within a molecular dynamics simulation and are in good agreement with measured values reported in the literature. The resulting instantaneous frequency of each nitrile group is decomposed into the contributions from each molecule in the liquid and by interaction type. This provides a detailed picture of the mechanisms of frequency shifts, including the number of surrounding molecules that contribute to the shift, the relationship between their position and relative contribution, and the roles of electrostatic and van der Waals interactions. These results provide insight into what information is contained in infrared (IR) and Raman spectra about the environment of the probed vibrational mode. © 2011 American Chemical Society

Programmed necrosis and necroptosis – molecular mechanisms

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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.

Advances on molecular mechanism of the adaptive evolution of Chiroptera (bats).

Science.gov (United States)

Yunpeng, Liang; Li, Yu

2015-01-01

As the second biggest animal group in mammals, Chiroptera (bats) demonstrates many unique adaptive features in terms of flight, echolocation, auditory acuity, feeding habit, hibernation and immune defense, providing an excellent system for understanding the molecular basis of how organisms adapt to the living environments encountered. In this review, we summarize the researches on the molecular mechanism of the adaptive evolution of Chiroptera, especially the recent researches at the genome levels, suggesting a far more complex evolutionary pattern and functional diversity than previously thought. In the future, along with the increasing numbers of Chiroptera species genomes available, new evolutionary patterns and functional divergence will be revealed, which can promote the further understanding of this animal group and the molecular mechanism of adaptive evolution.

HPV epigenetic mechanisms related to Oropharyngeal and Cervix cancers.

Science.gov (United States)

Di Domenico, Marina; Giovane, Giancarlo; Kouidhi, Soumaya; Iorio, Rosamaria; Romano, Maurizio; De Francesco, Francesco; Feola, Antonia; Siciliano, Camilla; Califano, Luigi; Giordano, Antonio

2017-03-31

Human Papilloma Virus infection is very frequent in humans and is mainly transmitted sexually. The majority of infections are transient and asymptomatic, however, if the infection persists, it can occur with a variety of injuries to skin and mucous membranes, depending on the type of HPV involved. Some types of HPV are classified as high oncogenic risk as associated with the onset of cancer. The tumors most commonly associated with HPV are cervical and oropharyngeal cancer, epigenetic mechanisms related to HPV infection include methylation changes to host and viral DNA and chromatin modification in host species. This review is focused about epigenethic mechanism, such as MiRNAs expression, related to cervix and oral cancer. Specifically it discuss about molecular markers associated to a more aggressive phenotype. In this way we will analyze genes involved in meiotic sinaptonemal complex, transcriptional factors, of orthokeratins, sinaptogirin, they are all expressed in cancer in a way not more dependent on cell differentiation but HPV-dependent.

Different routes, same pathways: Molecular mechanisms under silver ion and nanoparticle exposures in the soil sentinel Eisenia fetida

International Nuclear Information System (INIS)

Novo, Marta; Lahive, Elma; Díez-Ortiz, María; Matzke, Marianne; Morgan, Andrew J.; Spurgeon, David J.; Svendsen, Claus; Kille, Peter

2015-01-01

Use of nanotechnology products is increasing; with silver (Ag) nanoparticles particularly widely used. A key uncertainty surrounding the risk assessment of AgNPs is whether their effects are driven through the same mechanism of action that underlies the toxic effects of Ag ions. We present the first full transcriptome study of the effects of Ag ions and NPs in an ecotoxicological model soil invertebrate, the earthworm Eisenia fetida. Gene expression analyses indicated similar mechanisms for both silver forms with toxicity being exerted through pathways related to ribosome function, sugar and protein metabolism, molecular stress, disruption of energy production and histones. The main difference seen between Ag ions and NPs was associated with potential toxicokinetic effects related to cellular internalisation and communication, with pathways related to endocytosis and cilia being significantly enriched. These results point to a common final toxicodynamic response, but initial internalisation driven by different exposure routes and toxicokinetic mechanisms. - Highlights: • Molecular effects underlying Ag ions and NPs exposure were studied in Eisenia fetida. • Full transcriptomic study of a genetically characterised lineage. • NPs and ions presented a similar toxicodynamic response. • Internalisation of the two Ag forms by different toxicokinetic mechanisms. - Transcriptomic analyses after exposure of earthworms to silver NPs or ions showed a final common toxicodynamic response, but internalisation by different toxicokinetic mechanisms

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.

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.

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.

Biological markers of amyloid beta-related mechanisms in Alzheimer's disease.

LENUS (Irish Health Repository)

Hampel, Harald

2010-06-01

Recent research progress has given detailed knowledge on the molecular pathogenesis of Alzheimer\\'s disease (AD), which has been translated into an intense, ongoing development of disease-modifying treatments. Most new drug candidates are targeted on inhibiting amyloid beta (Abeta) production and aggregation. In drug development, it is important to co-develop biomarkers for Abeta-related mechanisms to enable early diagnosis and patient stratification in clinical trials, and to serve as tools to identify and monitor the biochemical effect of the drug directly in patients. Biomarkers are also requested by regulatory authorities to serve as safety measurements. Molecular aberrations in the AD brain are reflected in the cerebrospinal fluid (CSF). Core CSF biomarkers include Abeta isoforms (Abeta40\\/Abeta42), soluble APP isoforms, Abeta oligomers and beta-site APP-cleaving enzyme 1 (BACE1). This article reviews recent research advances on core candidate CSF and plasma Abeta-related biomarkers, and gives a conceptual review on how to implement biomarkers in clinical trials in AD.

Biological markers of amyloid beta-related mechanisms in Alzheimer's disease.

LENUS (Irish Health Repository)

Hampel, Harald

2012-02-01

Recent research progress has given detailed knowledge on the molecular pathogenesis of Alzheimer\\'s disease (AD), which has been translated into an intense, ongoing development of disease-modifying treatments. Most new drug candidates are targeted on inhibiting amyloid beta (Abeta) production and aggregation. In drug development, it is important to co-develop biomarkers for Abeta-related mechanisms to enable early diagnosis and patient stratification in clinical trials, and to serve as tools to identify and monitor the biochemical effect of the drug directly in patients. Biomarkers are also requested by regulatory authorities to serve as safety measurements. Molecular aberrations in the AD brain are reflected in the cerebrospinal fluid (CSF). Core CSF biomarkers include Abeta isoforms (Abeta40\\/Abeta42), soluble APP isoforms, Abeta oligomers and beta-site APP-cleaving enzyme 1 (BACE1). This article reviews recent research advances on core candidate CSF and plasma Abeta-related biomarkers, and gives a conceptual review on how to implement biomarkers in clinical trials in AD.

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.

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

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

Science.gov (United States)

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

2016-01-01

Research has suggested that teaching and learning in molecular and cellular biology (MCB) is difficult. We used a new lens to understand undergraduate reasoning about molecular mechanisms: the knowledge-integration approach to conceptual change. Knowledge integration is the dynamic process by which learners acquire new ideas, develop connections between ideas, and reorganize and restructure prior knowledge. Semistructured, clinical think-aloud interviews were conducted with introductory and upper-division MCB students. Interviews included a written conceptual assessment, a concept-mapping activity, and an opportunity to explain the biomechanisms of DNA replication, transcription, and translation. Student reasoning patterns were explored through mixed-method analyses. Results suggested that students must sort mechanistic entities into appropriate mental categories that reflect the nature of MCB mechanisms and that conflation between these categories is common. We also showed how connections between molecular mechanisms and their biological roles are part of building an integrated knowledge network as students develop expertise. We observed differences in the nature of connections between ideas related to different forms of reasoning. Finally, we provide a tentative model for MCB knowledge integration and suggest its implications for undergraduate learning. © 2016 K. Southard et al. CBE—Life Sciences Education © 2016 The American Society for Cell Biology. This article is distributed by The American Society for Cell Biology under license from the author(s). It is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age-Related Diseases

Directory of Open Access Journals (Sweden)

Pierpaola Davalli

2016-01-01

Full Text Available The aging process worsens the human body functions at multiple levels, thus causing its gradual decrease to resist stress, damage, and disease. Besides changes in gene expression and metabolic control, the aging rate has been associated with the production of high levels of Reactive Oxygen Species (ROS and/or Reactive Nitrosative Species (RNS. Specific increases of ROS level have been demonstrated as potentially critical for induction and maintenance of cell senescence process. Causal connection between ROS, aging, age-related pathologies, and cell senescence is studied intensely. Senescent cells have been proposed as a target for interventions to delay the aging and its related diseases or to improve the diseases treatment. Therapeutic interventions towards senescent cells might allow restoring the health and curing the diseases that share basal processes, rather than curing each disease in separate and symptomatic way. Here, we review observations on ROS ability of inducing cell senescence through novel mechanisms that underpin aging processes. Particular emphasis is addressed to the novel mechanisms of ROS involvement in epigenetic regulation of cell senescence and aging, with the aim to individuate specific pathways, which might promote healthy lifespan and improve aging.

New Insight in Understanding the mechanical responses of polymer glasses using molecular dynamic simulation

Science.gov (United States)

Zheng, Yexin; Wang, Shi-Qing; Tsige, Mesfin

The Kremer-Grest bead-spring model has been the standard model in molecular dynamics simulation of polymer glasses. However, due to current computational limitations in accessing relevant time scales in polymer glasses in a reasonable amount of CPU time, simulation of mechanical response of polymer glasses in molecular dynamic simulations requires a much higher quenching rate and deformation rate than used in experiments. Despite several orders of magnitude difference in time scale between simulation and experiment, previous studies have shown that simulations can produce meaningful results that can be directly compared with experimental results. In this work we show that by tuning the quenching rate and deformation rate relative to the segmental relaxation times, a reasonable mechanical response shows up in the glassy state. Specifically, we show a younger glass prepared with a faster quenching rate shows glassy responses only when the imposed deformation rate is proportionally higher. the National Science Foundation (DMR-1444859 and DMR-1609977).

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

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)

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.

Using molecular mechanics to predict bulk material properties of fibronectin fibers.

Directory of Open Access Journals (Sweden)

Mark J Bradshaw

Full Text Available The structural proteins of the extracellular matrix (ECM form fibers with finely tuned mechanical properties matched to the time scales of cell traction forces. Several proteins such as fibronectin (Fn and fibrin undergo molecular conformational changes that extend the proteins and are believed to be a major contributor to the extensibility of bulk fibers. The dynamics of these conformational changes have been thoroughly explored since the advent of single molecule force spectroscopy and molecular dynamics simulations but remarkably, these data have not been rigorously applied to the understanding of the time dependent mechanics of bulk ECM fibers. Using measurements of protein density within fibers, we have examined the influence of dynamic molecular conformational changes and the intermolecular arrangement of Fn within fibers on the bulk mechanical properties of Fn fibers. Fibers were simulated as molecular strands with architectures that promote either equal or disparate molecular loading under conditions of constant extension rate. Measurements of protein concentration within micron scale fibers using deep ultraviolet transmission microscopy allowed the simulations to be scaled appropriately for comparison to in vitro measurements of fiber mechanics as well as providing estimates of fiber porosity and water content, suggesting Fn fibers are approximately 75% solute. Comparing the properties predicted by single molecule measurements to in vitro measurements of Fn fibers showed that domain unfolding is sufficient to predict the high extensibility and nonlinear stiffness of Fn fibers with surprising accuracy, with disparately loaded fibers providing the best fit to experiment. This work shows the promise of this microstructural modeling approach for understanding Fn fiber properties, which is generally applicable to other ECM fibers, and could be further expanded to tissue scale by incorporating these simulated fibers into three dimensional

A density functional theory study on the molecular mechanism of the cycloaddition between (E)-methyl cinnamate and cyclopentadiene

International Nuclear Information System (INIS)

Alves, C.N.; Camilo, F.F.; Gruber, J.; Silva, A.B.F. da

2004-01-01

The molecular mechanism of the Diels-Alder reaction between (E)-methyl cinnamate and cyclopentadiene has been characterized by means of density functional theory method at the B3LYP/6-31G* theory level. Stationary points for two reactive channels, endo-cis and exo-cis, on potential energy surfaces, have been characterized. Three Lewis acids, boron trifluoride (BF 3 ), aluminum trichloride (AlCl 3 ) and catechol boron bromide (CBB), have been used as catalysts taking into account the formation of a complex between the boron or aluminum atom and the carbonyl oxygen of (E)-methyl cinnamate. The molecular mechanism of the uncatalyzed reaction corresponds to a concerted process. In the presence of BF 3 and AlCl 3 , enhancement of both the asynchronicity and charge transfer between diene and the dienophile, with small decreased energy barriers, were obtained. With CBB, the molecular mechanism changes and the reaction takes place along a stepwise mechanism. The inclusion of the CBB catalyst drastically decreases the energy barrier associated with the carbon-carbon bond formation of the first step relative to the concerted process. The results obtained in this work are compared with experimental data and AM1 semiempirical calculation

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.

Cardiac molecular-acclimation mechanisms in response to swimming-induced exercise in Atlantic salmon.

Directory of Open Access Journals (Sweden)

Vicente Castro

Full Text Available Cardiac muscle is a principal target organ for exercise-induced acclimation mechanisms in fish and mammals, given that sustained aerobic exercise training improves cardiac output. Yet, the molecular mechanisms underlying such cardiac acclimation have been scarcely investigated in teleosts. Consequently, we studied mechanisms related to cardiac growth, contractility, vascularization, energy metabolism and myokine production in Atlantic salmon pre-smolts resulting from 10 weeks exercise-training at three different swimming intensities: 0.32 (control, 0.65 (medium intensity and 1.31 (high intensity body lengths s(-1. Cardiac responses were characterized using growth, immunofluorescence and qPCR analysis of a large number of target genes encoding proteins with significant and well-characterized function. The overall stimulatory effect of exercise on cardiac muscle was dependent on training intensity, with changes elicited by high intensity training being of greater magnitude than either medium intensity or control. Higher protein levels of PCNA were indicative of cardiac growth being driven by cardiomyocyte hyperplasia, while elevated cardiac mRNA levels of MEF2C, GATA4 and ACTA1 suggested cardiomyocyte hypertrophy. In addition, up-regulation of EC coupling-related genes suggested that exercised hearts may have improved contractile function, while higher mRNA levels of EPO and VEGF were suggestive of a more efficient oxygen supply network. Furthermore, higher mRNA levels of PPARα, PGC1α and CPT1 all suggested a higher capacity for lipid oxidation, which along with a significant enlargement of mitochondrial size in cardiac myocytes of the compact layer of fish exercised at high intensity, suggested an enhanced energetic support system. Training also elevated transcription of a set of myokines and other gene products related to the inflammatory process, such as TNFα, NFκB, COX2, IL1RA and TNF decoy receptor. This study provides the first

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.

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.

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.

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.

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

Molecular Mechanisms Underlying Curcumin-Mediated Therapeutic Effects in Type 2 Diabetes and Cancer

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Marzena Wojcik

2018-01-01

Full Text Available The growing prevalence of age-related diseases, especially type 2 diabetes mellitus (T2DM and cancer, has become global health and economic problems. Due to multifactorial nature of both diseases, their pathophysiology is not completely understood so far. Compelling evidence indicates that increased oxidative stress, resulting from an imbalance between production of reactive oxygen species (ROS and their clearance by antioxidant defense mechanisms, as well as the proinflammatory state contributes to the development and progression of the diseases. Curcumin (CUR; diferuloylmethane, a well-known polyphenol derived from the rhizomes of turmeric Curcuma longa, has attracted a great deal of attention as a natural compound with beneficial antidiabetic and anticancer properties, partly due to its antioxidative and anti-inflammatory actions. Although this polyphenolic compound is increasingly being recognized for its growing number of protective health effects, the precise molecular mechanisms through which it reduces diabetes- and cancer-related pathological events have not been fully unraveled. Hence, CUR is the subject of intensive research in the fields Diabetology and Oncology as a potential candidate in the treatment of both T2DM and cancer, particularly since current therapeutic options for their treatment are not satisfactory in clinics. In this review, we summarize the recent progress made on the molecular targets and pathways involved in antidiabetic and anticancer activities of CUR that are responsible for its beneficial health effects.

The molecular-scale arrangement and mechanical strength of phospholipid/cholesterol mixed bilayers investigated by frequency modulation atomic force microscopy in liquid

Energy Technology Data Exchange (ETDEWEB)

Asakawa, Hitoshi; Fukuma, Takeshi [Frontier Science Organization, Kanazawa University, Kakuma-machi, 920-1192 Kanazawa (Japan)], E-mail: hi_asa@staff.kanazawa-u.ac.jp, E-mail: fukuma@staff.kanazawa-u.ac.jp

2009-07-01

Cholesterols play key roles in controlling molecular fluidity in a biological membrane, yet little is known about their molecular-scale arrangements in real space. In this study, we have directly imaged lipid-cholesterol complexes in a model biological membrane consisting of dipalmitoylphosphatidylcholine (DPPC) and cholesterols by frequency modulation atomic force microscopy (FM-AFM) in phosphate buffer solution. FM-AFM images of a DPPC/cholesterol bilayer in the liquid-ordered phase showed higher energy dissipation values compared to those measured on a nanoscale DPPC domain in the gel phase, reflecting the increased molecular fluidity due to the insertion of cholesterols. Molecular-resolution FM-AFM images of a DPPC/cholesterol bilayer revealed the existence of a rhombic molecular arrangement (lattice constants: a = 0.46 nm, b = 0.71 nm) consisting of alternating rows of DPPC and cholesterols as well as the increased defect density and reduced molecular ordering. The mechanical strength of a DPPC/cholesterol bilayer was quantitatively evaluated by measuring a loading force required to penetrate the membrane with an AFM tip. The result revealed the significant decrease of mechanical strength upon insertion of cholesterols. Based on the molecular-scale arrangement found in this study, we propose a model to explain the reduced mechanical strength in relation to the formation of lipid-ion networks.

The molecular-scale arrangement and mechanical strength of phospholipid/cholesterol mixed bilayers investigated by frequency modulation atomic force microscopy in liquid

International Nuclear Information System (INIS)

Asakawa, Hitoshi; Fukuma, Takeshi

2009-01-01

Cholesterols play key roles in controlling molecular fluidity in a biological membrane, yet little is known about their molecular-scale arrangements in real space. In this study, we have directly imaged lipid-cholesterol complexes in a model biological membrane consisting of dipalmitoylphosphatidylcholine (DPPC) and cholesterols by frequency modulation atomic force microscopy (FM-AFM) in phosphate buffer solution. FM-AFM images of a DPPC/cholesterol bilayer in the liquid-ordered phase showed higher energy dissipation values compared to those measured on a nanoscale DPPC domain in the gel phase, reflecting the increased molecular fluidity due to the insertion of cholesterols. Molecular-resolution FM-AFM images of a DPPC/cholesterol bilayer revealed the existence of a rhombic molecular arrangement (lattice constants: a = 0.46 nm, b = 0.71 nm) consisting of alternating rows of DPPC and cholesterols as well as the increased defect density and reduced molecular ordering. The mechanical strength of a DPPC/cholesterol bilayer was quantitatively evaluated by measuring a loading force required to penetrate the membrane with an AFM tip. The result revealed the significant decrease of mechanical strength upon insertion of cholesterols. Based on the molecular-scale arrangement found in this study, we propose a model to explain the reduced mechanical strength in relation to the formation of lipid-ion networks.

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

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.

Molecular Mechanism of Somite Development

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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

Protective molecular mechanisms of resveratrol in UVR-induced Skin carcinogenesis.

Science.gov (United States)

Aziz, Saba W; Aziz, Moammir H

2018-01-01

Skin cancer is a major health problem worldwide. It is the most common cancer in the United States and poses a significant healthcare burden. Excessive UVR exposure is the most common cause of skin cancer. Despite various precautionary measures to avoid direct UVR exposure, the incidence of skin cancer and mortality related to it remains high. Furthermore, the current treatment options are expensive and have side effects including toxicity to normal cells. Thus, a safe and effective approach is needed to prevent and treat skin cancer. Chemopreventive strategy using naturally occurring compounds, such as resveratrol, is a promising approach to reduce the incidence of UVR-induced skin cancer and delay its progression. This review highlights the current body of evidence related to chemopreventive role of resveratrol and its molecular mechanisms in UVR-induced skin carcinogenesis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Epigenetic mechanisms of alcoholism and stress-related disorders.

Science.gov (United States)

Palmisano, Martina; Pandey, Subhash C

2017-05-01

Stress-related disorders, such as anxiety, early life stress, and posttraumatic stress disorder appear to be important factors in promoting alcoholism, as alcohol consumption can temporarily attenuate the negative affective symptoms of these disorders. Several molecules involved in signaling pathways may contribute to the neuroadaptation induced during alcohol dependence and stress disorders, and among these, brain-derived neurotrophic factor (BDNF), corticotropin releasing factor (CRF), neuropeptide Y (NPY) and opioid peptides (i.e., nociceptin and dynorphin) are involved in the interaction of stress and alcohol. In fact, alterations in the expression and function of these molecules have been associated with the pathophysiology of stress-related disorders and alcoholism. In recent years, various studies have focused on the epigenetic mechanisms that regulate chromatin architecture, thereby modifying gene expression. Interestingly, epigenetic modifications in specific brain regions have been shown to be associated with the neurobiology of psychiatric disorders, including alcoholism and stress. In particular, the enzymes responsible for chromatin remodeling (i.e., histone deacetylases and methyltransferases, DNA methyltransferases) have been identified as common molecular mechanisms for the interaction of stress and alcohol and have become promising therapeutic targets to treat or prevent alcoholism and associated emotional disorders. Published by Elsevier Inc.

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

Molecular dynamics simulations of graphoepitaxy of organic semiconductors, sexithiophene, and pentacene: Molecular-scale mechanisms of organic graphoepitaxy

Science.gov (United States)

Ikeda, Susumu

2018-03-01

Molecular dynamics (MD) simulations of the organic semiconductors α-sexithiophene (6T) and pentacene were carried out to clarify the mechanism of organic graphoepitaxy at the molecular level. First, the models of the grooved substrates were made and the surfaces of the inside of the grooves were modified with -OH or -OSi(CH3)3, making the surfaces hydrophilic or hydrophobic. By the MD simulations of 6T, it was found that three stable azimuthal directions exist (0, ˜45, and 90° the angle that the c-axis makes with the groove), being consistent with experimental results. MD simulations of deposition processes of 6T and pentacene were also carried out, and pentacene molecules showed the spontaneous formation of herringbone packing during deposition. Some pentacene molecules stood on the surface and formed a cluster whose a-axis was parallel to the groove. It is expected that a deep understanding of the molecular-scale mechanisms will lead graphoepitaxy to practical applications, improving the performance of organic devices.

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

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.

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.

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.)

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.

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

Dependence of mechanical characteristics from composition and structure and optimization of mechanical fracture energy of polymer composite material based on high-molecular rubbers

Directory of Open Access Journals (Sweden)

E. Nurullaev

2017-07-01

Full Text Available By means of numerical experiment the authors investigate dependence of conventional rupturing stress and mechanical fracture energy at uniaxial tension from fractional composition of dispersed filler, plasticizer volume fraction in polymer binder, effective density of transverse bonds, applied to development of covering for different purposes and with advanced service life in temperature range from 223 to 323 K. They compare mechanical characteristics of polymer composite materials (PCMs based on high- and low-molecular rubbers. It was shown that rupturing stress of high-molecular rubber-based PCM is of a higher magnitude than the stress of low-molecular rubber-based one at almost invariable rupturing deformation. Numerical simulation by variation of composition parameters and molecular structure enables evaluation of its maximum fracture energy which is 1000 times higher than mechanical fracture energy of similar composites based on low-molecular rubbers.

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.

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:.

Molecular Dynamics Simulation for the Mechanical Properties of CNT/Polymer Nanocomposites

International Nuclear Information System (INIS)

Yang, Seung Hwa; Cho, Maeg Hyo

2007-01-01

In order to obtain mechanical properties of CNT/Polymer nano-composites, molecular dynamics simulation is performed. Overall system was modeled as a flexible unit cell in which carbon nanotubes are embedded into a polyethylene matrix for N σ T ensemble simulation. COMPASS force field was chosen to describe inter and intra molecular potential and bulk effect was achieved via periodic boundary conditions. In CNT-polymer interface, only Lennard-Jones non-bond potential was considered. Using Parrinello-Rahman fluctuation method, mechanical properties of orthotropic nano-composites under various temperatures were successfully obtained. Also, we investigated thermal behavior of the short CNT reinforced nanocomposites system with predicting glass transition temperature

Combined quantum mechanical and molecular mechanical method for metal-organic frameworks: proton topologies of NU-1000.

Science.gov (United States)

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

2018-01-17

Metal-organic frameworks (MOFs) are materials with applications in catalysis, gas separations, and storage. Quantum mechanical (QM) calculations can provide valuable guidance to understand and predict their properties. In order to make the calculations faster, rather than modeling these materials as periodic (infinite) systems, it is useful to construct finite models (called cluster models) and use subsystem methods such as fragment methods or combined quantum mechanical and molecular mechanical (QM/MM) methods. Here we employ a QM/MM methodology to study one particular MOF that has been of widespread interest because of its wide pores and good solvent and thermal stability, namely NU-1000, which contains hexanuclear zirconium nodes and 1,3,6,8-tetrakis(p-benzoic acid)pyrene (TBAPy 4- ) linkers. A modified version of the Bristow-Tiana-Walsh transferable force field has been developed to allow QM/MM calculations on NU-1000; we call the new parametrization the NU1T force field. We consider isomeric structures corresponding to various proton topologies of the [Zr 6 (μ 3 -O) 8 O 8 H 16 ] 8+ node of NU-1000, and we compute their relative energies using a QM/MM scheme designed for the present kind of problem. We compared the results to full quantum mechanical (QM) energy calculations and found that the QM/MM models can reproduce the full QM relative energetics (which span a range of 334 kJ mol -1 ) with a mean unsigned deviation (MUD) of only 2 kJ mol -1 . Furthermore, we found that the structures optimized by QM/MM are nearly identical to their full QM optimized counterparts.

Molecular mechanisms of D-cycloserine in facilitating fear extinction: insights from RNAseq.

Science.gov (United States)

Malan-Müller, Stefanie; Fairbairn, Lorren; Daniels, Willie M U; Dashti, Mahjoubeh Jalali Sefid; Oakeley, Edward J; Altorfer, Marc; Kidd, Martin; Seedat, Soraya; Gamieldien, Junaid; Hemmings, Sîan Megan Joanna

2016-02-01

D-cycloserine (DCS) has been shown to be effective in facilitating fear extinction in animal and human studies, however the precise mechanisms whereby the co-administration of DCS and behavioural fear extinction reduce fear are still unclear. This study investigated the molecular mechanisms of intrahippocampally administered D-cycloserine in facilitating fear extinction in a contextual fear conditioning animal model. Male Sprague Dawley rats (n = 120) were grouped into four experimental groups (n = 30) based on fear conditioning and intrahippocampal administration of either DCS or saline. The light/dark avoidance test was used to differentiate maladapted (MA) (anxious) from well-adapted (WA) (not anxious) subgroups. RNA extracted from the left dorsal hippocampus was used for RNA sequencing and gene expression data was compared between six fear-conditioned + saline MA (FEAR + SALINE MA) and six fear-conditioned + DCS WA (FEAR + DCS WA) animals. Of the 424 significantly downregulated and 25 significantly upregulated genes identified in the FEAR + DCS WA group compared to the FEAR + SALINE MA group, 121 downregulated and nine upregulated genes were predicted to be relevant to fear conditioning and anxiety and stress-related disorders. The majority of downregulated genes transcribed immune, proinflammatory and oxidative stress systems molecules. These molecules mediate neuroinflammation and cause neuronal damage. DCS also regulated genes involved in learning and memory processes, and genes associated with anxiety, stress-related disorders and co-occurring diseases (e.g., cardiovascular diseases, digestive system diseases and nervous system diseases). Identifying the molecular underpinnings of DCS-mediated fear extinction brings us closer to understanding the process of fear extinction.

Neurobiology of Chronic Stress-Related Psychiatric Disorders: Evidence from Molecular Imaging Studies

Science.gov (United States)

Davis, Margaret T.; Holmes, Sophie E.; Pietrzak, Robert H.; Esterlis, Irina

2018-01-01

Chronic stress accounts for billions of dollars of economic loss annually in the United States alone, and is recognized as a major source of disability and mortality worldwide. Robust evidence suggests that chronic stress plays a significant role in the onset of severe and impairing psychiatric conditions, including major depressive disorder, bipolar disorder, and posttraumatic stress disorder. Application of molecular imaging techniques such as positron emission tomography and single photon emission computed tomography in recent years has begun to provide insight into the molecular mechanisms by which chronic stress confers risk for these disorders. The present paper provides a comprehensive review and synthesis of all positron emission tomography and single photon emission computed tomography imaging publications focused on the examination of molecular targets in individuals with major depressive disorder, posttraumatic stress disorder, or bipolar disorder to date. Critical discussion of discrepant findings and broad strengths and weaknesses of the current body of literature is provided. Recommended future directions for the field of molecular imaging to further elucidate the neurobiological substrates of chronic stress-related disorders are also discussed. This article is part of the inaugural issue for the journal focused on various aspects of chronic stress. PMID:29862379

Practical Photoemission Characterization Of Molecular Films And Related Interfaces

International Nuclear Information System (INIS)

Ivanco, J.

2013-01-01

Even though the term ‘organic electronics’ evokes rather organic devices, a significant part of its scope deals with physical properties of ‘active elements’ such as organic films and interfaces. Examination of the film growth and the evolution of the interface formation are particularly needful for the understanding a mechanism controlling their final properties. Performing such experiments in an ultra-high vacuum allows both to ‘stretch’ the time scale for pseudo real-time observations and to control properties of the probed systems on the atomic level. Photoemission technique probes directly electronic and chemical structure and it has thereby established among major tools employed in the field.This review primarily focuses to electronic properties of oligomeric molecular films and their interfaces examined by photoemission. Yet, it does not aspire after a complete overview on the topic; it rather aims to otherwise standard issues encountered at the photoemission characterization and analysis of the organic materials, though requiring to consider particularities of molecular films in terms of the growth, electronic properties, and their characterization and analysis. In particular, the fundamental electronic parameters of molecular films such as the work function, the ionization energy, and the interfacial energy level alignment, and their interplay, will be pursued with considering often neglected influence of the molecular orientation. Further, the implication on the band bending in molecular films based on photoemission characterization, and a model on the driving mechanism for the interfacial energy level alignment will be addressed. (author)

Molecular Mechanics of the Moisture Effect on Epoxy/Carbon Nanotube Nanocomposites

Directory of Open Access Journals (Sweden)

Lik-ho Tam

2017-10-01

Full Text Available The strong structural integrity of polymer nanocomposite is influenced in the moist environment; but the fundamental mechanism is unclear, including the basis for the interactions between the absorbed water molecules and the structure, which prevents us from predicting the durability of its applications across multiple scales. In this research, a molecular dynamics model of the epoxy/single-walled carbon nanotube (SWCNT nanocomposite is constructed to explore the mechanism of the moisture effect, and an analysis of the molecular interactions is provided by focusing on the hydrogen bond (H-bond network inside the nanocomposite structure. The simulations show that at low moisture concentration, the water molecules affect the molecular interactions by favorably forming the water-nanocomposite H-bonds and the small cluster, while at high concentration the water molecules predominantly form the water-water H-bonds and the large cluster. The water molecules in the epoxy matrix and the epoxy-SWCNT interface disrupt the molecular interactions and deteriorate the mechanical properties. Through identifying the link between the water molecules and the nanocomposite structure and properties, it is shown that the free volume in the nanocomposite is crucial for its structural integrity, which facilitates the moisture accumulation and the distinct material deteriorations. This study provides insights into the moisture-affected structure and properties of the nanocomposite from the nanoscale perspective, which contributes to the understanding of the nanocomposite long-term performance under the moisture effect.

Molecular Mechanics of the Moisture Effect on Epoxy/Carbon Nanotube Nanocomposites.

Science.gov (United States)

Tam, Lik-Ho; Wu, Chao

2017-10-13

The strong structural integrity of polymer nanocomposite is influenced in the moist environment; but the fundamental mechanism is unclear, including the basis for the interactions between the absorbed water molecules and the structure, which prevents us from predicting the durability of its applications across multiple scales. In this research, a molecular dynamics model of the epoxy/single-walled carbon nanotube (SWCNT) nanocomposite is constructed to explore the mechanism of the moisture effect, and an analysis of the molecular interactions is provided by focusing on the hydrogen bond (H-bond) network inside the nanocomposite structure. The simulations show that at low moisture concentration, the water molecules affect the molecular interactions by favorably forming the water-nanocomposite H-bonds and the small cluster, while at high concentration the water molecules predominantly form the water-water H-bonds and the large cluster. The water molecules in the epoxy matrix and the epoxy-SWCNT interface disrupt the molecular interactions and deteriorate the mechanical properties. Through identifying the link between the water molecules and the nanocomposite structure and properties, it is shown that the free volume in the nanocomposite is crucial for its structural integrity, which facilitates the moisture accumulation and the distinct material deteriorations. This study provides insights into the moisture-affected structure and properties of the nanocomposite from the nanoscale perspective, which contributes to the understanding of the nanocomposite long-term performance under the moisture effect.

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.

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.

Study on radiation protective effect of resveratrol and its molecular mechanism

International Nuclear Information System (INIS)

Lv Qiujun; Wen Liqing; Zhang Min; Guo Shaoming; Chen Yuanyuan; Wu Zuze

2004-01-01

Objective: To investigate radiation-protective effect of resveratrol and its molecular mechanism. Methods: Kunming mice were administered with resveratrol before 60 Co γ-irradiation. Thirty-day survival rate and the average life span of dead mice post-irradiation were observed. The apoptosis of spleen from irradiated mice was detected by FACS and in situ terminal labeling method. The effect of resveratrol on the activities of Caspase-3 and Caspase-8, and the expression levels of Bcl-2 and Fas were examined. Results: Administration with resveratrol resulted in increases of 30-day survival rate and prolongation of average life span of the dead mice. Apoptotic rate of spleen cells decreased, expression level of bcl-2 increased, the expression of Fas did not change, and the activities of Caspase-3 and Caspase-8 increased in spleen cells of irradiation groups. Conclusion: The results indicate that resveratrol has radiation-protective effect and its mechanism might be related with its suppression of apoptosis of radiation-sensitive cells

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.

The molecular genetic basis of age-related macular degeneration ...

Indian Academy of Sciences (India)

2009-12-10

Dec 10, 2009 ... this review, we have provided an overview on the underlying molecular genetic mechanisms in AMD worldwide and highlight ..... eases like diabetes (Scott et al. ...... 2006 Systematic review and meta-analysis of.

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

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 explanations made by experts from different biology subdisciplines at a university support the validity of this model? Guided by the modeling framework of R. S. Justi and J. K. Gilbert, the validity of an initial model was tested by asking seven biologists to explain a molecular mechanism of their choice. Data were collected from interviews, artifacts, and drawings, and then subjected to thematic analysis. We found that biologists explained the specific activities and organization of entities of the mechanism. In addition, they contextualized explanations according to their biological and social significance; integrated explanations with methods, instruments, and measurements; and used analogies and narrated stories. The derived methods, analogies, context, and how themes informed the development of our final MACH model of mechanistic explanations. Future research will test the potential of the MACH model as a guiding framework for instruction to enhance the quality of student explanations. PMID:25999313

Atomistic mechanism of microRNA translation upregulation via molecular dynamics simulations.

Directory of Open Access Journals (Sweden)

Wei Ye

Full Text Available MicroRNAs are endogenous 23-25 nt RNAs that play important gene-regulatory roles in animals and plants. Recently, miR369-3 was found to upregulate translation of TNFα mRNA in quiescent (G0 mammalian cell lines. Knock down and immunofluorescence experiments suggest that microRNA-protein complexes (with FXR1 and AGO2 are necessary for the translation upregulation. However the molecular mechanism of microRNA translation activation is poorly understood. In this study we constructed the microRNA-mRNA-AGO2-FXR1 quadruple complex by bioinformatics and molecular modeling, followed with all atom molecular dynamics simulations in explicit solvent to investigate the interaction mechanisms for the complex. A combined analysis of experimental and computational data suggests that AGO2-FXR1 complex relocalize microRNA:mRNA duplex to polysomes in G0. The two strands of dsRNA are then separated upon binding of AGO2 and FXR1. Finally, polysomes may improve the translation efficiency of mRNA. The mutation research confirms the stability of microRNA-mRNA-FXR1 and illustrates importance of key residue of Ile304. This possible mechanism can shed more light on the microRNA-dependent upregulation of translation.

Cation solvation with quantum chemical effects modeled by a size-consistent multi-partitioning quantum mechanics/molecular mechanics method.

Science.gov (United States)

Watanabe, Hiroshi C; Kubillus, Maximilian; Kubař, Tomáš; Stach, Robert; Mizaikoff, Boris; Ishikita, Hiroshi

2017-07-21

In the condensed phase, quantum chemical properties such as many-body effects and intermolecular charge fluctuations are critical determinants of the solvation structure and dynamics. Thus, a quantum mechanical (QM) molecular description is required for both solute and solvent to incorporate these properties. However, it is challenging to conduct molecular dynamics (MD) simulations for condensed systems of sufficient scale when adapting QM potentials. To overcome this problem, we recently developed the size-consistent multi-partitioning (SCMP) quantum mechanics/molecular mechanics (QM/MM) method and realized stable and accurate MD simulations, using the QM potential to a benchmark system. In the present study, as the first application of the SCMP method, we have investigated the structures and dynamics of Na + , K + , and Ca 2+ solutions based on nanosecond-scale sampling, a sampling 100-times longer than that of conventional QM-based samplings. Furthermore, we have evaluated two dynamic properties, the diffusion coefficient and difference spectra, with high statistical certainty. Furthermore the calculation of these properties has not previously been possible within the conventional QM/MM framework. Based on our analysis, we have quantitatively evaluated the quantum chemical solvation effects, which show distinct differences between the cations.

Molecular sieving through a graphene nanopore: non-equilibrium molecular dynamics simulation

Institute of Scientific and Technical Information of China (English)

Chengzhen Sun; Bofeng Bai

2017-01-01

Two-dimensional graphene nanopores have shown great promise as ultra-permeable molecular sieves based on their size-sieving effects.We design a nitrogen/hydrogen modified graphene nanopore and conduct a transient non-equilibrium molecular dynamics simulation on its molecular sieving effects.The distinct time-varying molecular crossing numbers show that this special nanopore can efficiently sieve CO2 and H2S molecules from CH4 molecules with high selectivity.By analyzing the molecular structure and pore functionalization-related molecular orientation and permeable zone in the nanopore,density distribution in the molecular adsorption layer on the graphene surface,as well as other features,the molecular sieving mechanisms of graphene nanopores are revealed.Finally,several implications on the design of highly-efficient graphene nanopores,especially for determining the porosity and chemical functionalization,as gas separation membranes are summarized based on the identified phenomena and mechanisms.

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.

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

Insights into the Molecular Mechanisms of Alzheimer’s and Parkinson’s Diseases with Molecular Simulations: Understanding the Roles of Artificial and Pathological Missense Mutations in Intrinsically Disordered Proteins Related to Pathology

Directory of Open Access Journals (Sweden)

Orkid Coskuner-Weber

2018-01-01

Full Text Available Amyloid-β and α-synuclein are intrinsically disordered proteins (IDPs, which are at the center of Alzheimer’s and Parkinson’s disease pathologies, respectively. These IDPs are extremely flexible and do not adopt stable structures. Furthermore, both amyloid-β and α-synuclein can form toxic oligomers, amyloid fibrils and other type of aggregates in Alzheimer’s and Parkinson’s diseases. Experimentalists face challenges in investigating the structures and thermodynamic properties of these IDPs in their monomeric and oligomeric forms due to the rapid conformational changes, fast aggregation processes and strong solvent effects. Classical molecular dynamics simulations complement experiments and provide structural information at the atomic level with dynamics without facing the same experimental limitations. Artificial missense mutations are employed experimentally and computationally for providing insights into the structure-function relationships of amyloid-β and α-synuclein in relation to the pathologies of Alzheimer’s and Parkinson’s diseases. Furthermore, there are several natural genetic variations that play a role in the pathogenesis of familial cases of Alzheimer’s and Parkinson’s diseases, which are related to specific genetic defects inherited in dominant or recessive patterns. The present review summarizes the current understanding of monomeric and oligomeric forms of amyloid-β and α-synuclein, as well as the impacts of artificial and pathological missense mutations on the structural ensembles of these IDPs using molecular dynamics simulations. We also emphasize the recent investigations on residual secondary structure formation in dynamic conformational ensembles of amyloid-β and α-synuclein, such as β-structure linked to the oligomerization and fibrillation mechanisms related to the pathologies of Alzheimer’s and Parkinson’s diseases. This information represents an important foundation for the successful and

[Ginseng prescription rules and molecular mechanism in treating coronary heart disease based on data mining and integrative pharmacology].

Science.gov (United States)

Li, Sen; Tang, Shi-Huan; Liu, Jin-Ling; Su, Jin; He, Fu-Yuan

2018-04-01

The ancient dragon Materia Medica, Compendium of Materia Medica and other works recorded that the main effect of ginseng is tonifying qi. It is reported that the main active ingredient of ginseng is ginsenoside. Modern studies have found that ginseng mono saponins are effective for cardiovascular related diseases. This paper preliminary clarified the efficacy of traditional ginseng-nourishing qi and cardiovascular disease through the traditional Chinese medicine (TCM) inheritance auxiliary platform and integration platform of association of pharmacology. With the help of TCM inheritance auxiliary platform-analysis of "Chinese medicine database", Chinese medicine treatment of modern diseases that ginseng rules, so the traditional effect associated with modern medicine and pharmacology; application integration platform enrichment analysis on the target of drug and gene function, metabolic pathway, to further explore the molecular mechanism of ginseng in the treatment of coronary heart disease, aimed at mining the molecular mechanism of ginseng in the treatment of coronary heart disease. Chinese medicine containing ginseng 307 prescriptions, 87 kinds of disease indications, western medicine disease Chinese medicine therapy for ginseng main coronary heart disease; analysis of molecular mechanism of ginseng pharmacology integration platform for the treatment of coronary heart disease. Ginsenosides（Ra₁, Ra₂, Rb₁, Rb₂, Rg₁, Ro) bind these targets, PRKAA1, PRKAA2, NDUFA4, COX5B, UQCRC1, affect chemokines, non-alcoholic fatty liver, gonadotropin, carbon metabolism, glucose metabolism and other pathways to treat coronary heart disease indirectly. The molecular mechanism of Panax ginseng's multi-component, multi-target and synergistic action is preliminarily elucidated in this paper. Copyright© by the Chinese Pharmaceutical Association.

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.

Quantum mechanical calculations related to ionization and charge transfer in DNA

International Nuclear Information System (INIS)

Cauët, E; Liévin, J; Valiev, M; Weare, J H

2012-01-01

Ionization and charge migration in DNA play crucial roles in mechanisms of DNA damage caused by ionizing radiation, oxidizing agents and photo-irradiation. Therefore, an evaluation of the ionization properties of the DNA bases is central to the full interpretation and understanding of the elementary reactive processes that occur at the molecular level during the initial exposure and afterwards. Ab initio quantum mechanical (QM) methods have been successful in providing highly accurate evaluations of key parameters, such as ionization energies (IE) of DNA bases. Hence, in this study, we performed high-level QM calculations to characterize the molecular energy levels and potential energy surfaces, which shed light on ionization and charge migration between DNA bases. In particular, we examined the IEs of guanine, the most easily oxidized base, isolated and embedded in base clusters, and investigated the mechanism of charge migration over two and three stacked guanines. The IE of guanine in the human telomere sequence has also been evaluated. We report a simple molecular orbital analysis to explain how modifications in the base sequence are expected to change the efficiency of the sequence as a hole trap. Finally, the application of a hybrid approach combining quantum mechanics with molecular mechanics brings an interesting discussion as to how the native aqueous DNA environment affects the IE threshold of nucleobases.

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.

Coarse-grained simulation of molecular mechanisms of recovery in thermally activated shape-memory polymers

Science.gov (United States)

Abberton, Brendan C.; Liu, Wing Kam; Keten, Sinan

2013-12-01

Thermally actuated shape-memory polymers (SMPs) are capable of being programmed into a temporary shape and then recovering their permanent reference shape upon exposure to heat, which facilitates a phase transition that allows dramatic increase in molecular mobility. Experimental, analytical, and computational studies have established empirical relations of the thermomechanical behavior of SMPs that have been instrumental in device design. However, the underlying mechanisms of the recovery behavior and dependence on polymer microstructure remain to be fully understood for copolymer systems. This presents an opportunity for bottom-up studies through molecular modeling; however, the limited time-scales of atomistic simulations prohibit the study of key performance metrics pertaining to recovery. In order to elucidate the effects of phase fraction, recovery temperature, and deformation temperature on shape recovery, here we investigate the shape-memory behavior in a copolymer model with coarse-grained potentials using a two-phase molecular model that reproduces physical crosslinking. Our simulation protocol allows observation of upwards of 90% strain recovery in some cases, at time-scales that are on the order of the timescale of the relevant relaxation mechanism (stress relaxation in the unentangled soft-phase). Partial disintegration of the glassy phase during mechanical deformation is found to contribute to irrecoverable strain. Temperature dependence of the recovery indicates nearly full elastic recovery above the trigger temperature, which is near the glass-transition temperature of the rubbery switching matrix. We find that the trigger temperature is also directly correlated with the deformation temperature, indicating that deformation temperature influences the recovery temperatures required to obtain a given amount of shape recovery, until the plateau regions overlap above the transition region. Increasing the fraction of glassy phase results in higher strain

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.

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...

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

Comparative analysis of the molecular mechanisms of recombination in hepatitis C virus

DEFF Research Database (Denmark)

Galli, Andrea; Bukh, Jens

2014-01-01

Genetic recombination is an important evolutionary mechanism for RNA viruses. The significance of this phenomenon for hepatitis C virus (HCV) has recently become evident, with the identification of circulating recombinant forms in HCV-infected individuals and by novel data from studies permitted...... by advances in HCV cell culture systems and genotyping protocols. HCV is readily able to produce viable recombinants, using replicative and non-replicative molecular mechanisms. However, our knowledge of the required molecular mechanisms remains limited. Understanding how HCV recombines might be instrumental...... for a better monitoring of global epidemiology, to clarify the virus evolution, and evaluate the impact of recombinant forms on the efficacy of oncoming combination drug therapies. For the latter, frequency and location of recombination events could affect the efficacy of multidrug regimens. This review...

Quantum Mechanics/Molecular Mechanics Method Combined with Hybrid All-Atom and Coarse-Grained Model: Theory and Application on Redox Potential Calculations.

Science.gov (United States)

Shen, Lin; Yang, Weitao

2016-04-12

We developed a new multiresolution method that spans three levels of resolution with quantum mechanical, atomistic molecular mechanical, and coarse-grained models. The resolution-adapted all-atom and coarse-grained water model, in which an all-atom structural description of the entire system is maintained during the simulations, is combined with the ab initio quantum mechanics and molecular mechanics method. We apply this model to calculate the redox potentials of the aqueous ruthenium and iron complexes by using the fractional number of electrons approach and thermodynamic integration simulations. The redox potentials are recovered in excellent accordance with the experimental data. The speed-up of the hybrid all-atom and coarse-grained water model renders it computationally more attractive. The accuracy depends on the hybrid all-atom and coarse-grained water model used in the combined quantum mechanical and molecular mechanical method. We have used another multiresolution model, in which an atomic-level layer of water molecules around redox center is solvated in supramolecular coarse-grained waters for the redox potential calculations. Compared with the experimental data, this alternative multilayer model leads to less accurate results when used with the coarse-grained polarizable MARTINI water or big multipole water model for the coarse-grained layer.

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.

Genetic and Molecular Mechanisms of Quantitative Trait Loci Controlling Maize Inflorescence Architecture.

Science.gov (United States)

Li, Manfei; Zhong, Wanshun; Yang, Fang; Zhang, Zuxin

2018-03-01

The establishment of inflorescence architecture is critical for the reproduction of flowering plant species. The maize plant generates two types of inflorescences, the tassel and the ear, and their architectures have a large effect on grain yield and yield-related traits that are genetically controlled by quantitative trait loci (QTLs). Since ear and tassel architecture are deeply affected by the activity of inflorescence meristems, key QTLs and genes regulating meristematic activity have important impacts on inflorescence development and show great potential for optimizing grain yield. Isolation of yield trait-related QTLs is challenging, but these QTLs have direct application in maize breeding. Additionally, characterization and functional dissection of QTLs can provide genetic and molecular knowledge of quantitative variation in inflorescence architecture. In this review, we summarize currently identified QTLs responsible for the establishment of ear and tassel architecture and discuss the potential genetic control of four ear-related and four tassel-related traits. In recent years, several inflorescence architecture-related QTLs have been characterized at the gene level. We review the mechanisms of these characterized QTLs.

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...

RNA sequencing of Populus x canadensis roots identifies key molecular mechanisms underlying physiological adaption to excess zinc.

Directory of Open Access Journals (Sweden)

Andrea Ariani

Full Text Available Populus x canadensis clone I-214 exhibits a general indicator phenotype in response to excess Zn, and a higher metal uptake in roots than in shoots with a reduced translocation to aerial parts under hydroponic conditions. This physiological adaptation seems mainly regulated by roots, although the molecular mechanisms that underlie these processes are still poorly understood. Here, differential expression analysis using RNA-sequencing technology was used to identify the molecular mechanisms involved in the response to excess Zn in root. In order to maximize specificity of detection of differentially expressed (DE genes, we consider the intersection of genes identified by three distinct statistical approaches (61 up- and 19 down-regulated and validate them by RT-qPCR, yielding an agreement of 93% between the two experimental techniques. Gene Ontology (GO terms related to oxidation-reduction processes, transport and cellular iron ion homeostasis were enriched among DE genes, highlighting the importance of metal homeostasis in adaptation to excess Zn by P. x canadensis clone I-214. We identified the up-regulation of two Populus metal transporters (ZIP2 and NRAMP1 probably involved in metal uptake, and the down-regulation of a NAS4 gene involved in metal translocation. We identified also four Fe-homeostasis transcription factors (two bHLH38 genes, FIT and BTS that were differentially expressed, probably for reducing Zn-induced Fe-deficiency. In particular, we suggest that the down-regulation of FIT transcription factor could be a mechanism to cope with Zn-induced Fe-deficiency in Populus. These results provide insight into the molecular mechanisms involved in adaption to excess Zn in Populus spp., but could also constitute a starting point for the identification and characterization of molecular markers or biotechnological targets for possible improvement of phytoremediation performances of poplar trees.

THE RELATION BETWEEN MID-PLANE PRESSURE AND MOLECULAR HYDROGEN IN GALAXIES: ENVIRONMENTAL DEPENDENCE

International Nuclear Information System (INIS)

Feldmann, Robert; Hernandez, Jose; Gnedin, Nickolay Y.

2012-01-01

Molecular hydrogen (H 2 ) is the primary component of the reservoirs of cold, dense gas that fuel star formation in our Galaxy. While the H 2 abundance is ultimately regulated by physical processes operating on small scales in the interstellar medium (ISM), observations have revealed a tight correlation between the ratio of molecular to atomic hydrogen in nearby spiral galaxies and the pressure in the mid-plane of their disks. This empirical relation has been used to predict H 2 abundances in galaxies with potentially very different ISM conditions, such as metal-deficient galaxies at high redshifts. Here, we test the validity of this approach by studying the dependence of the pressure-H 2 relation on environmental parameters of the ISM. To this end, we follow the formation and destruction of H 2 explicitly in a suite of hydrodynamical simulations of galaxies with different ISM parameters. We find that a pressure-H 2 relation arises naturally in our simulations for a variety of dust-to-gas ratios or strengths of the interstellar radiation field in the ISM. Fixing the dust-to-gas ratio and the UV radiation field to values measured in the solar neighborhood results in fair agreement with the relation observed in nearby galaxies with roughly solar metallicity. However, the parameters (slope and normalization) of the pressure-H 2 relation vary in a systematical way with ISM properties. A particularly strong trend is the decrease of the normalization of the relation with a lowering of the dust-to-gas ratio of the ISM. We show how this trend and other properties of the pressure-H 2 relation arise from the atomic-to-molecular phase transition in the ISM caused by a combination of H 2 formation, destruction, and shielding mechanisms.

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

Perfect/complete scattering experiments probing quantum mechanics on atomic and molecular collisions and coincidences

CERN Document Server

Kleinpoppen, Hans; Grum-Grzhimailo, Alexei N

2013-01-01

The main goal of this book is to elucidate what kind of experiment must be performed in order to determine the full set of independent parameters which can be extracted and calculated from theory, where electrons, photons, atoms, ions, molecules, or molecular ions may serve as the interacting constituents of matter.  The feasibility of such perfect' and-or `complete' experiments, providing the complete quantum mechanical knowledge of the process, is associated with the enormous potential of modern research techniques, both, in experiment and theory.  It is even difficult to overestimate the role of theory in setting of the complete experiment, starting with the fact that an experiment can be complete only within a certain theoretical framework, and ending with the direct prescription of what, and in what conditions should be measured to make the experiment `complete'.  The language of the related theory is the language of quantum mechanical amplitudes and their relative phases.  This book captures the spi...

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

Science.gov (United States)

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

2017-02-14

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

Silk Fibroin Degradation Related to Rheological and Mechanical Properties.

Science.gov (United States)

Partlow, Benjamin P; Tabatabai, A Pasha; Leisk, Gary G; Cebe, Peggy; Blair, Daniel L; Kaplan, David L

2016-05-01

Regenerated silk fibroin has been proposed as a material substrate for biomedical, optical, and electronic applications. Preparation of the silk fibroin solution requires extraction (degumming) to remove contaminants, but results in the degradation of the fibroin protein. Here, a mechanism of fibroin degradation is proposed and the molecular weight and polydispersity is characterized as a function of extraction time. Rheological analysis reveals significant changes in the viscosity of samples while mechanical characterization of cast and drawn films shows increased moduli, extensibility, and strength upon drawing. Fifteen minutes extraction time results in degraded fibroin that generates the strongest films. Structural analysis by wide angle X-ray scattering (WAXS) and Fourier transform infrared spectroscopy (FTIR) indicates molecular alignment in the drawn films and shows that the drawing process converts amorphous films into the crystalline, β-sheet, secondary structure. Most interesting, by using selected extraction times, films with near-native crystallinity, alignment, and molecular weight can be achieved; yet maximal mechanical properties for the films from regenerated silk fibroin solutions are found with solutions subjected to some degree of degradation. These results suggest that the regenerated solutions and the film casting and drawing processes introduce more complexity than native spinning processes. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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.

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.

Molecular Mechanisms of Innate Immune Inhibition by Non-Segmented Negative-Sense RNA Viruses

Energy Technology Data Exchange (ETDEWEB)

Chatterjee, Srirupa; Basler, Christopher F.; Amarasinghe, Gaya K.; Leung, Daisy W.

2016-08-01

The host innate immune system serves as the first line of defense against viral infections. Germline-encoded pattern recognition receptors detect molecular patterns associated with pathogens and activate innate immune responses. Of particular relevance to viral infections are those pattern recognition receptors that activate type I interferon responses, which establish an antiviral state. The order Mononegavirales is composed of viruses that possess single-stranded, non-segmented negative-sense (NNS) RNA genomes and are important human pathogens that consistently antagonize signaling related to type I interferon responses. NNS viruses have limited encoding capacity compared to many DNA viruses, and as a likely consequence, most open reading frames encode multifunctional viral proteins that interact with host factors in order to evade host cell defenses while promoting viral replication. In this review, we will discuss the molecular mechanisms of innate immune evasion by select NNS viruses. A greater understanding of these interactions will be critical in facilitating the development of effective therapeutics and viral countermeasures.

The corticotropin-releasing hormone network and the hypothalamic-pituitary-adrenal axis: molecular and cellular mechanisms involved.

Science.gov (United States)

Bonfiglio, Juan José; Inda, Carolina; Refojo, Damián; Holsboer, Florian; Arzt, Eduardo; Silberstein, Susana

2011-01-01

Corticotropin-releasing hormone (CRH) plays a key role in adjusting the basal and stress-activated hypothalamic-pituitary-adrenal axis (HPA). CRH is also widely distributed in extrahypothalamic circuits, where it acts as a neuroregulator to integrate the complex neuroendocrine, autonomic, and behavioral adaptive response to stress. Hyperactive and/or dysregulated CRH circuits are involved in neuroendocrinological disturbances and stress-related mood disorders such as anxiety and depression. This review describes the main physiological features of the CRH network and summarizes recent relevant information concerning the molecular mechanism of CRH action obtained from signal transduction studies using cells and wild-type and transgenic mice lines. Special focus is placed on the MAPK signaling pathways triggered by CRH through the CRH receptor 1 that plays an essential role in CRH action in pituitary corticotrophs and in specific brain structures. Recent findings underpin the concept of specific CRH-signaling pathways restricted to specific anatomical areas. Understanding CRH action at molecular levels will not only provide insight into the precise CRH mechanism of action, but will also be instrumental in identifying novel targets for pharmacological intervention in neuroendocrine tissues and specific brain areas involved in CRH-related disorders. Copyright © 2011 S. Karger AG, Basel.

Insights into the Lactonase Mechanism of Serum Paraoxonase 1 (PON1): Experimental and Quantum Mechanics/Molecular Mechanics (QM/MM) Studies.

Science.gov (United States)

Le, Quang Anh Tuan; Kim, Seonghoon; Chang, Rakwoo; Kim, Yong Hwan

2015-07-30

Serum paraoxonase 1 (PON1) is a versatile enzyme for the hydrolysis of various substrates (e.g., lactones, phosphotriesters) and for the formation of a promising chemical platform γ-valerolactone. Elucidation of the PON1-catalyzed lactonase reaction mechanism is very important for understanding the enzyme function and for engineering this enzyme for specific applications. Kinetic study and hybrid quantum mechanics/molecular mechanics (QM/MM) method were used to investigate the PON1-catalyzed lactonase reaction of γ-butyrolactone (GBL) and (R)-γ-valerolactone (GVL). The activation energies obtained from the QM/MM calculations were in good agreement with the experiments. Interestingly, the QM/MM energy barriers at MP2/3-21G(d,p) level for the lactonase of GVL and GBL were respectively 14.3-16.2 and 11.5-13.1 kcal/mol, consistent with the experimental values (15.57 and 14.73 kcal/mol derived from respective kcat values of 36.62 and 147.21 s(-1)). The QM/MM energy barriers at MP2/6-31G(d) and MP2/6-31G(d,p) levels were also in relatively good agreements with the experiments. Importantly, the difference in the QM/MM energy barriers at MP2 level with all investigated basis sets for the lactonase of GVL and GBL were in excellent agreement with the experiments (0.9-3.1 and 0.8 kcal/mol, respectively). A detailed mechanism for the PON1-catalyzed lactonase reaction was also proposed in this study.

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.

Molecular mechanisms of resistance to Rituximab and pharmacologic strategies for its circumvention.

Science.gov (United States)

Stolz, Claudia; Schuler, Martin

2009-06-01

The introduction of Rituximab has greatly improved therapeutic options for patients with B-cell non-Hodgkin lymphoma (B-NHL). However, a substantial fraction of patients with aggressive B-NHL fails first-line therapy, and most patients with relapsing indolent B-NHL eventually acquire Rituximab resistance. Molecular understanding of the underlying mechanisms facilitates the development of pharmacologic strategies to overcome resistance. Rituximab exerts its activity on CD20-expressing B-cells by indirect and direct effector mechanisms. Indirect mechanisms are complement-dependent cytotoxicity (CDC), and antibody-dependent cell-mediated cytotoxicity (ADCC). Direct activities, such as growth inhibition, induction of apoptosis and chemosensitisation, have been reported, but are less defined. Moreover, the relative contribution of CDC, ADCC and direct mechanisms to the activity of Rituximab in vivo is unclear. Down-regulation of CD20 and expression of complement inhibitors have been described as escape mechanisms in B-NHL. Recent reports suggest that deregulated phosphoinositide-3-kinase (PI3K)/Akt, mitogen-activated kinases (MAPK) and nuclear-factor kappaB (NF-kappaB), as well as up-regulation of anti-apoptotic proteins may determine the efficacy of Rituximab to kill B-NHL cells in vitro and in vivo. The latter signalling pathways are attractive targets for pharmacologic modulation of resistance to Rituximab. With the advent of new inhibitors and antibodies, rationally designed clinical trials addressing Rituximab resistance are feasible.

Review on Molecular Mechanisms of Antifouling Compounds: An Update since 2012.

Science.gov (United States)

Chen, Lianguo; Qian, Pei-Yuan

2017-08-28

Better understanding of the mechanisms of antifouling compounds is recognized to be of high value in establishing sensitive biomarkers, allowing the targeted optimization of antifouling compounds and guaranteeing environmental safety. Despite vigorous efforts to find new antifouling compounds, information about the mechanisms of antifouling is still scarce. This review summarizes the progress into understanding the molecular mechanisms underlying antifouling activity since 2012. Non-toxic mechanisms aimed at specific targets, including inhibitors of transmembrane transport, quorum sensing inhibitors, neurotransmission blockers, adhesive production/release inhibitors and enzyme/protein inhibitors, are put forward for natural antifouling products or shelf-stable chemicals. Several molecular targets show good potential for use as biomarkers in future mechanistic screening, such as acetylcholine esterase for neurotransmission, phenoloxidase/tyrosinase for the formation of adhesive plaques, N -acyl homoserine lactone for quorum sensing and intracellular Ca 2+ levels as second messenger. The studies on overall responses to challenges by antifoulants can be categorized as general targets, including protein expression/metabolic activity regulators, oxidative stress inducers, neurotransmission blockers, surface modifiers, biofilm inhibitors, adhesive production/release inhibitors and toxic killing. Given the current situation and the knowledge gaps regarding the development of alternative antifoulants, a basic workflow is proposed that covers the indispensable steps, including preliminary mechanism- or bioassay-guided screening, evaluation of environmental risks, field antifouling performance, clarification of antifouling mechanisms and the establishment of sensitive biomarkers, which are combined to construct a positive feedback loop.

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)

Establishing whether the structural feature controlling the mechanical properties of starch films is molecular or crystalline.

Science.gov (United States)

Li, Ming; Xie, Fengwei; Hasjim, Jovin; Witt, Torsten; Halley, Peter J; Gilbert, Robert G

2015-03-06

The effects of molecular and crystalline structures on the tensile mechanical properties of thermoplastic starch (TPS) films from waxy, normal, and high-amylose maize were investigated. Starch structural variations were obtained through extrusion and hydrothermal treatment (HTT). The molecular and crystalline structures were characterized using size-exclusion chromatography and X-ray diffractometry, respectively. TPS from high-amylose maize showed higher elongation at break and tensile strength than those from normal maize and waxy maize starches when processed with 40% plasticizer. Within the same amylose content, the mechanical properties were not affected by amylopectin molecular size or the crystallinity of TPS prior to HTT. This lack of correlation between the molecular size, crystallinity and mechanical properties may be due to the dominant effect of the plasticizer on the mechanical properties. Further crystallization of normal maize TPS by HTT increased the tensile strength and Young's modulus, while decreasing the elongation at break. The results suggest that the crystallinity from the remaining ungelatinized starch granules has less significant effect on the mechanical properties than that resulting from starch recrystallization, possibly due to a stronger network from leached-out amylose surrounding the remaining starch granules. Copyright © 2014 Elsevier Ltd. All rights reserved.

Probing the molecular mechanism behind the cognitive impairment induced by THC

Czech Academy of Sciences Publication Activity Database

Botta, J.; Cordomi, A.; Bondar, Alexey; Lazar, Josef; Pardo, L.; McCormick, P. J.

2017-01-01

Roč. 121, č. 2 (2017), s. 11-12 ISSN 1742-7835 Institutional support: RVO:67179843 Keywords : THC * molecular mechanism * cognitive impairment Subject RIV: FR - Pharmacology ; Medidal Chemistry OBOR OECD: Toxicology Impact factor: 3.176, year: 2016

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.

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.

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.

Antiproliferative and Molecular Mechanism of Eugenol-Induced Apoptosis in Cancer Cells

Directory of Open Access Journals (Sweden)

Eko Supriyanto

2012-05-01

Full Text Available Phenolic phytochemicals are a broad class of nutraceuticals found in plants which have been extensively researched by scientists for their health-promoting potential. One such a compound which has been comprehensively used is eugenol (4-allyl-2-methoxyphenol, which is the active component of Syzigium aromaticum (cloves. Aromatic plants like nutmeg, basil, cinnamon and bay leaves also contain eugenol. Eugenol has a wide range of applications like perfumeries, flavorings, essential oils and in medicine as a local antiseptic and anesthetic. Increasing volumes of literature showed eugenol possesses antioxidant, antimutagenic, antigenotoxic, anti-inflammatory and anticancer properties. Molecular mechanism of eugenol-induced apoptosis in melanoma, skin tumors, osteosarcoma, leukemia, gastric and mast cells has been well documented. This review article will highlight the antiproliferative activity and molecular mechanism of the eugenol induced apoptosis against the cancer cells and animal models.

Quantum Mechanical Studies of DNA and LNA

DEFF Research Database (Denmark)

Koch, Troels; Shim, Irene; Lindow, Morten

2014-01-01

Quantum mechanical (QM) methodology has been employed to study the structure activity relations of DNA and locked nucleic acid (LNA). The QM calculations provide the basis for construction of molecular structure and electrostatic surface potentials from molecular orbitals. The topologies of the e......Quantum mechanical (QM) methodology has been employed to study the structure activity relations of DNA and locked nucleic acid (LNA). The QM calculations provide the basis for construction of molecular structure and electrostatic surface potentials from molecular orbitals. The topologies...

Electroporation of Skin Stratum Corneum Lipid Bilayer and Molecular Mechanism of Drug Transport: A Molecular Dynamics Study.

Science.gov (United States)

Gupta, Rakesh; Rai, Beena

2018-04-30

Skin electroporation has been used significantly to increase the drug permeation. However, molecular mechanism, which resulted in enhancement of flux through skin, is still not known. In this study, extensive atomistic molecular dynamics simulation of skin lipids (made up of ceramide (CER), cholesterol (CHOL) and free fatty acid (FFA)) have been performed at various external electric field. We show for the first time the pore formation in the skin lipid bilayer during the electroporation. We show the effect of applied external electrical field on the pore formation dynamics in lipid bilayer of different size and composition. The pore formation and resealing kinetics were different and was found to be highly dependent on the composition of skin lipid bilayer. The pore formation time decreased with increase in the bilayer size. The pore sustaining electric field was found to be in the range of 0.20-0.25 V/nm for equimolar CER, CHOL and FFA lipid bilayer. The skin lipid bilayer (1:1:1), sealed itself within 20 ns after the removal of external electric field. We also present the molecular mechanism of enhancement of drug permeation in the presence of external field as compared to the passive diffusion. The molecular level understanding obtained here could help in optimizing/designing the electroporation experiments for effective drug delivery. For a given skin composition and size of drug molecule, the combination of pore formation time and pore growth model can be used to know aproiri the desired electric field and time for application of electric field.

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.

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

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.

Revealing molecular mechanisms by integrating high-dimensional functional screens with protein interaction data.

Directory of Open Access Journals (Sweden)

Angela Simeone

2014-09-01

Full Text Available Functional genomics screens using multi-parametric assays are powerful approaches for identifying genes involved in particular cellular processes. However, they suffer from problems like noise, and often provide little insight into molecular mechanisms. A bottleneck for addressing these issues is the lack of computational methods for the systematic integration of multi-parametric phenotypic datasets with molecular interactions. Here, we present Integrative Multi Profile Analysis of Cellular Traits (IMPACT. The main goal of IMPACT is to identify the most consistent phenotypic profile among interacting genes. This approach utilizes two types of external information: sets of related genes (IMPACT-sets and network information (IMPACT-modules. Based on the notion that interacting genes are more likely to be involved in similar functions than non-interacting genes, this data is used as a prior to inform the filtering of phenotypic profiles that are similar among interacting genes. IMPACT-sets selects the most frequent profile among a set of related genes. IMPACT-modules identifies sub-networks containing genes with similar phenotype profiles. The statistical significance of these selections is subsequently quantified via permutations of the data. IMPACT (1 handles multiple profiles per gene, (2 rescues genes with weak phenotypes and (3 accounts for multiple biases e.g. caused by the network topology. Application to a genome-wide RNAi screen on endocytosis showed that IMPACT improved the recovery of known endocytosis-related genes, decreased off-target effects, and detected consistent phenotypes. Those findings were confirmed by rescreening 468 genes. Additionally we validated an unexpected influence of the IGF-receptor on EGF-endocytosis. IMPACT facilitates the selection of high-quality phenotypic profiles using different types of independent information, thereby supporting the molecular interpretation of functional screens.

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

ANLIZE: a molecular mechanics force field visualization tool and its application to 18-crown-6.

Science.gov (United States)

Stolworthy, L D; Shirts, R B

1997-03-01

We describe a software tool that allows one to visualize and analyze the importance of each individual steric interaction in a molecular mechanics force field. ANLIZE is presently implemented for the Dreiding force field for use with the Cerius2 software package, but could be implemented in any molecular mechanics package with a graphical user interface. ANLIZE calculates individual interactions in the force field, sorts them by size, and displays them in several ways from a menu of choices. This allows the user to scan through selected interactions to visualize which interactions are the primary determinants of preferred conformations. The features of ANLIZE are illustrated using 18-crown-6 as an example, and the factors governing conformational preference in 18-crown-6 are demonstrated. Users of molecular mechanics packages are encouraged to demand this functionality from commercial software producers.

Molecular mechanisms in the selective basal activation of pyrabactin receptor 1: Comparative analysis of mutants.

Science.gov (United States)

Dorosh, Lyudmyla; Rajagopalan, Nandhakishore; Loewen, Michele C; Stepanova, Maria

2014-01-01

Pyrabactin receptors (PYR) play a central role in abscisic acid (ABA) signal transduction; they are ABA receptors that inhibit type 2C protein phosphatases (PP2C). Molecular aspects contributing to increased basal activity of PYR against PP2C are studied by molecular dynamics (MD) simulations. An extensive series of MD simulations of the apo-form of mutagenized PYR1 as a homodimer and in complex with homology to ABA-insensitive 1 (HAB1) phosphatase are reported. In order to investigate the detailed molecular mechanisms mediating PYR1 activity, the MD data was analyzed by essential collective dynamics (ECD), a novel approach that allows the identification, with atomic resolution, of persistent dynamic correlations based on relatively short MD trajectories. Employing the ECD method, the effects of select mutations on the structure and dynamics of the PYR1 complexes were investigated and considered in the context of experimentally determined constitutive activities against HAB1. Approaches to rationally design constitutively active PYR1 constructs to increase PP2C inhibition are discussed.

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.

[Compatibility law of Baizhi formulae and molecular mechanism of core herbal pair "Baizhi-Chuanxiong"].

Science.gov (United States)

Su, Jin; Tang, Shi-Huan; Guo, Fei-Fei; Li, De-Feng; Zhang, Yi; Xu, Hai-Yu; Yang, Hong-Jun

2018-04-01

By using the traditional Chinese medicine inheritance support system (TCMISS) in this study, the prescription rules of Baizhi formulae were analyzed and the core herbal pair "Baizhi-Chuanxiong" was obtained. Through the systemic analysis of prescription rules of "Baizhi-Chuanxiong" and combined with the pharmacology thinking of "Baizhi-Chuanxiong" in treating headache, the paper was aimed to find out the combination rules containing Baizhi andits molecular mechanisms for treating headaches, and provide the theory basis for further research and reference of Baizhi and its formula. Totally 3 887 prescriptions were included in this study, involving 2 534 Chinese herbs. With a support degree of 20% in analysis, 16 most commonly used drug combinations were screened, which were mainly used to treat 15 types of diseases. Baizhi was often used to treat headache, and the core combination "Baizhi-Chuanxiong" was also often used to treat, consistent with ancient record. A chemical database was established; then the headache and migraine disease targets were retrieved and added in the database to build up the "compounds-targets-pathways "core network of "Baizhi-Chuanxiong" by the internet-based computation platform for IP of TCM (TCM-IP). TCM-IP was then applied to study the molecular mechanism of "Baizhi-Chuanxiong" treatment of headache. The results suggested that37 chemical compounds in the core combination "Baizhi-Chuanxiong" were closely related with headache treatment by adjusting serotonin levels or applying to inflammation-related targets and energy metabolism pathways such as purine metabolism, pyruvate metabolism, fatty acid degradation, carbon metabolism and gluconeogenesis. Copyright© by the Chinese Pharmaceutical Association.

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)

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...

Systematic study of imidazoles inhibiting IDO1 via the integration of molecular mechanics and quantum mechanics calculations.

Science.gov (United States)

Zou, Yi; Wang, Fang; Wang, Yan; Guo, Wenjie; Zhang, Yihua; Xu, Qiang; Lai, Yisheng

2017-05-05

Indoleamine 2,3-dioxygenase 1 (IDO1) is regarded as an attractive target for cancer immunotherapy. To rationalize the detailed interactions between IDO1 and its inhibitors at the atomic level, an integrated computational approach by combining molecular mechanics and quantum mechanics methods was employed in this report. Specifically, the binding modes of 20 inhibitors was initially investigated using the induced fit docking (IFD) protocol, which outperformed other two docking protocols in terms of correctly predicting ligand conformations. Secondly, molecular dynamics (MD) simulations and MM/PBSA free energy calculations were employed to determine the dynamic binding process and crucial residues were confirmed through close contact analysis, hydrogen-bond analysis and binding free energy decomposition calculations. Subsequent quantum mechanics and nonbonding interaction analysis were carried out to provide in-depth explanations on the critical role of those key residues, and Arg231 and 7-propionate of the heme group were major contributors to ligand binding, which lowed a great amount of interaction energy. We anticipate that these findings will be valuable for enzymatic studies and rational drug design. Copyright © 2017. Published by Elsevier Masson SAS.

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)

Molecular diagnostics of FUV and accretion-related heating in protoplanetary disks

Science.gov (United States)

Adamkovics, Mate; Najita, Joan R.

2017-10-01

Emission lines from the terrestrial planet forming regions of disks are diagnostic of both the physical processes that heat the gas and the chemistry that determines the inventory of nebular material available during the epoch of planet formation. Interpreting emission spectra is informed by models of radiative, thermal, physical, and chemical processes, such as: (i) the radiation transfer of X-rays and FUV --- both continuum and Ly-alpha, (ii) direct and indirect heating processes such as the photoelectric effect and photochemical heating, (iii) heating related to turbulent processes and viscous dissipation, and (iv) gas phase chemical reaction kinetics. Many of these processes depend on a the spatial distribution of dust grains and their properties, which temporally evolve during the lifetime of the disk and the formation of planets. Studies of disks atmospheres often predict a layered structure of hot (a few thousand K) atomic gas overlying warm (a few hundred K) molecular gas, which is generally consistent with the isothermal slab emission models that are used to interpret emission spectra. However, detailed comparison between observed spectra and models (e.g., comparing the total columns and the radial extent of warm emitting species) is rare.We present results including the implementation of Ly-alpha scattering, which is an important part of the photochemical heating and FUV heating radiation budget. By including these processes we find a new component of the disk atmosphere; hot molecular gas at ~2000K within radial distances of ~0.5AU, which is consistent with observations of UV-fluorescent H2 emission (Ádámkovics, Najita & Glassgold, 2016). Constraining the most optimistic contribution of radiative heating mechanisms via X-rays and FUV together with a favorable comparison to observations, allows us to explore and evaluate additional heating mechanisms. We find that the total columns of warm (90-400K) emitting molecules such as CO, arising directly below

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.

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

A dissociative quantum mechanical/molecular mechanical molecular dynamics simulation and infrared experiments reveal characteristics of the strongly hydrolytic arsenic(III).

Science.gov (United States)

Canaval, Lorenz R; Lutz, Oliver M D; Weiss, Alexander K H; Huck, Christian W; Hofer, Thomas S

2014-11-17

This work presents a hybrid ab initio quantum mechanical/molecular mechanical simulation at the RI-MP2 level of theory investigating the hydrolysis process of arsenic(III), ultimately leading to arsenous acid (H3AsO3). A newly implemented dissociative water model has been applied to treat the interactions in the classical region, which is capable of describing non-neutral water species such as hydroxide and oxonium ions. Three stages of hydrolysis have been observed during the simulation and besides profound dynamical considerations, detailed insights into structural changes and atomic partial charge shifts are presented. In particular, the geometrical properties of H-bonds involved in each of the three proton transfer events and subsequent proton hopping reactions are discussed. A Laguerre tessellation analysis has been employed to estimate the molecular volume of H3AsO3. Estimations of pKa values of the arsenic(III)-aquo-complexes have been obtained at the G4 and CBS-Q//B3 levels of theory using a thermodynamic cycle, whereas rate constants for the final hydrolysis step have been determined via reaction path optimization and transition state theory. Newly recorded Fourier transform infrared (FT-IR) spectroscopy measurements have been compared to power spectra obtained from the simulation data, confirming its quality. The simulation findings, as well as results from computational spectroscopic calculations utilizing the PT2-VSCF methodology, proved valuable for the interpretation of the experimental FT-IR data, elucidating the particularities of the strongly observed IR Raman noncoincidence effect.

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.

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.

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.

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

Nutraceuticals for prostate cancer chemoprevention: from molecular mechanisms to clinical application.

Science.gov (United States)

Wang, Zhijun; Fan, Jeffery; Liu, Mandy; Yeung, Steven; Chang, Andy; Chow, Moses S S; Pon, Doreen; Huang, Ying

2013-12-01

Nutraceutical is a food, or part of a food, used for the prevention and/or treatment of diseases. A number of nutraceuticals serve as candidates for development of prostate cancer chemopreventive agents because of promising epidemiological, preclinical and pilot clinical findings. Their mechanisms of action may involve an ability to target multiple molecular pathways in carcinogenesis without eliciting toxic side effects. This review provides an overview of several nutraceuticals, including green tea polyphenol, omega-3 fatty acids, vitamin D, lycopene, genistein, quercetin, resveratrol and sulforaphane, for the clinical relevance to chemoprevention of prostate cancer. Their mechanisms of action on regulating key processes of carcinogenesis are also discussed. For each of these agents, a brief summary of completed or currently ongoing clinical trials related to the chemopreventive efficacy on prostate cancer is given. Even though a few clinical trials have been conducted, review of these results indicate that further studies are required to confirm the clinical efficacy and safety, and to provide a guidance on how to use nutraceuticals for optimal effect. Future cancer prevention clinical trials for the nutraceuticals should recruit men with an increased risk of prostate cancer.

Combined quantum-mechanics/molecular-mechanics dynamics simulation of A-DNA double strands irradiated by ultra-low-energy carbon ions

Energy Technology Data Exchange (ETDEWEB)

Ngaojampa, C.; Nimmanpipug, P. [Computer Simulation and Modeling Laboratory (CSML), Department of Chemistry and Center for Innovation Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200 (Thailand); Yu, L.D., E-mail: yuld@fnrf.science.cmu.ac.t [Plasma and Beam Physics Research Facility, Department of Physics and Materials Science, Faculty of Science, Chiang Mai University, Chiang Mai 50200 (Thailand); Thailand Center of Excellence in Physics, Commission on Higher Education, 328 Si Ayutthaya Road, Bangkok 10400 (Thailand); Anuntalabhochai, S. [Molecular Biology Laboratory, Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai 50200 (Thailand); Lee, V.S., E-mail: vannajan@gmail.co [Computer Simulation and Modeling Laboratory (CSML), Department of Chemistry and Center for Innovation Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200 (Thailand); Thailand Center of Excellence in Physics, Commission on Higher Education, 328 Si Ayutthaya Road, Bangkok 10400 (Thailand)

2011-02-15

In order to promote understanding of the fundamentals of ultra-low-energy ion interaction with DNA, molecular dynamics simulations using combined quantum-mechanics/molecular-mechanics of poly-AT and poly-GC A-DNA double strands irradiated by <200 eV carbon ions were performed to investigate the molecular implications of mutation bias. The simulations were focused on the responses of the DNA backbones and nitrogenous bases to irradiation. Analyses of the root mean square displacements of the backbones and non-hydrogen atoms of base rings of the simulated DNA structure after irradiation revealed a potential preference of DNA double strand separation, dependent on the irradiating energy. The results show that for the backbones, the large difference in the displacement between poly-GC and poly-AT in the initial time period could be the reason for the backbone breakage; for the nitrogenous base pairs, A-T is 30% more sensitive or vulnerable to ion irradiation than G-C, demonstrating a preferential, instead of random, effect of irradiation-induced mutation.

Combined quantum-mechanics/molecular-mechanics dynamics simulation of A-DNA double strands irradiated by ultra-low-energy carbon ions

International Nuclear Information System (INIS)

Ngaojampa, C.; Nimmanpipug, P.; Yu, L.D.; Anuntalabhochai, S.; Lee, V.S.

2011-01-01

In order to promote understanding of the fundamentals of ultra-low-energy ion interaction with DNA, molecular dynamics simulations using combined quantum-mechanics/molecular-mechanics of poly-AT and poly-GC A-DNA double strands irradiated by <200 eV carbon ions were performed to investigate the molecular implications of mutation bias. The simulations were focused on the responses of the DNA backbones and nitrogenous bases to irradiation. Analyses of the root mean square displacements of the backbones and non-hydrogen atoms of base rings of the simulated DNA structure after irradiation revealed a potential preference of DNA double strand separation, dependent on the irradiating energy. The results show that for the backbones, the large difference in the displacement between poly-GC and poly-AT in the initial time period could be the reason for the backbone breakage; for the nitrogenous base pairs, A-T is 30% more sensitive or vulnerable to ion irradiation than G-C, demonstrating a preferential, instead of random, effect of irradiation-induced mutation.

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.

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.

Cellular and Molecular Mechanisms in Perioperative Hepatic Protection: A Review of Current Interventions

Directory of Open Access Journals (Sweden)

Zahra Talebi

2017-05-01

Full Text Available Liver is one of the most important organs needing great concern during the perioperative period. There are a number of different mechanisms that interact with liver cells and might affect their integrity and cell live. Though these mechanisms are not all the same, there is a great common point: all affect the metabolic pathways of the liver. Ischemia, anesthetic drug effects and other perioperative insults may affect the liver. Disturbance in an organ’s blood flow is an inherent part of diverse surgical procedures, which leads to lack of oxygen and nutrient supply. These ischemic periods can be particularly long in case of liver surgeries, such as resection of large hepatic tumors, management of hepatic trauma and liver transplant. Once the blood flow and oxygen supply are restored, the interruption of blood flow affects the oxygen dependent cells in liver, which require mitochondrial oxidative phosphorylation for their metabolism. Molecular mechanisms such as Redox status, ionic interchange disturbances as well as different mediators and cells like KC, SEC, dendritic cells, leukocytes, and lymphocytes, are involved in the process ultimately leading to cell death by apoptosis and necrosis. This review provides an overview on the cellular and molecular mechanisms involved in liver injuries, categorizing these mechanisms in 3 different classes: preoperative mechanisms, intraoperative mechanisms and postoperative mechanisms. Each of them are discussed in a different part of the manuscript

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.

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.

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

Science.gov (United States)

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

2017-02-21

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

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.

Physiological and molecular mechanisms associated with cross tolerance between hypoxia and low temperature in Thaumatotibia leucotreta

DEFF Research Database (Denmark)

Boardman, Leigh; Sørensen, Jesper Givskov; Terblanche, John S

2015-01-01

identified to date. Using larvae of false codling moth Thaumatotibia leucotreta, a pest of southern Africa, we investigated the physiological and molecular responses to hypoxia or temperature stress pre-treatments, followed by a standard low temperature exposure. Survival rates were significantly influenced...... by pretreatment conditions, although T. leucotreta shows relatively high basal resistance to various stressors (4% variation in larval survival across all pre-treatments). Results showed that mild pre-treatments with chilling and hypoxia increased resistance to low temperatures and that these responses were...... correlated with increased membrane fluidity (increased UFA:SFA) and/or alterations in heat shock protein 70 (HSP70); while general mechanical stress (shaking) and heat (2 h at 35 C) do not elicit cross tolerance (no change in survival or molecular responses). We therefore found support for some limited cold...

The mechanical properties modeling of nano-scale materials by molecular dynamics

NARCIS (Netherlands)

Yuan, C.; Driel, W.D. van; Poelma, R.; Zhang, G.Q.

2012-01-01

We propose a molecular modeling strategy which is capable of mod-eling the mechanical properties on nano-scale low-dielectric (low-k) materials. Such modeling strategy has been also validated by the bulking force of carbon nano tube (CNT). This modeling framework consists of model generation method,

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.

Molecular Mechanisms for Herpes Simplex Virus Type 1 Pathogenesis in Alzheimer’s Disease

Science.gov (United States)

Harris, Steven A.; Harris, Elizabeth A.

2018-01-01

This review focuses on research in the areas of epidemiology, neuropathology, molecular biology and genetics that implicates herpes simplex virus type 1 (HSV-1) as a causative agent in the pathogenesis of sporadic Alzheimer’s disease (AD). Molecular mechanisms whereby HSV-1 induces AD-related pathophysiology and pathology, including neuronal production and accumulation of amyloid beta (Aβ), hyperphosphorylation of tau proteins, dysregulation of calcium homeostasis, and impaired autophagy, are discussed. HSV-1 causes additional AD pathologies through mechanisms that promote neuroinflammation, oxidative stress, mitochondrial damage, synaptic dysfunction, and neuronal apoptosis. The AD susceptibility genes apolipoprotein E (APOE), phosphatidylinositol binding clathrin assembly protein (PICALM), complement receptor 1 (CR1) and clusterin (CLU) are involved in the HSV lifecycle. Polymorphisms in these genes may affect brain susceptibility to HSV-1 infection. APOE, for example, influences susceptibility to certain viral infections, HSV-1 viral load in the brain, and the innate immune response. The AD susceptibility gene cholesterol 25-hydroxylase (CH25H) is upregulated in the AD brain and is involved in the antiviral immune response. HSV-1 interacts with additional genes to affect cognition-related pathways and key enzymes involved in Aβ production, Aβ clearance, and hyperphosphorylation of tau proteins. Aβ itself functions as an antimicrobial peptide (AMP) against various pathogens including HSV-1. Evidence is presented supporting the hypothesis that Aβ is produced as an AMP in response to HSV-1 and other brain infections, leading to Aβ deposition and plaque formation in AD. Epidemiologic studies associating HSV-1 infection with AD and cognitive impairment are discussed. Studies are reviewed supporting subclinical chronic reactivation of latent HSV-1 in the brain as significant in the pathogenesis of AD. Finally, the rationale for and importance of clinical

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...

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.

Molecular Mechanism of Gastric Carcinogenesis in Helicobacter pylori-Infected Rodent Models

Directory of Open Access Journals (Sweden)

Takeshi Toyoda

2014-06-01

Full Text Available Since the discovery of Helicobacter pylori (H. pylori, many efforts have been made to establish animal models for the investigation of the pathological features and molecular mechanisms of gastric carcinogenesis. Among the animal models, Mongolian gerbils and mice are particularly useful for the analysis of H. pylori-associated inflammatory reactions and gastric cancer development. Inhibitors of oxidative stress, cyclooxygenase-2 (COX-2 and nuclear factor-κB, exert preventive effects on chronic gastritis and the development of adenocarcinomas in H. pylori-infected gerbils. Genetically-modified mouse models, including transgenic and knockout mice, have also revealed the importance of p53, COX-2/prostaglandin, Wnt/β-catenin, proinflammatory cytokines, gastrin and type III mucin in the molecular mechanisms of gastric carcinogenesis. Microarray technology is available for comprehensive gene analysis in the gastric mucosa of mouse models, and epigenetics, such as DNA methylation, could be an alternative approach to correlate the observations in animal models with the etiology in humans.

Study of the Mechanical Properties and Vibration Isolation Performance of a Molecular Spring Isolator

Directory of Open Access Journals (Sweden)

Muchun Yu

2016-01-01

Full Text Available Molecular Spring Isolator (MSI is a novel passive vibration isolation technique, providing High-Static-Low-Dynamic (HSLD stiffness based on the use of molecular spring material. The molecular spring material is a solid-liquid mixture consisting of water and hydrophobic nanoporous materials. Under a certain level of external pressure, water molecules can intrude into the hydrophobic pores of nanoporous materials, developing an additional solid-liquid interface. Such interfaces are able to store, release, and transform mechanical energy, providing properties like mechanical spring. Having been only recently developed, the basic mechanic properties of a MSI have not been studied in depth. This paper focuses on the stiffness influence factors, the dynamic frequency response, and the vibration isolation performance of a MSI; these properties help engineers to design MSIs for different engineering applications. First, the working mechanism of a MSI is introduced from a three-dimensional general view of the water infiltration massive hydrophobic nanoporous pores. Next, a wide range of influence factors on the stiffness properties of MSI are studied. In addition, the frequency response functions (FRFs of the MSI vibration isolation system are studied utilizing the matching method based on equivalent piecewise linear (EPL system. Finally, the vibration isolation properties of MSI are evaluated by force transmissibility.

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)

Methodologies for conformational studies of oligo- and poly-glucans: crystallography and molecular mechanics

International Nuclear Information System (INIS)

Tran, Huu Vinh

1983-01-01

After some considerations on the conformational analysis of polysaccharides, this research thesis outlines the interest of molecular mechanics as a method to study these components. Technical aspects are presented. The author reports the prediction of the conformations of some specific cyclic oligomers (glucans, glucore), the use of X-ray diffraction to study glucides (and the limitations of this method). He reports the search for another investigation method: relationships between X rays and molecular mechanics, situation with respect to other crystallographic methods, presentation of principle of the 'Packing' method, and applications. He reports the study of regular conformations of polysaccharides, the study of the statistic configuration of polymer chains and the application to alpha-glucans

Quantum mechanics/molecular mechanics modeling of photoelectron spectra: the carbon 1s core-electron binding energies of ethanol-water solutions.

Science.gov (United States)

Löytynoja, T; Niskanen, J; Jänkälä, K; Vahtras, O; Rinkevicius, Z; Ågren, H

2014-11-20

Using ethanol-water solutions as illustration, we demonstrate the capability of the hybrid quantum mechanics/molecular mechanics (QM/MM) paradigm to simulate core photoelectron spectroscopy: the binding energies and the chemical shifts. An integrated approach with QM/MM binding energy calculations coupled to preceding molecular dynamics sampling is adopted to generate binding energies averaged over the solute-solvent configurations available at a particular temperature and pressure and thus allowing for a statistical assessment with confidence levels for the final binding energies. The results are analyzed in terms of the contributions in the molecular mechanics model-electrostatic, polarization, and van der Waals-with atom or bond granulation of the corresponding MM charge and polarizability force-fields. The role of extramolecular charge transfer screening of the core-hole and explicit hydrogen bonding is studied by extending the QM core to cover the first solvation shell. The results are compared to those obtained from pure electrostatic and polarizable continuum models. Particularly, the dependence of the carbon 1s binding energies with respect to the ethanol concentration is studied. Our results indicate that QM/MM can be used as an all-encompassing model to study photoelectron binding energies and chemical shifts in solvent environments.

Failure of single electron descriptions of molecular orbital collision processes. [Electron promotion mechanism

Energy Technology Data Exchange (ETDEWEB)

Elston, S.B.

1978-01-01

Inner-shell excitation occurring in low and moderate (keV range) energy collisions between light atomic and ionic systems is frequently describable in terms of molecular promotion mechanisms, which were extensively explored both theoretically and experimentally. The bulk of such studies have concentrated on processes understandable through the use of single- and independent-electron models. Nonetheless, it is possible to find cases of inner-shell excitation in relatively simple collision systems which involve nearly simultaneous multiple-electron transitions and transitions induced by inherently two-electron interactions. Evidence for these many- and nonindependent-electron phenomena in inner-shell excitation processes and the importance of considering such effects in the interpretation of collisionally induced excitation spectra is discussed. 13 references.

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

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 ...

THE X-FACTOR IN GALAXIES. II. THE MOLECULAR-HYDROGEN-STAR-FORMATION RELATION

Energy Technology Data Exchange (ETDEWEB)

Feldmann, Robert; Gnedin, Nickolay Y.; Kravtsov, Andrey V.

2012-10-08

There is ample observational evidence that the star formation rate (SFR) surface density, Sigma_SFR, is closely correlated with the surface density of molecular hydrogen, Sigma_H2. This empirical relation holds both for galaxy-wide averages and for individual >=kpc sized patches of the interstellar medium (ISM), but appears to degrade substantially at a sub-kpc scale. Identifying the physical mechanisms that determine the scale-dependent properties of the observed Sigma_H2-Sigma_SFR relation remains a challenge from a theoretical perspective. To address this question, we analyze the slope and scatter of the Sigma_H2-Sigma_SFR relation using a set of cosmological, galaxy formation simulations with a peak resolution of ~100 pc. These simulations include a chemical network for molecular hydrogen, a model for the CO emission, and a simple, stochastic prescription for star formation that operates on ~100 pc scales. Specifically, star formation is modeled as a Poisson process in which the average SFR is directly proportional to the present mass of H2. The predictions of our numerical model are in good agreement with the observed Kennicutt-Schmidt and Sigma_H2-Sigma_SFR relations. We show that observations based on CO emission are ill suited to reliably measure the slope of the latter relation at low (<20 M_sun pc^-2) H2 surface densities on sub-kpc scales. Our models also predict that the inferred Sigma_H2-Sigma_SFR relation steepens at high H2 surface densities as a result of the surface density dependence of the CO/H2 conversion factor. Finally, we show that on sub-kpc scales most of the scatter in the relation is a consequence of discreteness effects in the star formation process. In contrast, variations of the CO/H2 conversion factor are responsible for most of the scatter measured on super-kpc scales.

Quantum Mechanics/Molecular Mechanics Free Energy Maps and Nonadiabatic Simulations for a Photochemical Reaction in DNA: Cyclobutane Thymine Dimer.

Science.gov (United States)

Mendieta-Moreno, Jesús I; Trabada, Daniel G; Mendieta, Jesús; Lewis, James P; Gómez-Puertas, Paulino; Ortega, José

2016-11-03

The absorption of ultraviolet radiation by DNA may result in harmful genetic lesions that affect DNA replication and transcription, ultimately causing mutations, cancer, and/or cell death. We analyze the most abundant photochemical reaction in DNA, the cyclobutane thymine dimer, using hybrid quantum mechanics/molecular mechanics (QM/MM) techniques and QM/MM nonadiabatic molecular dynamics. We find that, due to its double helix structure, DNA presents a free energy barrier between nonreactive and reactive conformations leading to the photolesion. Moreover, our nonadiabatic simulations show that most of the photoexcited reactive conformations return to standard B-DNA conformations after an ultrafast nonradiative decay to the ground state. This work highlights the importance of dynamical effects (free energy, excited-state dynamics) for the study of photochemical reactions in biological systems.

Oxyhydroxide of metallic nanowires in a molecular H2O and H2O2 environment and their effects on mechanical properties.

Science.gov (United States)

Aral, Gurcan; Islam, Md Mahbubul; Wang, Yun-Jiang; Ogata, Shigenobu; Duin, Adri C T van

2018-06-14

To avoid unexpected environmental mechanical failure, there is a strong need to fully understand the details of the oxidation process and intrinsic mechanical properties of reactive metallic iron (Fe) nanowires (NWs) under various aqueous reactive environmental conditions. Herein, we employed ReaxFF reactive molecular dynamics (MD) simulations to elucidate the oxidation of Fe NWs exposed to molecular water (H2O) and hydrogen peroxide (H2O2) environment, and the influence of the oxide shell layer on the tensile mechanical deformation properties of Fe NWs. Our structural analysis shows that oxidation of Fe NWs occurs with the formation of different iron oxide and hydroxide phases in the aqueous molecular H2O and H2O2 oxidizing environments. We observe that the resulting microstructure due to pre-oxide shell layer formation reduces the mechanical stress via increasing the initial defect sites in the vicinity of the oxide region to facilitate the onset of plastic deformation during tensile loading. Specifically, the oxide layer of Fe NWs formed in the H2O2 environment has a relatively significant effect on the deterioration of the mechanical properties of Fe NWs. The weakening of the yield stress and Young modulus of H2O2 oxidized Fe NWs indicates the important role of local oxide microstructures on mechanical deformation properties of individual Fe NWs. Notably, deformation twinning is found as the primary mechanical plastic deformation mechanism of all Fe NWs, but it is initially observed at low strain and stress level for the oxidized Fe NWs.

Cellular and molecular mechanisms in malignant transformation of diploid rodent and human cells by radiation

International Nuclear Information System (INIS)

Borek, C.

1985-01-01

The development of cell culture systems has made it possible to probe into the effects of radiation at a cellular and molecular level, under defined conditions where homeostatic mechanisms do not prevail. Using in vitro systems free of host-medicated influences, one can assess qualitatively and quantitatively dose-related and time-dependent interactions of radiation with single cells and to evaluate the influences of agents that may enhance or inhibit the oncogenic potential of radiation. These systems are useful in pragmatic studies where dose response relationships and cancer risk estimates are assessed with particular focus on the low dose range of radiation where epidemiological and animal studies are limiting. The in vitro systems serve well also in mechanistic studies where cellular and molecular processes underlying transformation can be elucidated and where the role of modulating factors which determine the frequency and quality of these events can be investigated

Peroxisome Proliferator-Activated Receptor (PPAR) in Regenerative Medicine: Molecular Mechanism for PPAR in Stem Cells' Adipocyte Differentiation.

Science.gov (United States)

Xie, Qiang; Tian, Taoran; Chen, Zhaozhao; Deng, Shuwen; Sun, Ke; Xie, Jing; Cai, Xiaoxiao

2016-01-01

Regenerative medicine plays an indispensable role in modern medicine and many trials and researches have therefore been developed to fit our medical needs. Tissue engineering has proven that adipose tissue can widely be used and brings advantages to regenerative medicine. Moreover, a trait of adipose stem cells being isolated and grown in vitro is a cornerstone to various applications. Since the adipose tissue has been widely used in regenerative medicine, numerous studies have been conducted to seek methods for gaining more adipocytes. To investigate molecular mechanism for adipocyte differentiation, peroxisome proliferator-activated receptor (PPAR) has been widely studied to find out its functional mechanism, as a key factor for adipocyte differentiation. However, the precise molecular mechanism is still unknown. This review thus summarizes recent progress on the study of molecular mechanism and role of PPAR in adipocyte differentiation.

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

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.

Molecular Mechanisms of Diabetic Retinopathy, General Preventive Strategies, and Novel Therapeutic Targets

Science.gov (United States)

Safi, Sher Zaman; Kumar, Selva; Ismail, Ikram Shah Bin

2014-01-01

The growing number of people with diabetes worldwide suggests that diabetic retinopathy (DR) and diabetic macular edema (DME) will continue to be sight threatening factors. The pathogenesis of diabetic retinopathy is a widespread cause of visual impairment in the world and a range of hyperglycemia-linked pathways have been implicated in the initiation and progression of this condition. Despite understanding the polyol pathway flux, activation of protein kinase C (KPC) isoforms, increased hexosamine pathway flux, and increased advanced glycation end-product (AGE) formation, pathogenic mechanisms underlying diabetes induced vision loss are not fully understood. The purpose of this paper is to review molecular mechanisms that regulate cell survival and apoptosis of retinal cells and discuss new and exciting therapeutic targets with comparison to the old and inefficient preventive strategies. This review highlights the recent advancements in understanding hyperglycemia-induced biochemical and molecular alterations, systemic metabolic factors, and aberrant activation of signaling cascades that ultimately lead to activation of a number of transcription factors causing functional and structural damage to retinal cells. It also reviews the established interventions and emerging molecular targets to avert diabetic retinopathy and its associated risk factors. PMID:25105142

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.

Active mechanics in living oocytes reveal molecular-scale force kinetics

Science.gov (United States)

Ahmed, Wylie; Fodor, Etienne; Almonacid, Maria; Bussonnier, Matthias; Verlhac, Marie-Helene; Gov, Nir; Visco, Paolo; van Wijland, Frederic; Betz, Timo

Unlike traditional materials, living cells actively generate forces at the molecular scale that change their structure and mechanical properties. This nonequilibrium activity is essential for cellular function, and drives processes such as cell division. Single molecule studies have uncovered the detailed force kinetics of isolated motor proteins in-vitro, however their behavior in-vivo has been elusive due to the complex environment inside the cell. Here, we quantify active forces and intracellular mechanics in living oocytes using in-vivo optical trapping and laser interferometry of endogenous vesicles. We integrate an experimental and theoretical framework to connect mesoscopic measurements of nonequilibrium properties to the underlying molecular- scale force kinetics. Our results show that force generation by myosin-V drives the cytoplasmic-skeleton out-of-equilibrium (at frequencies below 300 Hz) and actively softens the environment. In vivo myosin-V activity generates a force of F ~ 0 . 4 pN, with a power-stroke of length Δx ~ 20 nm and duration τ ~ 300 μs, that drives vesicle motion at vv ~ 320 nm/s. This framework is widely applicable to characterize living cells and other soft active materials.

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

Endogenous molecular network reveals two mechanisms of heterogeneity within gastric cancer

Science.gov (United States)

Li, Site; Zhu, Xiaomei; Liu, Bingya; Wang, Gaowei; Ao, Ping

2015-01-01

Intratumor heterogeneity is a common phenomenon and impedes cancer therapy and research. Gastric cancer (GC) cells have generally been classified into two heterogeneous cellular phenotypes, the gastric and intestinal types, yet the mechanisms of maintaining two phenotypes and controlling phenotypic transition are largely unknown. A qualitative systematic framework, the endogenous molecular network hypothesis, has recently been proposed to understand cancer genesis and progression. Here, a minimal network corresponding to such framework was found for GC and was quantified via a stochastic nonlinear dynamical system. We then further extended the framework to address the important question of intratumor heterogeneity quantitatively. The working network characterized main known features of normal gastric epithelial and GC cell phenotypes. Our results demonstrated that four positive feedback loops in the network are critical for GC cell phenotypes. Moreover, two mechanisms that contribute to GC cell heterogeneity were identified: particular positive feedback loops are responsible for the maintenance of intestinal and gastric phenotypes; GC cell progression routes that were revealed by the dynamical behaviors of individual key components are heterogeneous. In this work, we constructed an endogenous molecular network of GC that can be expanded in the future and would broaden the known mechanisms of intratumor heterogeneity. PMID:25962957

Molecular and Evolutionary Mechanisms of Cuticular Wax for Plant Drought Tolerance

Directory of Open Access Journals (Sweden)

Dawei Xue

2017-04-01

Full Text Available Cuticular wax, the first protective layer of above ground tissues of many plant species, is a key evolutionary innovation in plants. Cuticular wax safeguards the evolution from certain green algae to flowering plants and the diversification of plant taxa during the eras of dry and adverse terrestrial living conditions and global climate changes. Cuticular wax plays significant roles in plant abiotic and biotic stress tolerance and has been implicated in defense mechanisms against excessive ultraviolet radiation, high temperature, bacterial and fungal pathogens, insects, high salinity, and low temperature. Drought, a major type of abiotic stress, poses huge threats to global food security and health of terrestrial ecosystem by limiting plant growth and crop productivity. The composition, biochemistry, structure, biosynthesis, and transport of plant cuticular wax have been reviewed extensively. However, the molecular and evolutionary mechanisms of cuticular wax in plants in response to drought stress are still lacking. In this review, we focus on potential mechanisms, from evolutionary, molecular, and physiological aspects, that control cuticular wax and its roles in plant drought tolerance. We also raise key research questions and propose important directions to be resolved in the future, leading to potential applications of cuticular wax for water use efficiency in agricultural and environmental sustainability.

Light-operated machines based on threaded molecular structures.

Science.gov (United States)

Credi, Alberto; Silvi, Serena; Venturi, Margherita

2014-01-01

Rotaxanes and related species represent the most common implementation of the concept of artificial molecular machines, because the supramolecular nature of the interactions between the components and their interlocked architecture allow a precise control on the position and movement of the molecular units. The use of light to power artificial molecular machines is particularly valuable because it can play the dual role of "writing" and "reading" the system. Moreover, light-driven machines can operate without accumulation of waste products, and photons are the ideal inputs to enable autonomous operation mechanisms. In appropriately designed molecular machines, light can be used to control not only the stability of the system, which affects the relative position of the molecular components but also the kinetics of the mechanical processes, thereby enabling control on the direction of the movements. This step forward is necessary in order to make a leap from molecular machines to molecular motors.

Molecular mechanisms of the genetic risk factors in pathogenesis of Alzheimer disease.

Science.gov (United States)

Kanatsu, Kunihiko; Tomita, Taisuke

2017-01-01

Alzheimer disease (AD) is a neurodegenerative disease characterized by the extensive deposition of senile plaques and neurofibrillary tangles. Until recently, only the APOE gene had been known as a genetic risk factor for late-onset AD (LOAD), which accounts for more than 95% of all AD cases. However, in addition to this well-established genetic risk factor, genome-wide association studies have identified several single nucleotide polymorphisms as genetic risk factors of LOAD, such as PICALM and BIN1 . In addition, whole genome sequencing and exome sequencing have identified rare variants associated with LOAD, including TREM2 . We review the recent findings related to the molecular mechanisms by which these genetic risk factors contribute to AD, and our perspectives regarding the etiology of AD for the development of therapeutic agents.

Unraveling the molecular mechanisms of nitrogenase conformational protection against oxygen in diazotrophic bacteria.

Science.gov (United States)

Lery, Letícia M S; Bitar, Mainá; Costa, Mauricio G S; Rössle, Shaila C S; Bisch, Paulo M

2010-12-22

G. diazotrophicus and A. vinelandii are aerobic nitrogen-fixing bacteria. Although oxygen is essential for the survival of these organisms, it irreversibly inhibits nitrogenase, the complex responsible for nitrogen fixation. Both microorganisms deal with this paradox through compensatory mechanisms. In A. vinelandii a conformational protection mechanism occurs through the interaction between the nitrogenase complex and the FeSII protein. Previous studies suggested the existence of a similar system in G. diazotrophicus, but the putative protein involved was not yet described. This study intends to identify the protein coding gene in the recently sequenced genome of G. diazotrophicus and also provide detailed structural information of nitrogenase conformational protection in both organisms. Genomic analysis of G. diazotrophicus sequences revealed a protein coding ORF (Gdia0615) enclosing a conserved "fer2" domain, typical of the ferredoxin family and found in A. vinelandii FeSII. Comparative models of both FeSII and Gdia0615 disclosed a conserved beta-grasp fold. Cysteine residues that coordinate the 2[Fe-S] cluster are in conserved positions towards the metallocluster. Analysis of solvent accessible residues and electrostatic surfaces unveiled an hydrophobic dimerization interface. Dimers assembled by molecular docking presented a stable behaviour and a proper accommodation of regions possibly involved in binding of FeSII to nitrogenase throughout molecular dynamics simulations in aqueous solution. Molecular modeling of the nitrogenase complex of G. diazotrophicus was performed and models were compared to the crystal structure of A. vinelandii nitrogenase. Docking experiments of FeSII and Gdia0615 with its corresponding nitrogenase complex pointed out in both systems a putative binding site presenting shape and charge complementarities at the Fe-protein/MoFe-protein complex interface. The identification of the putative FeSII coding gene in G. diazotrophicus genome

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.

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

Differential protein expression of hepatic cells associated with MeHg exposure: deepening into the molecular mechanisms of toxicity

Energy Technology Data Exchange (ETDEWEB)

Cuello, Susana; Madrid, Yolanda; Luque-Garcia, Jose L.; Camara, Carmen [Complutense University of Madrid, Department of Analytical Chemistry, Faculty of Chemistry, Madrid (Spain); Ramos, Sonia [Institute of Food Science, Technology and Nutrition, Consejo Superior de Investigaciones Cientificas (CSIC), Madrid (Spain)

2012-08-15

Understanding the molecular mechanisms underlying MeHg toxicity and the way in which this molecule interacts with living organisms is a critical point since MeHg represents a well-known risk to ecosystems and human health. We used a quantitative proteomic approach based on stable isotopic labeling by amino acids in cell culture in combination with SDS-PAGE and nanoflow LC-ESI-LTQ for analyzing the differential protein expression of hepatic cells associated to MeHg exposure. Seventy-eight proteins were found de-regulated by more than 1.5-fold. We identified a number of proteins involved in different essential biological processes including apoptosis, mitochondrial dysfunction, cellular trafficking and energy production. Among these proteins, we found several molecules whose de-regulation has been already related to MeHg exposure, thus confirming the usefulness of our discovery approach, and new ones that helped to gain a deeper insight into the biomolecular mechanisms related to MeHg-induced toxicity. Overexpression of several HSPs and the proteasome 26S subunit itself showed the proteasome system as a molecular target of toxic MeHg. As for the interaction networks, the top ranked was the nucleic acid metabolism, where many of the identified de-regulated proteins are involved. (orig.)

Relative Contributions of Various Cellular Mechanisms to Loss of Algae during Cnidarian Bleaching.

Science.gov (United States)

Bieri, Tamaki; Onishi, Masayuki; Xiang, Tingting; Grossman, Arthur R; Pringle, John R

2016-01-01

When exposed to stress such as high seawater temperature, corals and other cnidarians can bleach due to loss of symbiotic algae from the host tissue and/or loss of pigments from the algae. Although the environmental conditions that trigger bleaching are reasonably well known, its cellular and molecular mechanisms are not well understood. Previous studies have reported the occurrence of at least four different cellular mechanisms for the loss of symbiotic algae from the host tissue: in situ degradation of algae, exocytic release of algae from the host, detachment of host cells containing algae, and death of host cells containing algae. The relative contributions of these several mechanisms to bleaching remain unclear, and it is also not known whether these relative contributions change in animals subjected to different types and/or durations of stresses. In this study, we used a clonal population of the small sea anemone Aiptasia, exposed individuals to various precisely controlled stress conditions, and quantitatively assessed the several possible bleaching mechanisms in parallel. Under all stress conditions tested, except for acute cold shock at 4°C, expulsion of intact algae from the host cells appeared to be by far the predominant mechanism of bleaching. During acute cold shock, in situ degradation of algae and host-cell detachment also became quantitatively significant, and the algae released under these conditions appeared to be severely damaged.

Relative Contributions of Various Cellular Mechanisms to Loss of Algae during Cnidarian Bleaching

Science.gov (United States)

Bieri, Tamaki; Onishi, Masayuki; Xiang, Tingting; Grossman, Arthur R.; Pringle, John R

2016-01-01

When exposed to stress such as high seawater temperature, corals and other cnidarians can bleach due to loss of symbiotic algae from the host tissue and/or loss of pigments from the algae. Although the environmental conditions that trigger bleaching are reasonably well known, its cellular and molecular mechanisms are not well understood. Previous studies have reported the occurrence of at least four different cellular mechanisms for the loss of symbiotic algae from the host tissue: in situ degradation of algae, exocytic release of algae from the host, detachment of host cells containing algae, and death of host cells containing algae. The relative contributions of these several mechanisms to bleaching remain unclear, and it is also not known whether these relative contributions change in animals subjected to different types and/or durations of stresses. In this study, we used a clonal population of the small sea anemone Aiptasia, exposed individuals to various precisely controlled stress conditions, and quantitatively assessed the several possible bleaching mechanisms in parallel. Under all stress conditions tested, except for acute cold shock at 4°C, expulsion of intact algae from the host cells appeared to be by far the predominant mechanism of bleaching. During acute cold shock, in situ degradation of algae and host-cell detachment also became quantitatively significant, and the algae released under these conditions appeared to be severely damaged. PMID:27119147

Exploring the molecular mechanisms of Traditional Chinese Medicine components using gene expression signatures and connectivity map.

Science.gov (United States)

Yoo, Minjae; Shin, Jimin; Kim, Hyunmin; Kim, Jihye; Kang, Jaewoo; Tan, Aik Choon

2018-04-04

Traditional Chinese Medicine (TCM) has been practiced over thousands of years in China and other Asian countries for treating various symptoms and diseases. However, the underlying molecular mechanisms of TCM are poorly understood, partly due to the "multi-component, multi-target" nature of TCM. To uncover the molecular mechanisms of TCM, we perform comprehensive gene expression analysis using connectivity map. We interrogated gene expression signatures obtained 102 TCM components using the next generation Connectivity Map (CMap) resource. We performed systematic data mining and analysis on the mechanism of action (MoA) of these TCM components based on the CMap results. We clustered the 102 TCM components into four groups based on their MoAs using next generation CMap resource. We performed gene set enrichment analysis on these components to provide additional supports for explaining these molecular mechanisms. We also provided literature evidence to validate the MoAs identified through this bioinformatics analysis. Finally, we developed the Traditional Chinese Medicine Drug Repurposing Hub (TCM Hub) - a connectivity map resource to facilitate the elucidation of TCM MoA for drug repurposing research. TCMHub is freely available in http://tanlab.ucdenver.edu/TCMHub. Molecular mechanisms of TCM could be uncovered by using gene expression signatures and connectivity map. Through this analysis, we identified many of the TCM components possess diverse MoAs, this may explain the applications of TCM in treating various symptoms and diseases. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Supramolecular Structure and Mechanical Characteristics of Ultrahigh-Molecular-Weight Polyethylene-Inorganic Nanoparticle Nanocomposites

International Nuclear Information System (INIS)

Okhlopkova, T. A.; Borisova, R. V.; Nikiforov, L. A.; Spiridonov, A. M.; Okhlopkova, A. A.; Cho, Jin-Ho; Jeong, Dae-Yong

2016-01-01

We investigated the mechanical properties and structure of polymeric nanocomposites (PNCs) with anultrahigh-molecular-weight polyethylene (UHMWPE) matrix and aluminum and silicon oxide and nitride nanoparticle (NP) fillers. Mixing with a paddle mixer or by joint mechanical activation in a planetary mill was used for the PNC preparation. Joint mechanical activation afforded PNCs with better mechanical properties than paddle mixing. Scanning electron microscopy suggested that the poorer mechanical properties can be attributed to the disordered regions and imperfect spherulites in the PNC supramolecular structure arising from paddle mixing. The better mechanical properties observed with joint mechanical activation may derive from the uniform NP distribution in the polymer matrix and absence of disordered regions.

Molecular diversity among seven Solanum (eggplant and relatives ...

African Journals Online (AJOL)

Admin

2012-11-08

Nov 8, 2012 ... Seven Solanum species (eggplants) were investigated for molecular diversity. Besides its ... Eggplant comprises three closely related cultivated species .... generated with SSR data was submitted to 2-way Mantel test (Man-.

Tissue organization by cadherin adhesion molecules: dynamic molecular and cellular mechanisms of morphogenetic regulation

Science.gov (United States)

Niessen, Carien M.; Leckband, Deborah; Yap, Alpha S.

2013-01-01

This review addresses the cellular and molecular mechanisms of cadherin-based tissue morphogenesis. Tissue physiology is profoundly influenced by the distinctive organizations of cells in organs and tissues. In metazoa, adhesion receptors of the classical cadherin family play important roles in establishing and maintaining such tissue organization. Indeed, it is apparent that cadherins participate in a range of morphogenetic events that range from support of tissue integrity to dynamic cellular rearrangements. A comprehensive understanding of cadherin-based morphogenesis must then define the molecular and cellular mechanisms that support these distinct cadherin biologies. Here we focus on four key mechanistic elements: the molecular basis for adhesion through cadherin ectodomains; the regulation of cadherin expression at the cell surface; cooperation between cadherins and the actin cytoskeleton; and regulation by cell signaling. We discuss current progress and outline issues for further research in these fields. PMID:21527735

Recent advances in biological effect and molecular mechanism of arabidopsis thaliana irradiated by ion beams

International Nuclear Information System (INIS)

Wu Dali; Hou Suiwen; Li Wenjian

2008-01-01

Newly research progresses were summarized in effect of ion beams on seed surface, biological effect, growth, development, gravitropism and so on. Furthermore, mutation molecular mechanism of Arabidopsis thaliana was discussed, for example, alteration of DNA bases, DNA damage, chromosomal recombination, characteristics of mutant transmissibility, etc. Meanwhile, the achievements of transfer- ring extraneous gene to Arabidopsis thaliana by ion beams were reviewed in the paper. At last, the future prospective are also discussed here in mutation molecular mechanism and the potential application of biological effect of heavy ion beams. (authors)

BATMAN-TCM: a Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine

Science.gov (United States)

Liu, Zhongyang; Guo, Feifei; Wang, Yong; Li, Chun; Zhang, Xinlei; Li, Honglei; Diao, Lihong; Gu, Jiangyong; Wang, Wei; Li, Dong; He, Fuchu

2016-02-01

Traditional Chinese Medicine (TCM), with a history of thousands of years of clinical practice, is gaining more and more attention and application worldwide. And TCM-based new drug development, especially for the treatment of complex diseases is promising. However, owing to the TCM’s diverse ingredients and their complex interaction with human body, it is still quite difficult to uncover its molecular mechanism, which greatly hinders the TCM modernization and internationalization. Here we developed the first online Bioinformatics Analysis Tool for Molecular mechANism of TCM (BATMAN-TCM). Its main functions include 1) TCM ingredients’ target prediction; 2) functional analyses of targets including biological pathway, Gene Ontology functional term and disease enrichment analyses; 3) the visualization of ingredient-target-pathway/disease association network and KEGG biological pathway with highlighted targets; 4) comparison analysis of multiple TCMs. Finally, we applied BATMAN-TCM to Qishen Yiqi dripping Pill (QSYQ) and combined with subsequent experimental validation to reveal the functions of renin-angiotensin system responsible for QSYQ’s cardioprotective effects for the first time. BATMAN-TCM will contribute to the understanding of the “multi-component, multi-target and multi-pathway” combinational therapeutic mechanism of TCM, and provide valuable clues for subsequent experimental validation, accelerating the elucidation of TCM’s molecular mechanism. BATMAN-TCM is available at http://bionet.ncpsb.org/batman-tcm.

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

Molecular Mechanisms of DNA Replication Checkpoint Activation

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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.

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.

Molecular mechanism of Mg2+-dependent gating in CorA

Science.gov (United States)

Dalmas, Olivier; Sompornpisut, Pornthep; Bezanilla, Francisco; Perozo, Eduardo

2014-04-01

CorA is the major transport system responsible for Mg2+ uptake in bacteria and can functionally substitute for its homologue Mrs2p in the yeast inner mitochondrial membrane. Although several CorA crystal structures are available, the molecular mechanism of Mg2+ uptake remains to be established. Here we use electron paramagnetic resonance spectroscopy, electrophysiology and molecular dynamic simulations to show that CorA is regulated by cytoplasmic Mg2+ acting as a ligand and elucidate the basic conformational rearrangements responsible for Mg2+-dependent gating. Mg2+ unbinding at the divalent cation sensor triggers a conformational change that leads to the inward motion of the stalk helix, which propagates to the pore-forming transmembrane helix TM1. Helical tilting and rotation in TM1 generates an iris-like motion that increases the diameter of the permeation pathway, triggering ion conduction. This work establishes the molecular basis of a Mg2+-driven negative feedback loop in CorA as the key physiological event controlling Mg2+ uptake and homeostasis in prokaryotes.

Energy-related atomic and molecular structure and scattering studies: Final report

International Nuclear Information System (INIS)

1987-01-01

The general goals of the DOE research concerned the use of molecular beams techniques in the study of atomic and molecular polarizabilities and the study of the interactions between electrons and highly polar molecules. Both of these goals are directly relevant to the general problem of the role played by long-range forces in atomic and molecular physics. Details related to this motivation can be found in the published literature. Here we will describe in general terms the work performed under DOE sponsorship in the atomic beams laboratory at NYU. Our original intent was to exploit techniques developed at NYU, mainly in the study of simple atomic systems, to the more complex atomic and molecular systems that are related to DOE interests. These included the developing understanding of the structure of molecular systems, particularly of alkali halide molecules, and the study of the interactions of electrons with such molecules. The structure experiments would serve as critical experimental benchmarks for computational techniques on molecular properties, including both molecular wave functions and derivative properties of them, such as vibrational and rotational constants, but in particular of molecular electric dipole polarizabilities. We believe that we have at least to some extent fulfilled these goals. 16 refs., 1 fig

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.

Calculating solution redox free energies with ab initio quantum mechanical/molecular mechanical minimum free energy path method

International Nuclear Information System (INIS)

Zeng Xiancheng; Hu Hao; Hu Xiangqian; Yang Weitao

2009-01-01

A quantum mechanical/molecular mechanical minimum free energy path (QM/MM-MFEP) method was developed to calculate the redox free energies of large systems in solution with greatly enhanced efficiency for conformation sampling. The QM/MM-MFEP method describes the thermodynamics of a system on the potential of mean force surface of the solute degrees of freedom. The molecular dynamics (MD) sampling is only carried out with the QM subsystem fixed. It thus avoids 'on-the-fly' QM calculations and thus overcomes the high computational cost in the direct QM/MM MD sampling. In the applications to two metal complexes in aqueous solution, the new QM/MM-MFEP method yielded redox free energies in good agreement with those calculated from the direct QM/MM MD method. Two larger biologically important redox molecules, lumichrome and riboflavin, were further investigated to demonstrate the efficiency of the method. The enhanced efficiency and uncompromised accuracy are especially significant for biochemical systems. The QM/MM-MFEP method thus provides an efficient approach to free energy simulation of complex electron transfer reactions.

Anti-inflammatory activity and molecular mechanism of delphinidin 3-sambubioside, a Hibiscus anthocyanin.

Science.gov (United States)

Sogo, Takayuki; Terahara, Norihiko; Hisanaga, Ayami; Kumamoto, Takuma; Yamashiro, Takaaki; Wu, Shusong; Sakao, Kozue; Hou, De-Xing

2015-01-01

Delphinidin 3-sambubioside (Dp3-Sam), a Hibiscus anthocyanin, was isolated from the dried calices of Hibiscus sabdariffa L, which has been used for folk beverages and herbal medicine although the molecular mechanisms are poorly defined. Based on the properties of Dp3-Sam and the information of inflammatory processes, we investigated the anti-inflammatory activity and molecular mechanisms in both cell and animal models in the present study. In the cell model, Dp3-Sam and Delphinidin (Dp) reduced the levels of inflammatory mediators including iNOS, NO, IL-6, MCP-1, and TNF-α induced by LPS. Cellular signaling analysis revealed that Dp3-Sam and Dp downregulated NF-κB pathway and MEK1/2-ERK1/2 signaling. In animal model, Dp3-Sam and Dp reduced the production of IL-6, MCP-1 and TNF-α and attenuated mouse paw edema induced by LPS. Our in vitro and in vivo data demonstrated that Hibiscus Dp3-Sam possessed potential anti-inflammatory properties. © 2015 International Union of Biochemistry and Molecular Biology.

An adaptive quantum mechanics/molecular mechanics method for the infrared spectrum of water: incorporation of the quantum effect between solute and solvent.

Science.gov (United States)

Watanabe, Hiroshi C; Banno, Misa; Sakurai, Minoru

2016-03-14

Quantum effects in solute-solvent interactions, such as the many-body effect and the dipole-induced dipole, are known to be critical factors influencing the infrared spectra of species in the liquid phase. For accurate spectrum evaluation, the surrounding solvent molecules, in addition to the solute of interest, should be treated using a quantum mechanical method. However, conventional quantum mechanics/molecular mechanics (QM/MM) methods cannot handle free QM solvent molecules during molecular dynamics (MD) simulation because of the diffusion problem. To deal with this problem, we have previously proposed an adaptive QM/MM "size-consistent multipartitioning (SCMP) method". In the present study, as the first application of the SCMP method, we demonstrate the reproduction of the infrared spectrum of liquid-phase water, and evaluate the quantum effect in comparison with conventional QM/MM simulations.

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...

A molecular dynamics investigation into the mechanisms of alectinib resistance of three ALK mutants.

Science.gov (United States)

He, Muyang; Li, Weikang; Zheng, Qingchuan; Zhang, Hongxing

2018-01-11

Alectinib, a highly selective next-genetation anaplastic lymphoma kinase (ALK) inhibitor, has demonstrated promising antitumor activity in patients with ALK-positive non-small cell lung carcinomas (NSCLC). However, the therapeutic benefits of alectinib is inescapably hampered by the development of acquired resistant mutations in ALK. Despite the availability of ample experimental mutagenesis data, the molecular origin and the structural motifs under alectinib binding affinity deficiencies are still ambiguous. Here, molecular dynamics (MD) simulations and molecular mechanics generalized born surface area (MM-GBSA) calculation approaches were employed to elucidate the mechanisms of alectinib resistance induced by the mutations I1171N, V1180L, and L1198F. The MD results reveal that the studied mutations could trigger the dislocation of alectinib as well as conformational changes at the inhibitor binding site, thus induce the interactional changes between alectinib and mutants. The most influenced regions are the ligand binding entrance and the hinge region, which are considered to be the dominant binding motifs accounting for the binding affinity loss in mutants. The "key and lock mechanism" between the ethyl group at position 9 of alectinib and a recognition cavity in the hinge region of ALK is presented to illustrate the major molecular origin of drug resistance. Our results provide mechanistic insight into the effect of ALK mutations resistant to alectinib, which could contribute to further rational design of inhibitors to combat the acquired resistance. © 2018 Wiley Periodicals, Inc.

The Role of Exercise in Cardiac Aging: From Physiology to Molecular Mechanisms.

Science.gov (United States)

Roh, Jason; Rhee, James; Chaudhari, Vinita; Rosenzweig, Anthony

2016-01-22

Aging induces structural and functional changes in the heart that are associated with increased risk of cardiovascular disease and impaired functional capacity in the elderly. Exercise is a diagnostic and therapeutic tool, with the potential to provide insights into clinical diagnosis and prognosis, as well as the molecular mechanisms by which aging influences cardiac physiology and function. In this review, we first provide an overview of how aging impacts the cardiac response to exercise, and the implications this has for functional capacity in older adults. We then review the underlying molecular mechanisms by which cardiac aging contributes to exercise intolerance, and conversely how exercise training can potentially modulate aging phenotypes in the heart. Finally, we highlight the potential use of these exercise models to complement models of disease in efforts to uncover new therapeutic targets to prevent or treat heart disease in the aging population. © 2016 American Heart Association, Inc.

Inhibitory effects and related molecular mechanisms of total flavonoids in Mosla chinensis Maxim against H1N1 influenza virus.

Science.gov (United States)

Zhang, Xiao-Xia; Wu, Qiao-Feng; Yan, Yun-Liang; Zhang, Feng-Ling

2018-02-01

The Shixiangru (Mosla chinensis Maxim) total flavonoids (STF) mainly contain luteolin and apigenin. The study aims to examine the inhibitory effects of STF on anti-H1N1 influenza virus and its related molecular mechanisms in pneumonia mice. The viral pneumonia mice were treated with Ribavirin or various doses of STF. We observed histological changes of lung by immunohistochemistry and measured lung index to value anti-influenza virus effects of STF. The concentrations of inflammatory cytokines and anti-oxidant factors were detected by ELISA. RT-PCR and western blot assays were used to determine the expression level of TLR pathway's key genes and proteins in lung tissues. We found that the pathological changes of lung in the viral pneumonia mice obviously alleviated by STF treatments and the STF (288 or 576 mg/kg) could significantly decrease lung indices. Moreover, the up-regulation (IL-6, TNF-α, IFN-γ, and NO) and down-regulation (IL-2, SOD and GSH) of inflammatory cytokines and anti-oxidant factors were associated with higher clearance of virus and reduction of inflammatory lung tissue damage. Meanwhile, the expression levels of TLR3, TLR7, MyD88, TRAF3 and NF-κB p65 of the TLR pathway were reduced by STF treatment. This study suggested that STF may be a promising candidate for treating H1N1 influenza and subsequent viral pneumonia.

Molecular mechanisms of disorders of lipid metabolism in chronic kidney disease.

Science.gov (United States)

Moradi, Hamid; Vaziri, Nosratola D

2018-01-01

Chronic kidney disease (CKD) is a progressive condition marked by protracted kidney damage which over time can lead to end stage renal disease (ESRD). CKD can be categorized into different stages based on the extent of renal damage and degree of renal dysfunction with ESRD requiring renal replacement therapy considered the final stage. It is important to note that CKD in all of its forms is associated with accelerated atherosclerosis, cardiovascular (CV) disease and poor CV outcomes. While a number of factors contribute to the high risk of CV mortality in this patient population, dyslipidemia is considered to be a key player in the pathogenesis of CV disease in CKD. Molecular mechanisms responsible for CKD-associated lipid disorders are unique and greatly influenced by the stage of renal disease, presence and degree of proteinuria and in patients with ESRD, modality of renal replacement therapy. This article provides a detailed overview of the molecular mechanisms which cause dyslipidemia and the nature of lipid disorders associated with CKD and ESRD.

Structural insight into molecular mechanism of poly(ethylene terephthalate) degradation

OpenAIRE

Joo, Seongjoon; Cho, In Jin; Seo, Hogyun; Son, Hyeoncheol Francis; Sagong, Hye-Young; Shin, Tae Joo; Choi, So Young; Lee, Sang Yup; Kim, Kyung-Jin

2018-01-01

Plastics, including poly(ethylene terephthalate) (PET), possess many desirable characteristics and thus are widely used in daily life. However, non-biodegradability, once thought to be an advantage offered by plastics, is causing major environmental problem. Recently, a PET-degrading bacterium, Ideonella sakaiensis, was identified and suggested for possible use in degradation and/or recycling of PET. However, the molecular mechanism of PET degradation is not known. Here we report the crystal ...

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

Molecular cloning and characterization of pathogenesis-related ...

African Journals Online (AJOL)

We described the cloning and characterization of pathogenesis-related protein 5 gene in maize, named ZmPR5 (GenBank Accession Number: HM230665). Molecular and bioinformatic analyses of ZmPR5 revealed an open reading frame (ORF) of 525 bp, encoding a protein of 175 amino acids (aa) and a deduced ...

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.

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.

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

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.

Evolutionary traces decode molecular mechanism behind fast pace of myosin XI

Directory of Open Access Journals (Sweden)

Syamaladevi Divya P

2011-09-01

Full Text Available Abstract Background Cytoplasmic class XI myosins are the fastest processive motors known. This class functions in high-velocity cytoplasmic streaming in various plant cells from algae to angiosperms. The velocities at which they process are ten times faster than its closest class V homologues. Results To provide sequence determinants and structural rationale for the molecular mechanism of this fast pace myosin, we have compared the sequences from myosin class V and XI through Evolutionary Trace (ET analysis. The current study identifies class-specific residues of myosin XI spread over the actin binding site, ATP binding site and light chain binding neck region. Sequences for ET analysis were accumulated from six plant genomes, using literature based text search and sequence searches, followed by triple validation viz. CDD search, string-based searches and phylogenetic clustering. We have identified nine myosin XI genes in sorghum and seven in grape by sequence searches. Both the plants possess one gene product each belonging to myosin type VIII as well. During this process, we have re-defined the gene boundaries for three sorghum myosin XI genes using fgenesh program. Conclusion Molecular modelling and subsequent analysis of putative interactions involving these class-specific residues suggest a structural basis for the molecular mechanism behind high velocity of plant myosin XI. We propose a model of a more flexible switch I region that contributes to faster ADP release leading to high velocity movement of the algal myosin XI.

The Frame of Fixed Stars in Relational Mechanics

Science.gov (United States)

Ferraro, Rafael

2017-01-01

Relational mechanics is a gauge theory of classical mechanics whose laws do not govern the motion of individual particles but the evolution of the distances between particles. Its formulation gives a satisfactory answer to Leibniz's and Mach's criticisms of Newton's mechanics: relational mechanics does not rely on the idea of an absolute space. When describing the behavior of small subsystems with respect to the so called "fixed stars", relational mechanics basically agrees with Newtonian mechanics. However, those subsystems having huge angular momentum will deviate from the Newtonian behavior if they are described in the frame of fixed stars. Such subsystems naturally belong to the field of astronomy; they can be used to test the relational theory.

Solvent dielectric effect and side chain mutation on the structural stability of Burkholderia cepacia lipase active site: a quantum mechanical/molecular mechanics study.

Science.gov (United States)

Tahan, A; Monajjemi, M

2011-12-01

Quantum mechanical and molecular dynamics methods were used to analyze the structure and stability of neutral and zwitterionic configurations of the extracted active site sequence from a Burkholderia cepacia lipase, histidyl-seryl-glutamin (His86-Ser87-Gln88) and its mutated form, histidyl-cysteyl-glutamin (His86-Cys87-Gln88) in vacuum and different solvents. The effects of solvent dielectric constant, explicit and implicit water molecules and side chain mutation on the structure and stability of this sequence in both neutral and zwitterionic forms are represented. The quantum mechanics computations represent that the relative stability of zwitterionic and neutral configurations depends on the solvent structure and its dielectric constant. Therefore, in vacuum and the considered non-polar solvents, the neutral form of the interested sequences is more stable than the zwitterionic form, while their zwitterionic form is more stable than the neutral form in the aqueous solution and the investigated polar solvents in most cases. However, on the potential energy surfaces calculated, there is a barrier to proton transfer from the positively charged ammonium group to the negatively charged carboxylat group or from the ammonium group to the adjacent carbonyl oxygen and or from side chain oxygen and sulfur to negatively charged carboxylat group. Molecular dynamics simulations (MD) were also performed by using periodic boundary conditions for the zwitterionic configuration of the hydrated molecules in a box of water molecules. The obtained results demonstrated that the presence of explicit water molecules provides the more compact structures of the studied molecules. These simulations also indicated that side chain mutation and replacement of sulfur with oxygen leads to reduction of molecular flexibility and packing.

Molecular mechanisms and in vitro antioxidant effects of Lactobacillus plantarum MA2.

Science.gov (United States)

Tang, Wei; Xing, Zhuqing; Li, Chao; Wang, Jinju; Wang, Yanping

2017-04-15

Lactobacillus plantarum MA2 was isolated from Chinese traditional Tibetan kefir grains. The antioxidant activities in vitro of this strain were evaluated extensively. The results showed that L. plantarum MA2 can tolerate hydrogen peroxide up to 2.0mM, and its fermentate (fermented supernatant, intact cell and cell-free extract) had strong reducing capacities, lipid peroxidation inhibition capacities, Fe 2+ -chelating abilities, as well as various free radical scavenging capacities. Additionally, both the fermented supernatant and cell homogenate exhibited glutathione peroxidase activity and superoxide dismutase activity. In order to investigate the antioxidant mechanism of L. plantarum MA2 at the molecular level, eight antioxidant-related genes were identified, and further analyzed. Three groups of genes cat, gshR and npx, were found up-regulated under H 2 O 2 challenge. Copyright © 2016 Elsevier Ltd. All rights reserved.

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.

Advanced in study of cellular and molecular mechanisms of radiation effects on central nervous system

International Nuclear Information System (INIS)

Zhang Wei; Tu Yu; Wang Lili

2008-01-01

Along with radiation treatment extensively applied, radiation injury also is valued gradually. The effect of radiation to the cellular and molecular of central nervous system (CNS) is a complicated and moderately advanced process and the mechanism is remains incompletely clear yet. Inquiring into the possible mechanism of the CNS including the injury and the restoration of neuron, neuroglia cells, endotheliocyte cell and blood-brain barrier and the molecular level of change induced by radiation, so as to provide beneficial thought for preventing and curing radiation injury clinically. Some neuroprotective strategies are also addressed in the review. (authors)

Tumour biology of obesity-related cancers: understanding the molecular concept for better diagnosis and treatment.

Science.gov (United States)

Teoh, Seong Lin; Das, Srijit

2016-11-01

Obesity continues to be a major global problem. Various cancers are related to obesity and proper understanding of their aetiology, especially their molecular tumour biology is important for early diagnosis and better treatment. Genes play an important role in the development of obesity. Few genes such as leptin, leptin receptor encoded by the db (diabetes), pro-opiomelanocortin, AgRP and NPY and melanocortin-4 receptors and insulin-induced gene 2 were linked to obesity. MicroRNAs control gene expression via mRNA degradation and protein translation inhibition and influence cell differentiation, cell growth and cell death. Overexpression of miR-143 inhibits tumour growth by suppressing B cell lymphoma 2, extracellular signal-regulated kinase-5 activities and KRAS oncogene. Cancers of the breast, uterus, renal, thyroid and liver are also related to obesity. Any disturbance in the production of sex hormones and insulin, leads to distortion in the balance between cell proliferation, differentiation and apoptosis. The possible mechanism linking obesity to cancer involves alteration in the level of adipokines and sex hormones. These mediators act as biomarkers for cancer progression and act as targets for cancer therapy and prevention. Interestingly, many anti-cancerous drugs are also beneficial in treating obesity and vice versa. We also reviewed the possible link in the mechanism of few drugs which act both on cancer and obesity. The present review may be important for molecular biologists, oncologists and clinicians treating cancers and also pave the way for better therapeutic options.

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.

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.

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.

Multilevel Quantum Mechanics Theories and Molecular Mechanics Calculations of the Cl- + CH3I Reaction in Water.

Science.gov (United States)

Liu, Peng; Li, Chen; Wang, Dunyou

2017-10-19

The Cl - + CH 3 I → CH 3 Cl + I - reaction in water was studied using combined multilevel quantum mechanism theories and molecular mechanics with an explicit water solvent model. The study shows a significant influence of aqueous solution on the structures of the stationary points along the reaction pathway. A detailed, atomic-level evolution of the reaction mechanism shows a concerted one-bond-broken and one-bond-formed mechanism, as well as a synchronized charge-transfer process. The potentials of mean force calculated with the CCSD(T) and DFT treatments of the solute produce a free activation barrier at 24.5 and 19.0 kcal/mol, respectively, which agrees with the experimental one at 22.0 kcal/mol. The solvent effects have also been quantitatively analyzed: in total, the solvent effects raise the activation energy by 20.2 kcal/mol, which shows a significant impact on this reaction in water.

Molecular Aspects of H. pylori-Related MALT Lymphoma

Directory of Open Access Journals (Sweden)

Scott R. Owens

2011-01-01

Full Text Available Helicobacter pylori-related extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue is a paradigm for malignancy arising in an inflammatory background. While the diagnosis of H. pylori gastritis is often straightforward, distinction between severe gastritis and early lymphoma can be difficult and requires careful assessment of clinical findings in addition to histological features and immunohistochemical results. A number of cytogenetic abnormalities have been discovered in H. pylori-related lymphomas and several have clinical importance, related to the responsiveness of lymphoma to H. pylori eradication therapy, but routine molecular studies are not widely utilized. While molecular methods may be used in equivocal cases, a trial of conservative therapy is warranted given the propensity for these lymphomas to regress with eradication of the organism. Once therapy is initiated, care must be taken to avoid a premature assignment of disease refractoriness because complete response can take several months to more than a year. Cases truly refractory to H. pylori eradication therapy may be treated with adjuvant chemoradiation with a high response rate.

The Role of Mechanical Force in Molecular and Cellular during Orthodontic Tooth Movement

Directory of Open Access Journals (Sweden)

Ida Bagus Narmada

2012-10-01

Full Text Available Application of mechanical force on abnormally positioned tooth, cause changes in tooth location and transmitted to the bone ia the periodontal ligament (PDL produce orthodontic tooth movement. This force application is further way that remodeling in the area occurs. In order to develop biological strategies for enhancing this movement of teeth in bone, the underlying mechanisms of bone resorption and apposition should be understood in detail. Analysis of gingival crevicular fluid (GCF may be a good means of examining the on going molecular and cellular process associated with gingival and bone turnover during orthodontic tooth movement. If it could be possible to biologically monitor and predict the outcome of orthodontic force, then the appliance management could be based on dividual tissue response and the effectiveness of the treatment could be improved and understanding their biology is critical to finding ways to modify bone biology to move teeth faster. The present article reviewed a short introduction to some mayors advanced mechanical force in molecular and cellular biology during orthodontic tooth movement.DOI: 10.14693/jdi.v15i3.30

Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications

Energy Technology Data Exchange (ETDEWEB)

Noridomi, Kaori; Watanabe, Go; Hansen, Melissa N.; Han, Gye Won; Chen, Lin (USC)

2017-04-25

The nicotinic acetylcholine receptor (nAChR) is a major target of autoantibodies in myasthenia gravis (MG), an autoimmune disease that causes neuromuscular transmission dysfunction. Despite decades of research, the molecular mechanisms underlying MG have not been fully elucidated. Here, we present the crystal structure of the nAChR α1 subunit bound by the Fab fragment of mAb35, a reference monoclonal antibody that causes experimental MG and competes with ~65% of antibodies from MG patients. Our structures reveal for the first time the detailed molecular interactions between MG antibodies and a core region on nAChR α1. These structures suggest a major nAChR-binding mechanism shared by a large number of MG antibodies and the possibility to treat MG by blocking this binding mechanism. Structure-based modeling also provides insights into antibody-mediated nAChR cross-linking known to cause receptor degradation. Our studies establish a structural basis for further mechanistic studies and therapeutic development of MG.

A Molecular Dynamics-Quantum Mechanics Theoretical Study of DNA-Mediated Charge Transport in Hydrated Ionic Liquids.

Science.gov (United States)

Meng, Zhenyu; Kubar, Tomas; Mu, Yuguang; Shao, Fangwei

2018-05-08

Charge transport (CT) through biomolecules is of high significance in the research fields of biology, nanotechnology, and molecular devices. Inspired by our previous work that showed the binding of ionic liquid (IL) facilitated charge transport in duplex DNA, in silico simulation is a useful means to understand the microscopic mechanism of the facilitation phenomenon. Here molecular dynamics simulations (MD) of duplex DNA in water and hydrated ionic liquids were employed to explore the helical parameters. Principal component analysis was further applied to capture the subtle conformational changes of helical DNA upon different environmental impacts. Sequentially, CT rates were calculated by a QM/MM simulation of the flickering resonance model based upon MD trajectories. Herein, MD simulation illustrated that the binding of ionic liquids can restrain dynamic conformation and lower the on-site energy of the DNA base. Confined movement among the adjacent base pairs was highly related to the increase of electronic coupling among base pairs, which may lead DNA to a CT facilitated state. Sequentially combining MD and QM/MM analysis, the rational correlations among the binding modes, the conformational changes, and CT rates illustrated the facilitation effects from hydrated IL on DNA CT and supported a conformational-gating mechanism.

PDMS Network Structure-Property Relationships: Influence of Molecular Architecture on Mechanical and Wetting Properties

Science.gov (United States)

Melillo, Matthew Joseph

/TDSS and commercial PDMS-based Sylgard 184 composite, but only keep improving with additional crosslinker in the silanol/TEOS systems due to in situ TEOS aggregation. We relate molecular network topology to mechanical properties using outputs from the Miller-Macosko model in the vinyl/TDSS system. The elastic fraction and storage modulus correlate well, as do the pendant fraction and the loss tangent, demonstrating the importance of each fraction in bulk mechanical properties. By studying the dynamic behavior of water droplets wetting PDMS substrates, we observe non-linear wetting behaviors that are markedly different from linear behaviors seen on glassy polymer substrates. The non-linear behavior is only observed prior to extraction, while after extraction, both systems demonstrate behavior similar to glassy polymers. This reveals the dramatic role small amounts of uncrosslinked materials present in the sol fraction play in the surface wetting dynamics of PDMS materials. We further demonstrate the role of uncrosslinked material by adding silicone oils into otherwise fully crosslinked PDMS networks and study their wetting properties. Through careful formulation and preparation of PDMS materials, compared to simply mixing two formulations present in Sylgard 184, one can apply polymer network models to glean useful information about network topology. The benefits of doing so outweigh the costs. We stress the importance of performing Soxhlet extraction to remove unreacted components from PDMS materials, even when using optimal stoichiometry. These mobile molecules that remain after crosslinking can alter significantly wetting behavior and readily leach into liquid environments. However, it is equally important to stress that Soxhlet extraction will not remove all unreacted material. Some will always remain in PDMS, which is often the practice in preparing microfluidic devices. While Sylgard 184 is very well suited for some applications, the results presented in this

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.

Modeling and Proposed Molecular Mechanism of Hydroxyurea Through Docking and Molecular Dynamic Simulation to Curtail the Action of Ribonucleotide Reductase.

Science.gov (United States)

Iman, Maryam; Khansefid, Zeynab; Davood, Asghar

2016-01-01

Ribonucleotide Reductase (RNR) is an important anticancer chemotherapy target. It has main key role in DNA synthesis and cell growth. Therefore several RNR inhibitors, such as hydroxyurea, have entered the clinical trials. Based on our proposed mechanism, radical site of RNR protein reacts with hydroxyurea in which hydroxyurea is converted into its oxidized form compound III, and whereby the tyrosyl radical is converted into a normal tyrosine residue. In this study, docking and molecular dynamics simulations were used for proposed molecular mechanism of hydroxyurea in RNR inhibition as anticancer agent. The binding affinity of hydroxyurea and compound III to RNR was studied by docking method. The docking study was performed for the crystal structure of human RNR with the radical scavenger Hydroxyurea and its oxidized form to inhibit the human RNR. hydroxyurea and compound III bind at the active site with Tyr-176, which are essential for free radical formation. This helps to understand the functional aspects and also aids in the development of novel inhibitors for the human RNR2. To confirm the binding mode of inhibitors, the molecular dynamics (MD) simulations were performed using GROMACS 4.5.5, based upon the docked conformation of inhibitors. Both of the studied compounds stayed in the active site. The results of MD simulations confirmed the binding mode of ligands, accuracy of docking and the reliability of active conformations which were obtained by AutoDock. MD studies confirm our proposed mechanism in which compound III reacts with the active site residues specially Tyr-176, and inhibits the radical generation and subsequently inhibits the RNR enzyme.

Gene expression analysis of molecular mechanisms of defense induced in Medicago truncatula parasitized by Orobanche crenata.

Science.gov (United States)

Die, José Vicente; González Verdejo, Clara I; Dita, Miguel A; Nadal, Salvador; Román, Belén

2009-07-01

The infection of Medicago truncatula Gaertn. roots with the obligate parasite Orobanche crenata Forsk. is a useful model for studying the molecular events involved in the legumes-parasite interaction. In order to gain insight into the identification of gene-regulatory elements involved in the resistance mechanism, the temporal expression pattern of ten defense-related genes was carried out using real-time quantitative reverse-transcription polymerase chain reaction assays. The induction of all of the analyzed transcripts significantly increased over a range from 2- to 321-fold higher than the control depending on the gene and time point. The transcriptional changes observed in response to O. crenata infection suggest that resistance could rely on both, the induction of general defense-related genes and more specific responses.

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: �

Global transcriptomic profiling of aspen trees under elevated [CO2] to identify potential molecular mechanisms responsible for enhanced radial growth.

Science.gov (United States)

Wei, Hairong; Gou, Jiqing; Yordanov, Yordan; Zhang, Huaxin; Thakur, Ramesh; Jones, Wendy; Burton, Andrew

2013-03-01

Aspen (Populus tremuloides) trees growing under elevated [CO(2)] at a free-air CO(2) enrichment (FACE) site produced significantly more biomass than control trees. We investigated the molecular mechanisms underlying the observed increase in biomass by producing transcriptomic profiles of the vascular cambium zone (VCZ) and leaves, and then performed a comparative study to identify significantly changed genes and pathways after 12 years exposure to elevated [CO(2)]. In leaves, elevated [CO(2)] enhanced expression of genes related to Calvin cycle activity and linked pathways. In the VCZ, the pathways involved in cell growth, cell division, hormone metabolism, and secondary cell wall formation were altered while auxin conjugation, ABA synthesis, and cytokinin glucosylation and degradation were inhibited. Similarly, the genes involved in hemicellulose and pectin biosynthesis were enhanced, but some genes that catalyze important steps in lignin biosynthesis pathway were inhibited. Evidence from systemic analysis supported the functioning of multiple molecular mechanisms that underpin the enhanced radial growth in response to elevated [CO(2)].

First-Principles Quantum Dynamics of Singlet Fission: Coherent versus Thermally Activated Mechanisms Governed by Molecular π Stacking

Science.gov (United States)

Tamura, Hiroyuki; Huix-Rotllant, Miquel; Burghardt, Irene; Olivier, Yoann; Beljonne, David

2015-09-01

Singlet excitons in π -stacked molecular crystals can split into two triplet excitons in a process called singlet fission that opens a route to carrier multiplication in photovoltaics. To resolve controversies about the mechanism of singlet fission, we have developed a first principles nonadiabatic quantum dynamical model that reveals the critical role of molecular stacking symmetry and provides a unified picture of coherent versus thermally activated singlet fission mechanisms in different acenes. The slip-stacked equilibrium packing structure of pentacene derivatives is found to enhance ultrafast singlet fission mediated by a coherent superexchange mechanism via higher-lying charge transfer states. By contrast, the electronic couplings for singlet fission strictly vanish at the C2 h symmetric equilibrium π stacking of rubrene. In this case, singlet fission is driven by excitations of symmetry-breaking intermolecular vibrations, rationalizing the experimentally observed temperature dependence. Design rules for optimal singlet fission materials therefore need to account for the interplay of molecular π -stacking symmetry and phonon-induced coherent or thermally activated mechanisms.

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...

Transport mechanisms and wetting dynamics in molecularly thin films of long-chain alkanes at solid/vapour interface : relation to the solid-liquid phase transition

OpenAIRE

Lazar, Paul

2005-01-01

Wetting and phase transitions play a very important role our daily life. Molecularly thin films of long-chain alkanes at solid/vapour interfaces (e.g. C30H62 on silicon wafers) are very good model systems for studying the relation between wetting behaviour and (bulk) phase transitions. Immediately above the bulk melting temperature the alkanes wet partially the surface (drops). In this temperature range the substrate surface is covered with a molecularly thin ordered, solid-like alkane film (...

Molecular mechanisms and theranostic potential of miRNAs in drug resistance of gastric cancer.

Science.gov (United States)

Yang, Wanli; Ma, Jiaojiao; Zhou, Wei; Cao, Bo; Zhou, Xin; Yang, Zhiping; Zhang, Hongwei; Zhao, Qingchuan; Fan, Daiming; Hong, Liu

2017-11-01

Systemic chemotherapy is a curative approach to inhibit gastric cancer cells proliferation. Despite the great progress in anti-cancer treatment achieved during the last decades, drug resistance and treatment refractoriness still extensively persists. Recently, accumulating studies have highlighted the role of miRNAs in drug resistance of gastric cancers by modulating some drug resistance-related proteins and genes expression. Pre-clinical reports indicate that miRNAs might serve as ideal biomarkers and potential targets, thus holding great promise for developing targeted therapy and personalized treatment for the patients with gastric cancer. Areas covered: This review provide a comprehensive overview of the current advances of miRNAs and molecular mechanisms underlying miRNA-mediated drug resistance in gastric cancer. We particularly focus on the potential values of drug resistance-related miRNAs as biomarkers and novel targets in gastric cancer therapy and envisage the future research developments of these miRNAs and challenges in translating the new findings into clinical applications. Expert opinion: Although the concrete mechanisms of miRNAs in drug resistance of gastric cancer have not been fully clarified, miRNA may be a promising theranostic approach. Further studies are still needed to facilitate the clinical applications of miRNAs in drug resistant gastric cancer.

Role of Molecular Weight on the Mechanical Device Properties of Organic Polymer Solar Cells

KAUST Repository

Bruner, Christopher

2014-02-11

For semiconducting polymers, such as regioregular poly(3-hexylthiophene-2, 5-diyl) (rr-P3HT), the molecular weight has been correlated to charge carrier field-effect mobilities, surface morphology, and gelation rates in solution and therefore has important implications for long-Term reliability, manufacturing, and future applications of electronic organic thin films. In this work, we show that the molecular weight rr-P3HT in organic solar cells can also significantly change the internal cohesion of the photoactive layer using micromechanical testing techniques. Cohesive values ranged from ∼0.5 to ∼17 J m -2, following the general trend of greater cohesion with increasing molecular weight. Using nanodynamic mechanical analysis, we attribute the increase in cohesion to increased plasticity which helps dissipate the applied energy. Finally, we correlate photovoltaic efficiency with cohesion to assess the device physics pertinent to optimizing device reliability. This research elucidates the fundamental parameters which affect both the mechanical stability and efficiency of polymer solar cells. © 2014 American Chemical Society.

Scientometrics of drug discovery efforts: pain-related molecular targets

Directory of Open Access Journals (Sweden)

Kissin I

2015-07-01

Full Text Available Igor KissinDepartment of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USAAbstract: The aim of this study was to make a scientometric assessment of drug discovery efforts centered on pain-related molecular targets. The following scientometric indices were used: the popularity index, representing the share of articles (or patents on a specific topic among all articles (or patents on pain over the same 5-year period; the index of change, representing the change in the number of articles (or patents on a topic from one 5-year period to the next; the index of expectations, representing the ratio of the number of all types of articles on a topic in the top 20 journals relative to the number of articles in all (>5,000 biomedical journals covered by PubMed over a 5-year period; the total number of articles representing Phase I–III trials of investigational drugs over a 5-year period; and the trial balance index, a ratio of Phase I–II publications to Phase III publications. Articles (PubMed database and patents (US Patent and Trademark Office database on 17 topics related to pain mechanisms were assessed during six 5-year periods from 1984 to 2013. During the most recent 5-year period (2009–2013, seven of 17 topics have demonstrated high research activity (purinergic receptors, serotonin, transient receptor potential channels, cytokines, gamma aminobutyric acid, glutamate, and protein kinases. However, even with these seven topics, the index of expectations decreased or did not change compared with the 2004–2008 period. In addition, publications representing Phase I–III trials of investigational drugs (2009–2013 did not indicate great enthusiasm on the part of the pharmaceutical industry regarding drugs specifically designed for treatment of pain. A promising development related to the new tool of molecular targeting, ie, monoclonal antibodies, for pain treatment has not

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

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.

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

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.

Latent memory facilitates relearning through molecular signaling mechanisms that are distinct from original learning.

Science.gov (United States)

Menges, Steven A; Riepe, Joshua R; Philips, Gary T

2015-09-01

A highly conserved feature of memory is that it can exist in a latent, non-expressed state which is revealed during subsequent learning by its ability to significantly facilitate (savings) or inhibit (latent inhibition) subsequent memory formation. Despite the ubiquitous nature of latent memory, the mechanistic nature of the latent memory trace and its ability to influence subsequent learning remains unclear. The model organism Aplysia californica provides the unique opportunity to make strong links between behavior and underlying cellular and molecular mechanisms. Using Aplysia, we have studied the mechanisms of savings due to latent memory for a prior, forgotten experience. We previously reported savings in the induction of three distinct temporal domains of memory: short-term (10min), intermediate-term (2h) and long-term (24h). Here we report that savings memory formation utilizes molecular signaling pathways that are distinct from original learning: whereas the induction of both original intermediate- and long-term memory in naïve animals requires mitogen activated protein kinase (MAPK) activation and ongoing protein synthesis, 2h savings memory is not disrupted by inhibitors of MAPK or protein synthesis, and 24h savings memory is not dependent on MAPK activation. Collectively, these findings reveal that during forgetting, latent memory for the original experience can facilitate relearning through molecular signaling mechanisms that are distinct from original learning. Copyright © 2015 Elsevier Inc. All rights reserved.

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.

Molecular imaging and the unification of multilevel mechanisms and data in medical physics

International Nuclear Information System (INIS)

Nikiforidis, George C.; Sakellaropoulos, George C.; Kagadis, George C.

2008-01-01

Molecular imaging (MI) constitutes a recently developed approach of imaging, where modalities and agents have been reinvented and used in novel combinations in order to expose and measure biologic processes occurring at molecular and cellular levels. It is an approach that bridges the gap between modalities acquiring data from high (e.g., computed tomography, magnetic resonance imaging, and positron-emitting isotopes) and low (e.g., PCR, microarrays) levels of a biological organization. While data integration methodologies will lead to improved diagnostic and prognostic performance, interdisciplinary collaboration, triggered by MI, will result in a better perception of the underlying biological mechanisms. Toward the development of a unifying theory describing these mechanisms, medical physicists can formulate new hypotheses, provide the physical constraints bounding them, and consequently design appropriate experiments. Their new scientific and working environment calls for interventions in their syllabi to educate scientists with enhanced capabilities for holistic views and synthesis.

An overview of the molecular mechanisms and novel roles of Nrf2 in neurodegenerative disorders.

Science.gov (United States)

Yang, Yang; Jiang, Shuai; Yan, Juanjuan; Li, Yue; Xin, Zhenlong; Lin, Yan; Qu, Yan

2015-02-01

Recently, growing evidence has demonstrated that nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal regulator of endogenous defense systems that function via the activation of a set of protective genes, and this is particularly clear in the central nervous system (CNS). Therefore, it is highly useful to summarize the current literature on the molecular mechanisms and role of Nrf2 in the CNS. In this review, we first briefly introduce the molecular features of Nrf2. We then discuss the regulation, cerebral actions, upstream modulators and downstream targets of Nrf2 pathway. Following this background, we expand our discussion to the role of Nrf2 in several major neurodegenerative disorders (NDDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic lateral sclerosis. Lastly, we discuss some potential future directions. The information reviewed here may be significant in the design of further experimental research and increase the potential of Nrf2 as a therapeutic target in the future. Copyright © 2014 Elsevier Ltd. All rights reserved.

Molecular Combing of DNA: Methods and Applications

DEFF Research Database (Denmark)

Nazari, Zeniab Esmail; Gurevich, Leonid

2013-01-01

studies to nanoelectronics. While molecular combing has been applied in a variety of DNA-related studies, no comprehensive review has been published on different combing methods proposed so far. In this review, the underlying mechanisms of molecular combing of DNA are described followed by discussion...

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.

Towards a Better Understanding of the Molecular Mechanisms Involved in Sunlight-Induced Melanoma

Directory of Open Access Journals (Sweden)

Williams Mandy

2005-01-01

Full Text Available Although much less prevalent than its nonmelanoma skin cancer counterparts, cutaneous malignant melanoma (CMM is the most lethal human skin cancer. Epidemiological and biological studies have established a strong link between lifetime exposure to ultraviolet (UV light, particularly sunburn in childhood, and the development of melanoma. However, the specific molecular targets of this environmental carcinogen are not known. Data obtained from genetic and molecular studies over the last few years have identified the INK4a/ARF locus as the “gatekeeper” melanoma suppressor, encoding two tumour suppressor proteins in human, p16 INK4a and p14 ARF . Recent developments in molecular biotechnology and research using laboratory animals have made a significant gene breakthrough identifying the components of the p16 INK4a /Rb pathway as the principal and rate-limiting targets of UV radiation actions in melanoma formation. This review summarizes the current knowledge of the molecular mechanisms involved in melanoma development and its relationship to sunlight UV radiation.

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.

Understanding the molecular mechanisms involved in the interfacial self-healing of supramolecular rubbers

NARCIS (Netherlands)

Bose, R.K.; Garcia Espallargas, S.J.; Van der Zwaag, S.

2013-01-01

Supramolecular rubbers based on 2-aminoethylimidazolidone and fatty acids with epoxy crosslinks have been shown to self-heal via multiple hydrogen bonding sites. In this work, several tools are used to investigate the molecular mechanisms taking place at the interface to understand cohesive healing

Direct neutron capture and related mechanisms

International Nuclear Information System (INIS)

Lynn, J.E.; Raman, S.

1990-01-01

We consider the evidence for the role of direct and related mechanisms in neutron capture at low and medium energies. Firstly, we compare the experimental data on the thermal neutron cross sections for El transitions in light nuclei with careful estimates of direct capture. Over the full range of light nuclei with small cross sections direct capture is found to be the predominant mechanism, in some cases being remarkable accurate, but in a few showing evidence for collective effects. When resonance effects become substantial there is evidence for an important contribution from the closely related valence mechanism, but full agreement with the data in such cases appears to require the introduction of a more generalised valence model. The possibility of direct and valence mechanisms playing a role in M1 capture is studied, and it is concluded that in light nuclei at relatively low gamma ray energies, it does indeed play some role. In heavier nuclei it appears that the evidence, especially from the correlations between E1 and M1 transitions to the same final states, favours the hypothesis that the main transition strength is governed by the M1 giant resonance. 31 refs., 2 tabs

Molecular Mechanisms for Age-Associated Mitochondrial Deficiency in Skeletal Muscle

Directory of Open Access Journals (Sweden)

Akira Wagatsuma

2012-01-01

Full Text Available The abundance, morphology, and functional properties of mitochondria decay in skeletal muscle during the process of ageing. Although the precise mechanisms remain to be elucidated, these mechanisms include decreased mitochondrial DNA (mtDNA repair and mitochondrial biogenesis. Mitochondria possess their own protection system to repair mtDNA damage, which leads to defects of mtDNA-encoded gene expression and respiratory chain complex enzymes. However, mtDNA mutations have shown to be accumulated with age in skeletal muscle. When damaged mitochondria are eliminated by autophagy, mitochondrial biogenesis plays an important role in sustaining energy production and physiological homeostasis. The capacity for mitochondrial biogenesis has shown to decrease with age in skeletal muscle, contributing to progressive mitochondrial deficiency. Understanding how these endogenous systems adapt to altered physiological conditions during the process of ageing will provide a valuable insight into the underlying mechanisms that regulate cellular homeostasis. Here we will summarize the current knowledge about the molecular mechanisms responsible for age-associated mitochondrial deficiency in skeletal muscle. In particular, recent findings on the role of mtDNA repair and mitochondrial biogenesis in maintaining mitochondrial functionality in aged skeletal muscle will be highlighted.

Molecular mechanisms of drug resistance in natural Leishmania populations vary with genetic background.

Directory of Open Access Journals (Sweden)

Saskia Decuypere

Full Text Available The evolution of drug-resistance in pathogens is a major global health threat. Elucidating the molecular basis of pathogen drug-resistance has been the focus of many studies but rarely is it known whether a drug-resistance mechanism identified is universal for the studied pathogen; it has seldom been clarified whether drug-resistance mechanisms vary with the pathogen's genotype. Nevertheless this is of critical importance in gaining an understanding of the complexity of this global threat and in underpinning epidemiological surveillance of pathogen drug resistance in the field. This study aimed to assess the molecular and phenotypic heterogeneity that emerges in natural parasite populations under drug treatment pressure. We studied lines of the protozoan parasite Leishmania (L. donovani with differential susceptibility to antimonial drugs; the lines being derived from clinical isolates belonging to two distinct genetic populations that circulate in the leishmaniasis endemic region of Nepal. Parasite pathways known to be affected by antimonial drugs were characterised on five experimental levels in the lines of the two populations. Characterisation of DNA sequence, gene expression, protein expression and thiol levels revealed a number of molecular features that mark antimonial-resistant parasites in only one of the two populations studied. A final series of in vitro stress phenotyping experiments confirmed this heterogeneity amongst drug-resistant parasites from the two populations. These data provide evidence that the molecular changes associated with antimonial-resistance in natural Leishmania populations depend on the genetic background of the Leishmania population, which has resulted in a divergent set of resistance markers in the Leishmania populations. This heterogeneity of parasite adaptations provides severe challenges for the control of drug resistance in the field and the design of molecular surveillance tools for widespread

Entanglements in P3HT and their influence on thin-film mechanical properties: Insights from molecular dynamics simulations

KAUST Repository

Tummala, Naga Rajesh; Risko, Chad; Bruner, Christopher; Dauskardt, Reinhold H.; Bredas, Jean-Luc

2015-01-01

Due to their inherent mechanical flexibility and stretchability, organic-based electronic devices have garnered a great deal of academic and industrial interest. Here, molecular-dynamics simulations are used to examine the molecular-scale details that govern the relationships among molecular weight, chain entanglement, persistence length, and the elastic characteristics of the widely studied π-conjugated polymer poly-(3-hexyl thiophene), P3HT. Oligomers containing at least 50 monomer units are required in the simulations to observe elastic behavior in P3HT, while much longer chains are required to ensure description of appropriate levels of entanglement: only when the molecular weight is greater than 50 kDa, that is, oligomers with approximately 400 monomer units, is truly entangled behavior observed. Interestingly, results from primitive path analysis of amorphous P3HT matches well with the observed onsets of inter-chain excitonic coherence with increased molecular weight. The simulations also indicate that the P3HT modulus saturates at 1.6 GPa for chain lengths of 50–100 monomers, a result that compares well with experimental results. This work highlights the care that needs to be taken to accurately model P3HT morphologies in relation to experimental measurements. © 2015 The Authors. Journal of Polymer Science Part B: Polymer Physics Published by Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2015

Entanglements in P3HT and their influence on thin-film mechanical properties: Insights from molecular dynamics simulations

KAUST Repository

Tummala, Naga Rajesh

2015-04-01

Due to their inherent mechanical flexibility and stretchability, organic-based electronic devices have garnered a great deal of academic and industrial interest. Here, molecular-dynamics simulations are used to examine the molecular-scale details that govern the relationships among molecular weight, chain entanglement, persistence length, and the elastic characteristics of the widely studied π-conjugated polymer poly-(3-hexyl thiophene), P3HT. Oligomers containing at least 50 monomer units are required in the simulations to observe elastic behavior in P3HT, while much longer chains are required to ensure description of appropriate levels of entanglement: only when the molecular weight is greater than 50 kDa, that is, oligomers with approximately 400 monomer units, is truly entangled behavior observed. Interestingly, results from primitive path analysis of amorphous P3HT matches well with the observed onsets of inter-chain excitonic coherence with increased molecular weight. The simulations also indicate that the P3HT modulus saturates at 1.6 GPa for chain lengths of 50–100 monomers, a result that compares well with experimental results. This work highlights the care that needs to be taken to accurately model P3HT morphologies in relation to experimental measurements. © 2015 The Authors. Journal of Polymer Science Part B: Polymer Physics Published by Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2015

Understanding the molecular mechanisms of human microtia via a pig model of HOXA1 syndrome

Directory of Open Access Journals (Sweden)

Ruimin Qiao

2015-06-01

Full Text Available Microtia is a congenital malformation of the outer ears. Although both genetic and environmental components have been implicated in microtia, the genetic causes of this innate disorder are poorly understood. Pigs have naturally occurring diseases comparable to those in humans, providing exceptional opportunity to dissect the molecular mechanism of human inherited diseases. Here we first demonstrated that a truncating mutation in HOXA1 causes a monogenic disorder of microtia in pigs. We further performed RNA sequencing (RNA-Seq analysis on affected and healthy pig embryos (day 14.25. We identified a list of 337 differentially expressed genes (DEGs between the normal and mutant samples, shedding light on the transcriptional network involving HOXA1. The DEGs are enriched in biological processes related to cardiovascular system and embryonic development, and neurological, renal and urological diseases. Aberrant expressions of many DEGs have been implicated in human innate deformities corresponding to microtia-associated syndromes. After applying three prioritizing algorithms, we highlighted appealing candidate genes for human microtia from the 337 DEGs. We searched for coding variants of functional significance within six candidate genes in 147 microtia-affected individuals. Of note, we identified one EVC2 non-synonymous mutation (p.Asp1174Asn as a potential disease-implicating variant for a human microtia-associated syndrome. The findings advance our understanding of the molecular mechanisms underlying human microtia, and provide an interesting example of the characterization of human disease-predisposing variants using pig models.

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.

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...

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.

Hybrid Quantum Mechanics/Molecular Mechanics Solvation Scheme for Computing Free Energies of Reactions at Metal-Water Interfaces.

Science.gov (United States)

Faheem, Muhammad; Heyden, Andreas

2014-08-12

We report the development of a quantum mechanics/molecular mechanics free energy perturbation (QM/MM-FEP) method for modeling chemical reactions at metal-water interfaces. This novel solvation scheme combines planewave density function theory (DFT), periodic electrostatic embedded cluster method (PEECM) calculations using Gaussian-type orbitals, and classical molecular dynamics (MD) simulations to obtain a free energy description of a complex metal-water system. We derive a potential of mean force (PMF) of the reaction system within the QM/MM framework. A fixed-size, finite ensemble of MM conformations is used to permit precise evaluation of the PMF of QM coordinates and its gradient defined within this ensemble. Local conformations of adsorbed reaction moieties are optimized using sequential MD-sampling and QM-optimization steps. An approximate reaction coordinate is constructed using a number of interpolated states and the free energy difference between adjacent states is calculated using the QM/MM-FEP method. By avoiding on-the-fly QM calculations and by circumventing the challenges associated with statistical averaging during MD sampling, a computational speedup of multiple orders of magnitude is realized. The method is systematically validated against the results of ab initio QM calculations and demonstrated for C-C cleavage in double-dehydrogenated ethylene glycol on a Pt (111) model surface.

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.

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

Science.gov (United States)

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

2015-04-14

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

Atom Tunneling in the Hydroxylation Process of Taurine/α-Ketoglutarate Dioxygenase Identified by Quantum Mechanics/Molecular Mechanics Simulations.

Science.gov (United States)

Álvarez-Barcia, Sonia; Kästner, Johannes

2017-06-01

Taurine/α-ketoglutarate dioxygenase is one of the most studied α-ketoglutarate-dependent dioxygenases (αKGDs), involved in several biotechnological applications. We investigated the key step in the catalytic cycle of the αKGDs, the hydrogen transfer process, by a quantum mechanics/molecular mechanics approach (B3LYP/CHARMM22). Analysis of the charge and spin densities during the reaction demonstrates that a concerted mechanism takes place, where the H atom transfer happens simultaneously with the electron transfer from taurine to the Fe═O cofactor. We found the quantum tunneling of the hydrogen atom to increase the rate constant by a factor of 40 at 5 °C. As a consequence, a quite high kinetic isotope effect close to 60 is obtained, which is consistent with the experimental value.

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.

Relation between molecular electronic structure and nuclear spin-induced circular dichroism

DEFF Research Database (Denmark)

Štěpánek, Petr; Coriani, Sonia; Sundholm, Dage

2017-01-01

with spatially localized, high-resolution information. To survey the factors relating the molecular and electronic structure to the NSCD signal, we theoretically investigate NSCD of twenty structures of the four most common nucleic acid bases (adenine, guanine, thymine, cytosine). The NSCD signal correlates...... with the spatial distribution of the excited states and couplings between them, reflecting changes in molecular structure and conformation. This constitutes a marked difference to the nuclear magnetic resonance (NMR) chemical shift, which only reflects the local molecular structure in the ground electronic state....... The calculated NSCD spectra are rationalized by means of changes in the electronic density and by a sum-over-states approach, which allows to identify the contributions of the individual excited states. Two separate contributions to NSCD are identified and their physical origins and relative magnitudes...

Congenital heart disease and genetic syndromes: new insights into molecular mechanisms.

Science.gov (United States)

Calcagni, Giulio; Unolt, Marta; Digilio, Maria Cristina; Baban, Anwar; Versacci, Paolo; Tartaglia, Marco; Baldini, Antonio; Marino, Bruno

2017-09-01

Advances in genetics allowed a better definition of the role of specific genetic background in the etiology of syndromic congenital heart defects (CHDs). The identification of a number of disease genes responsible for different syndromes have led to the identification of several transcriptional regulators and signaling transducers and modulators that are critical for heart morphogenesis. Understanding the genetic background of syndromic CHDs allowed a better characterization of the genetic basis of non-syndromic CHDs. In this sense, the well-known association of typical CHDs in Down syndrome, 22q11.2 microdeletion and Noonan syndrome represent paradigms as chromosomal aneuploidy, chromosomal microdeletion and intragenic mutation, respectively. Area covered: For each syndrome the anatomical features, distinctive cardiac phenotype and molecular mechanisms are discussed. Moreover, the authors include recent genetic findings that may shed light on some aspects of still unclear molecular mechanisms of these syndromes. Expert commentary: Further investigations are needed to enhance the translational approach in the field of genetics of CHDs. When there is a well-established definition of genotype-phenotype (reverse medicine) and genotype-prognosis (predictive and personalized medicine) correlations, hopefully preventive medicine will make its way in this field. Subsequently a reduction will be achieved in the morbidity and mortality of children with CHDs.

Study on the mechanism of chiral recognition with molecularly imprinted polymers

International Nuclear Information System (INIS)

Lu Yan; Li Chenxi; Zhang Hesheng; Liu Xiaohang

2003-01-01

This study aimed at elucidating the chiral recognition mechanism with molecularly imprinted polymers (MIPs) in aqueous environment. The system used ethylene glycol dimethacrylate (EGDMA), methacrylic acid (MAA), and 4-L-phenylalanylamino-pyridine (4-L-PheNHPy) as the cross-linking monomer, functional monomer and template, respectively, to assemble the imprinted polymer. A self-assembly mechanism, which includes the pre-organizing functional monomers around template before polymerization process, was proposed. This mechanism was supported by 1 H NMR titration test. Interactions between functional monomer and template were observed using UV-Vis spectroscopy of solutions of these components as well. These studies indicated a 1:2 molecular complex dominantly formed between 4-L-PheNHPy and MAA. Association constant was estimated to be 97,000 M -2 . Based on these results, a model mainly involving two-spot interaction was proposed evolving from our reported concept of exact placement of functional group. Ionic interaction between the primary amino group of 4-L-PheNHPy and carboxylic acid group inside the microcavity on MIPs was believed to play a predominate role in the enantioselectivity as supported by the observation of the relationship between the retention factor of 4-L-PheNHPy and the pH of mobile phase. While thermodynamic study at different pH revealed that, the interaction between the pyridyl group of 4-L-PheNHPy and the carboxylic acid group on the MIPs is also strong, implying that it also plays a profound role in determining the highly chiral selectivity of MIPs

Molecular mechanisms of synaptic remodeling in alcoholism.

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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.

Azobenzene as a photoregulator covalently attached to RNA: a quantum mechanics/molecular mechanics-surface hopping dynamics study.

Science.gov (United States)

Mondal, Padmabati; Granucci, Giovanni; Rastädter, Dominique; Persico, Maurizio; Burghardt, Irene

2018-05-28

The photoregulation of nucleic acids by azobenzene photoswitches has recently attracted considerable interest in the context of emerging biotechnological applications. To understand the mechanism of photoinduced isomerisation and conformational control in these complex biological environments, we employ a Quantum Mechanics/Molecular Mechanics (QM/MM) approach in conjunction with nonadiabatic Surface Hopping (SH) dynamics. Two representative RNA-azobenzene complexes are investigated, both of which contain the azobenzene chromophore covalently attached to an RNA double strand via a β-deoxyribose linker. Due to the pronounced constraints of the local RNA environment, it is found that trans -to- cis isomerization is slowed down to a time scale of ∼10-15 picoseconds, in contrast to 500 femtoseconds in vacuo , with a quantum yield reduced by a factor of two. By contrast, cis -to- trans isomerization remains in a sub-picosecond regime. A volume-conserving isomerization mechanism is found, similarly to the pedal-like mechanism previously identified for azobenzene in solution phase. Strikingly, the chiral RNA environment induces opposite right-handed and left-handed helicities of the ground-state cis -azobenzene chromophore in the two RNA-azobenzene complexes, along with an almost completely chirality conserving photochemical pathway for these helical enantiomers.

How to recover Newtonian mechanics from non-relative quantum mechanics in limit ℎ→0

International Nuclear Information System (INIS)

Mei Shizhong

2001-01-01

It is assumed that when ℎ→0, correct non-relative quantum mechanics should be equivalent to Newtonian mechanics. Starting from this point, the authors slightly revised the widely accepted non-relative quantum mechanics such that the mechanics after modification is strictly equivalent to that before the modification when ℎ≠0, and equivalent to Newtonian mechanics in the limit ℎ→0. The significance lies in the possibility that if authors further postulate that corrected relative quantum mechanics is equivalent to Einstein's theory of relativity in the case ℎ→0, then authors may obtain different predictions from what produced by the former that will help to verify or improve it

Multi-level quantum mechanics theories and molecular mechanics study of the double-inversion mechanism of the F- + CH3I reaction in aqueous solution.

Science.gov (United States)

Liu, Peng; Zhang, Jingxue; Wang, Dunyou

2017-06-07

A double-inversion mechanism of the F - + CH 3 I reaction was discovered in aqueous solution using combined multi-level quantum mechanics theories and molecular mechanics. The stationary points along the reaction path show very different structures to the ones in the gas phase due to the interactions between the solvent and solute, especially strong hydrogen bonds. An intermediate complex, a minimum on the potential of mean force, was found to serve as a connecting-link between the abstraction-induced inversion transition state and the Walden-inversion transition state. The potentials of mean force were calculated with both the DFT/MM and CCSD(T)/MM levels of theory. Our calculated free energy barrier of the abstraction-induced inversion is 69.5 kcal mol -1 at the CCSD(T)/MM level of theory, which agrees with the one at 72.9 kcal mol -1 calculated using the Born solvation model and gas-phase data; and our calculated free energy barrier of the Walden inversion is 24.2 kcal mol -1 , which agrees very well with the experimental value at 25.2 kcal mol -1 in aqueous solution. The calculations show that the aqueous solution makes significant contributions to the potentials of mean force and exerts a big impact on the molecular-level evolution along the reaction pathway.

Asbestos-related diseases in automobile mechanics.

Science.gov (United States)

Ameille, Jacques; Rosenberg, Nicole; Matrat, Mireille; Descatha, Alexis; Mompoint, Dominique; Hamzi, Lounis; Atassi, Catherine; Vasile, Manuela; Garnier, Robert; Pairon, Jean-Claude

2012-01-01

Automobile mechanics have been exposed to asbestos in the past, mainly due to the presence of chrysotile asbestos in brakes and clutches. Despite the large number of automobile mechanics, little is known about the non-malignant respiratory diseases observed in this population. The aim of this retrospective multicenter study was to analyse the frequency of pleural and parenchymal abnormalities on high-resolution computed tomography (HRCT) in a population of automobile mechanics. The study population consisted of 103 automobile mechanics with no other source of occupational exposure to asbestos, referred to three occupational health departments in the Paris area for systematic screening of asbestos-related diseases. All subjects were examined by HRCT and all images were reviewed separately by two independent readers; who in the case of disagreement discussed until they reached agreement. Multiple logistic regression models were constructed to investigate factors associated with pleural plaques. Pleural plaques were observed in five cases (4.9%) and interstitial abnormalities consistent with asbestosis were observed in one case. After adjustment for age, smoking status, and a history of non-asbestos-related respiratory diseases, multiple logistic regression models showed a significant association between the duration of exposure to asbestos and pleural plaques. The asbestos exposure experienced by automobile mechanics may lead to pleural plaques. The low prevalence of non-malignant asbestos-related diseases, using a very sensitive diagnostic tool, is in favor of a low cumulative exposure to asbestos in this population of workers.

Asbestos-related diseases in automobile mechanics

Science.gov (United States)

Ameille, Jacques; Rosenberg, Nicole; Matrat, Mireille; Descatha, Alexis; Mompoint, Dominique; Hamzi, Lounis; Atassi, Catherine; Vasile, Manuela; Garnier, Robert; Pairon, Jean-Claude

2012-01-01

Purpose Automobile mechanics have been exposed to asbestos in the past, mainly due to the presence of chrysotile asbestos in brakes and clutches. Despite the large number of automobile mechanics, little is known about the non-malignant respiratory diseases observed in this population. The aim of this retrospective multicenter study was to analyze the frequency of pleural and parenchymal abnormalities on HRCT in a population of automobile mechanics. Methods The study population consisted of 103 automobile mechanics with no other source of occupational exposure to asbestos, referred to three occupational health departments in the Paris area for systematic screening of asbestos–related diseases. All subjects were examined by HRCT and all images were reviewed separately by two independent readers, with further consensus in the case of disagreement. Multiple logistic regression models were constructed to investigate factors associated with pleural plaques. Results Pleural plaques were observed in 5 cases (4.9%) and interstitial abnormalities consistent with asbestosis were observed in 1 case. After adjustment for age, smoking status, and a history of non-asbestos-related respiratory diseases, multiple logistic regression models showed a significant association between the duration of exposure to asbestos and pleural plaques. Conclusions The asbestos exposure experienced by automobile mechanics may lead to pleural plaques. The low prevalence of non-malignant asbestos-related diseases, using a very sensitive diagnostic tool, is in favor of a low cumulative exposure to asbestos in this population of workers. PMID:21965465

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.

The molecular mechanisms of signaling by cooperative assembly formation in innate immunity pathways.

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Vajjhala, Parimala R; Ve, Thomas; Bentham, Adam; Stacey, Katryn J; Kobe, Bostjan

2017-06-01

The innate immune system is the first line of defense against infection and responses are initiated by pattern recognition receptors (PRRs) that detect pathogen-associated molecular patterns (PAMPs). PRRs also detect endogenous danger-associated molecular patterns (DAMPs) that are released by damaged or dying cells. The major PRRs include the Toll-like receptor (TLR) family members, the nucleotide binding and oligomerization domain, leucine-rich repeat containing (NLR) family, the PYHIN (ALR) family, the RIG-1-like receptors (RLRs), C-type lectin receptors (CLRs) and the oligoadenylate synthase (OAS)-like receptors and the related protein cyclic GMP-AMP synthase (cGAS). The different PRRs activate specific signaling pathways to collectively elicit responses including the induction of cytokine expression, processing of pro-inflammatory cytokines and cell-death responses. These responses control a pathogenic infection, initiate tissue repair and stimulate the adaptive immune system. A central theme of many innate immune signaling pathways is the clustering of activated PRRs followed by sequential recruitment and oligomerization of adaptors and downstream effector enzymes, to form higher-order arrangements that amplify the response and provide a scaffold for proximity-induced activation of the effector enzymes. Underlying the formation of these complexes are co-operative assembly mechanisms, whereby association of preceding components increases the affinity for downstream components. This ensures a rapid immune response to a low-level stimulus. Structural and biochemical studies have given key insights into the assembly of these complexes. Here we review the current understanding of assembly of immune signaling complexes, including inflammasomes initiated by NLR and PYHIN receptors, the myddosomes initiated by TLRs, and the MAVS CARD filament initiated by RIG-1. We highlight the co-operative assembly mechanisms during assembly of each of these complexes. Copyright �

Cytotoxicity of polycations: Relationship of molecular weight and the hydrolytic theory of the mechanism of toxicity.

Science.gov (United States)

Monnery, Bryn D; Wright, Michael; Cavill, Rachel; Hoogenboom, Richard; Shaunak, Sunil; Steinke, Joachim H G; Thanou, Maya

2017-04-15

The mechanism of polycation cytotoxicity and the relationship to polymer molecular weight is poorly understood. To gain an insight into this important phenomenon a range of newly synthesised uniform (near monodisperse) linear polyethylenimines, commercially available poly(l-lysine)s and two commonly used PEI-based transfectants (broad 22kDa linear and 25kDa branched) were tested for their cytotoxicity against the A549 human lung carcinoma cell line. Cell membrane damage assays (LDH release) and cell viability assays (MTT) showed a strong relationship to dose and polymer molecular weight, and increasing incubation times revealed that even supposedly "non-toxic" low molecular weight polymers still damage cell membranes. The newly proposed mechanism of cell membrane damage is acid catalysed hydrolysis of lipidic phosphoester bonds, which was supported by observations of the hydrolysis of DOPC liposomes. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Studies on the molecular mechanism of nucleotide excision repair in human cells

International Nuclear Information System (INIS)

Friedberg, E.C.

1987-01-01

Studies in this laboratory have focused on attempts to define the mechanism of nucleotide excision repair of DNA in human cells, with a view to understanding the molecular pathogenesis of the disease XP. With the advent of recombinant DNA technology, they directed their efforts to the molecular cloning of human genes defective in XP, with a view to using the cloned genes to overexpress proteins of interest for biochemical investigations. Initial studies exploited the selectable phenotype of marked sensitivity to killing of XP group A cells by UV radiation and by other DNA damaging agents. However, except for a single report in 1982 there has been no reproducible demonstration of complementation of the UV sensitivity of XP cells by DNA-mediated transfection. The apparent difficulties associated with transfection of XP cells have been the subject of several recent studies. In view of the multiple problems associated with stable transfection of XP cells using total genomic DNA, they have embarked on an alternative strategy designed to facilitate the cloning of human XP genes. This strategy involves the transfer of single human chromosomes into XP cells and screening for this relatively high frequency event. The idea is to identify chromosomes on which particular XP genes reside and then to isolate non-complementing derivatives of these chromosomes so that highly enriched DNA pools containing genes of interest can be generated by employing one or more subtractive strategies

Cellular, molecular, and epigenetic mechanisms in non-associative conditioning: implications for pain and memory.

Science.gov (United States)

Rahn, Elizabeth J; Guzman-Karlsson, Mikael C; David Sweatt, J

2013-10-01

Sensitization is a form of non-associative conditioning in which amplification of behavioral responses can occur following presentation of an aversive or noxious stimulus. Understanding the cellular and molecular underpinnings of sensitization has been an overarching theme spanning the field of learning and memory as well as that of pain research. In this review we examine how sensitization, both in the context of learning as well as pain processing, shares evolutionarily conserved behavioral, cellular/synaptic, and epigenetic mechanisms across phyla. First, we characterize the behavioral phenomenon of sensitization both in invertebrates and vertebrates. Particular emphasis is placed on long-term sensitization (LTS) of withdrawal reflexes in Aplysia following aversive stimulation or injury, although additional invertebrate models are also covered. In the context of vertebrates, sensitization of mammalian hyperarousal in a model of post-traumatic stress disorder (PTSD), as well as mammalian models of inflammatory and neuropathic pain is characterized. Second, we investigate the cellular and synaptic mechanisms underlying these behaviors. We focus our discussion on serotonin-mediated long-term facilitation (LTF) and axotomy-mediated long-term hyperexcitability (LTH) in reduced Aplysia systems, as well as mammalian spinal plasticity mechanisms of central sensitization. Third, we explore recent evidence implicating epigenetic mechanisms in learning- and pain-related sensitization. This review illustrates the fundamental and functional overlay of the learning and memory field with the pain field which argues for homologous persistent plasticity mechanisms in response to sensitizing stimuli or injury across phyla. Copyright © 2013 Elsevier Inc. All rights reserved.

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

Molecular mechanism of ligand recognition by membrane transport protein, Mhp1

Science.gov (United States)

Simmons, Katie J; Jackson, Scott M; Brueckner, Florian; Patching, Simon G; Beckstein, Oliver; Ivanova, Ekaterina; Geng, Tian; Weyand, Simone; Drew, David; Lanigan, Joseph; Sharples, David J; Sansom, Mark SP; Iwata, So; Fishwick, Colin WG; Johnson, A Peter; Cameron, Alexander D; Henderson, Peter JF

2014-01-01

The hydantoin transporter Mhp1 is a sodium-coupled secondary active transport protein of the nucleobase-cation-symport family and a member of the widespread 5-helix inverted repeat superfamily of transporters. The structure of Mhp1 was previously solved in three different conformations providing insight into the molecular basis of the alternating access mechanism. Here, we elucidate detailed events of substrate binding, through a combination of crystallography, molecular dynamics, site-directed mutagenesis, biochemical/biophysical assays, and the design and synthesis of novel ligands. We show precisely where 5-substituted hydantoin substrates bind in an extended configuration at the interface of the bundle and hash domains. They are recognised through hydrogen bonds to the hydantoin moiety and the complementarity of the 5-substituent for a hydrophobic pocket in the protein. Furthermore, we describe a novel structure of an intermediate state of the protein with the external thin gate locked open by an inhibitor, 5-(2-naphthylmethyl)-L-hydantoin, which becomes a substrate when leucine 363 is changed to an alanine. We deduce the molecular events that underlie acquisition and transport of a ligand by Mhp1. PMID:24952894

Revealing Atomic-Level Mechanisms of Protein Allostery with Molecular Dynamics Simulations.

Directory of Open Access Journals (Sweden)

Samuel Hertig

2016-06-01

Full Text Available Molecular dynamics (MD simulations have become a powerful and popular method for the study of protein allostery, the widespread phenomenon in which a stimulus at one site on a protein influences the properties of another site on the protein. By capturing the motions of a protein's constituent atoms, simulations can enable the discovery of allosteric binding sites and the determination of the mechanistic basis for allostery. These results can provide a foundation for applications including rational drug design and protein engineering. Here, we provide an introduction to the investigation of protein allostery using molecular dynamics simulation. We emphasize the importance of designing simulations that include appropriate perturbations to the molecular system, such as the addition or removal of ligands or the application of mechanical force. We also demonstrate how the bidirectional nature of allostery-the fact that the two sites involved influence one another in a symmetrical manner-can facilitate such investigations. Through a series of case studies, we illustrate how these concepts have been used to reveal the structural basis for allostery in several proteins and protein complexes of biological and pharmaceutical interest.

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

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.

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...

From wave mechanics to quantum chemistry

International Nuclear Information System (INIS)

Daudel, R.

1996-01-01

The origin of wave mechanics, which is now called quantum mechanics, is evoked. The main stages of the birth of quantum chemistry are related as resulting from the application of quantum mechanics to the study of molecular properties and chemical reactions. (author). 14 refs

Benchmarking Quantum Mechanics/Molecular Mechanics (QM/MM) Methods on the Thymidylate Synthase-Catalyzed Hydride Transfer.

Science.gov (United States)

Świderek, Katarzyna; Arafet, Kemel; Kohen, Amnon; Moliner, Vicent

2017-03-14

Given the ubiquity of hydride-transfer reactions in enzyme-catalyzed processes, identifying the appropriate computational method for evaluating such biological reactions is crucial to perform theoretical studies of these processes. In this paper, the hydride-transfer step catalyzed by thymidylate synthase (TSase) is studied by examining hybrid quantum mechanics/molecular mechanics (QM/MM) potentials via multiple semiempirical methods and the M06-2X hybrid density functional. Calculations of protium and tritium transfer in these reactions across a range of temperatures allowed calculation of the temperature dependence of kinetic isotope effects (KIE). Dynamics and quantum-tunneling effects are revealed to have little effect on the reaction rate, but are significant in determining the KIEs and their temperature dependence. A good agreement with experiments is found, especially when computed for RM1/MM simulations. The small temperature dependence of quantum tunneling corrections and the quasiclassical contribution term cancel each other, while the recrossing transmission coefficient seems to be temperature-independent over the interval of 5-40 °C.

Spectroscopical analysis and molecular mechanics calculation of 8,9-Seco-lanostane; Analise espectroscopica e calculos de mecanica molecular de 8,9-seco-lanostanos

Energy Technology Data Exchange (ETDEWEB)

Rehder, Vera G; Fujiwara, Fred Y; Marsaioli, Anita J [Universidade Estadual de Campinas, SP (Brazil). Inst. de Quimica

1992-12-31

8.9-Seco-lanostane derivatives have been synthesized visualizing their application as intermediates in chiral building block syntheses and we are here presenting their spectroscopy analyses and MM2 molecular mechanic calculations. (author) 5 refs., 4 figs.

Caenorhabditis elegans as a Model to Study the Molecular and Genetic Mechanisms of Drug Addiction

Science.gov (United States)

Engleman, Eric A.; Katner, Simon N.; Neal-Beliveau, Bethany S.

2016-01-01

Drug addiction takes a massive toll on society. Novel animal models are needed to test new treatments and understand the basic mechanisms underlying addiction. Rodent models have identified the neurocircuitry involved in addictive behavior and indicate that rodents possess some of the same neurobiologic mechanisms that mediate addiction in humans. Recent studies indicate that addiction is mechanistically and phylogenetically ancient and many mechanisms that underlie human addiction are also present in invertebrates. The nematode Caenorhabditis elegans has conserved neurobiologic systems with powerful molecular and genetic tools and a rapid rate of development that enables cost-effective translational discovery. Emerging evidence suggests that C. elegans is an excellent model to identify molecular mechanisms that mediate drug-induced behavior and potential targets for medications development for various addictive compounds. C. elegans emit many behaviors that can be easily quantitated including some that involve interactions with the environment. Ethanol (EtOH) is the best-studied drug-of-abuse in C. elegans and at least 50 different genes/targets have been identified as mediating EtOH’s effects and polymorphisms in some orthologs in humans are associated with alcohol use disorders. C. elegans has also been shown to display dopamine and cholinergic system–dependent attraction to nicotine and demonstrate preference for cues previously associated with nicotine. Cocaine and methamphetamine have been found to produce dopamine-dependent reward-like behaviors in C. elegans. These behavioral tests in combination with genetic/molecular manipulations have led to the identification of dozens of target genes/systems in C. elegans that mediate drug effects. The one target/gene identified as essential for drug-induced behavioral responses across all drugs of abuse was the cat-2 gene coding for tyrosine hydroxylase, which is consistent with the role of dopamine

Caenorhabditis elegans as a Model to Study the Molecular and Genetic Mechanisms of Drug Addiction.

Science.gov (United States)

Engleman, Eric A; Katner, Simon N; Neal-Beliveau, Bethany S

2016-01-01

Drug addiction takes a massive toll on society. Novel animal models are needed to test new treatments and understand the basic mechanisms underlying addiction. Rodent models have identified the neurocircuitry involved in addictive behavior and indicate that rodents possess some of the same neurobiologic mechanisms that mediate addiction in humans. Recent studies indicate that addiction is mechanistically and phylogenetically ancient and many mechanisms that underlie human addiction are also present in invertebrates. The nematode Caenorhabditis elegans has conserved neurobiologic systems with powerful molecular and genetic tools and a rapid rate of development that enables cost-effective translational discovery. Emerging evidence suggests that C. elegans is an excellent model to identify molecular mechanisms that mediate drug-induced behavior and potential targets for medications development for various addictive compounds. C. elegans emit many behaviors that can be easily quantitated including some that involve interactions with the environment. Ethanol (EtOH) is the best-studied drug-of-abuse in C. elegans and at least 50 different genes/targets have been identified as mediating EtOH's effects and polymorphisms in some orthologs in humans are associated with alcohol use disorders. C. elegans has also been shown to display dopamine and cholinergic system-dependent attraction to nicotine and demonstrate preference for cues previously associated with nicotine. Cocaine and methamphetamine have been found to produce dopamine-dependent reward-like behaviors in C. elegans. These behavioral tests in combination with genetic/molecular manipulations have led to the identification of dozens of target genes/systems in C. elegans that mediate drug effects. The one target/gene identified as essential for drug-induced behavioral responses across all drugs of abuse was the cat-2 gene coding for tyrosine hydroxylase, which is consistent with the role of dopamine neurotransmission

A parametric study of surface roughness and bonding mechanisms of aluminum alloys with epoxies: a molecular dynamics simulation

Science.gov (United States)

Timilsina, Rajendra; Termaath, Stephanie

The marine environment is highly aggressive towards most materials. However, aluminium-magnesium alloys (Al-Mg, specifically, 5xxx series) have exceptionally long service life in such aggressive marine environments. For instance, an Al-Mg alloy, AA5083, is extensively used in naval structures because of its good mechanical strength, formability, seawater corrosion resistance and weldability. However, bonding mechanisms of these alloys with epoxies in a rough surface environment are not fully understood yet. It requires a rigorous investigation at molecular or atomic levels. We performed a molecular dynamics simulation to study an adherend surface preparation and surface bonding mechanisms of Al-Mg alloy (AA5083) with different epoxies by developing several computer models. Various distributions of surface roughness are introduced in the models and performed molecular dynamics simulations. Formation of a beta phase (Al3Mg2) , microstructures, bonding energies at the interface, bonding strengths and durability are investigated. Office of Naval Research.

Understanding the Catalytic Mechanism and the Nature of the Transition State of an Attractive Drug-Target Enzyme (Shikimate Kinase) by Quantum Mechanical/Molecular Mechanical (QM/MM) Studies.

Science.gov (United States)

Yao, Jianzhuang; Wang, Xia; Luo, Haixia; Gu, Pengfei

2017-11-16

Shikimate kinase (SK) is the fifth bacterial enzyme involved in the shikimate pathway for biosynthesis of life-indispensable components, such as aromatic amino acids. The absence of the shikimate pathway in humans makes SK an attractive target for the rational design of drugs aimed at pathogenesis bacteria, such as Mycobacterium tuberculosis and Helicobacter pylori. However, an effective inhibitor of SK (e.g., a transition-state analogue) is still not available on the market due, at least in part, to a lack of knowledge on the catalytic mechanism and the nature of the rate-limiting transition state. Herein, quantum mechanical/molecular mechanical (QM/MM) reaction coordinate, molecular dynamics (MD), and free-energy simulations have been performed to answer these questions. The results presented herein demonstrate that the phosphoryl-transfer process, which is the rate-limiting step of SK-catalyzed phosphorylation of shikimic acid (SKM), is a concerted one-step reaction proceeding through a loose transition state. The computational results agree well with those of experimental studies, specifically NMR results, X-ray crystal structure observation, and activation free-energy barrier. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

On uncertainty relations in quantum mechanics

International Nuclear Information System (INIS)

Ignatovich, V.K.

2004-01-01

Uncertainty relations (UR) are shown to have nothing specific for quantum mechanics (QM), being the general property valid for the arbitrary function. A wave function of a particle simultaneously having a precisely defined position and momentum in QM is demonstrated. Interference on two slits in a screen is shown to exist in classical mechanics. A nonlinear classical system of equations replacing the QM Schroedinger equation is suggested. This approach is shown to have nothing in common with the Bohm mechanics

Biotechnological Wood Modification with Selective White-Rot Fungi and Its Molecular Mechanisms

Directory of Open Access Journals (Sweden)

Cornelia Gradinger

2007-01-01

Full Text Available Microbial mechanisms of lignin degradation may be utilised for solid-state fermentations other than biopulping, during which the selective conversion of lignin is required. The current paper reviews current work into selective lignin conversion, with emphasis on the contributions made by our research group, which consists of researchers from five different laboratories. Three of them cooperate within Wood K plus. The recent research of this group has focussed on fermentations utilising the unique metabolism of selective white-rot fungi to modify wood surfaces during relatively short fermentation times of less than one week and on research into the molecular mechanisms causing these modifications. Lignin degradation by selective fungi (e.g. Ceriporiopsis subvermispora and species of the genus Phlebia on the wood surfaces was significant after three days. After seven days the overall lignin content of spruce wood shavings was reduced by more than 3.5 %. Lignin loss was accompanied by an increase of extractable substances. To evaluate small changes and to trace the fungal modification processes, Fourier transform infrared spectroscopic (FTIR techniques and electron paramagnetic resonance (EPR spectroscopy were applied and adapted. The spectra recorded in the near infrared region (FT-NIR turned out to be very useful for kinetic studies of the biopulping/biomodification processes and a good method to evaluate the capabilities of fungi to modify wood surfaces within this short period.

Molecular mechanisms underlying mancozeb-induced inhibition of TNF-alpha production

International Nuclear Information System (INIS)

Corsini, Emanuela; Viviani, Barbara; Birindelli, Sarah; Gilardi, Federica; Torri, Anna; Codeca, Ilaria; Lucchi, Laura; Bartesaghi, Stefano; Galli, Corrado L.; Marinovich, Marina; Colosio, Claudio

2006-01-01

Mancozeb, a polymeric complex of manganese ethylenebisdithiocarbamate with zinc salt, is widely used in agriculture as fungicide. Literature data indicate that ethylenebisdithiocarbamates (EBDTCs) may have immunomodulatory effects in humans. We have recently found in agricultural workers occupationally exposed to the fungicide mancozeb a statistically significant decrease in lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF) production in leukocytes. TNF is an essential proinflammatory cytokine whose production is normally stimulated during an infection. The purpose of this work was to establish an in vitro model reflecting in vivo data and to characterize the molecular mechanism of action of mancozeb. The human promyelocytic cell line THP-1 was used as in vitro model to study the effects of mancozeb and its main metabolite ethylenthiourea (ETU) on LPS-induced TNF release. Mancozeb, but not ETU, at non-cytotoxic concentrations (1-100 μg/ml), induced a dose- and time-dependent inhibition of LPS-induced TNF release, reflecting in vivo data. The modulatory effect observed was not limited to mancozeb but also other EBDTCs, namely zineb and ziram, showed similar inhibitory effects. Mancozeb must be added before or simultaneously to LPS in order to observe the effect, indicating that it acts on early events triggered by LPS. It is known that nuclear factor-κB (NF-κB) tightly regulates TNF transcription. We could demonstrate that mancozeb, modulating LPS-induced reactive oxygen species generation, prevented IκB degradation and NF-κB nuclear translocation, which in turn resulted in decreased TNF production. To further understand the mechanism of the effect of mancozeb on TNF transcription, THP-1 cells were transfected with NF-κB promoter-luciferase construct, and the effect of mancozeb on luciferase activity was measured. Cells transfected with promoter constructs containing κB site showed decreased LPS-induced luciferase activity relative to control

Molecular Mechanisms of Liver Fibrosis in HIV/HCV Coinfection

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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.

The effect of fasting on the important molecular mechanisms related to cancer treatment

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Vahideh Keyvani

2014-11-01

Full Text Available Fasting does have remarkable benefits in the treatment of cancer and another diseases such as metabolic syndrome, diabetes, and a multitude of other chronic diseases. It has been determined that fasting could play an important role during cancer treatment and progression via the regulation of insulin-like growth factor-1 (IGF-1 as well as other growth factors. Also, it has been shown that fasting would enhance the chemotherapy effect in cancer patients, selectively protects normal cells and organisms from chemotherapy toxicity, while simultaneously sensitizing tumors. In this article, we discuss the benefits of fasting in the treatment of cancer through several different molecular pathways.

Molecular Dynamics Simulation of Nanoindentation-induced Mechanical Deformation and Phase Transformation in Monocrystalline Silicon

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Jian Sheng-Rui

2008-01-01

Full Text Available AbstractThis work presents the molecular dynamics approach toward mechanical deformation and phase transformation mechanisms of monocrystalline Si(100 subjected to nanoindentation. We demonstrate phase distributions during loading and unloading stages of both spherical and Berkovich nanoindentations. By searching the presence of the fifth neighboring atom within a non-bonding length, Si-III and Si-XII have been successfully distinguished from Si-I. Crystallinity of this mixed-phase was further identified by radial distribution functions.

Mechanism by which DHA inhibits the aggregation of KLVFFA peptides: A molecular dynamics study

Science.gov (United States)

Zhou, Hong; Liu, Shengtang; Shao, Qiwen; Ma, Dongfang; Yang, Zaixing; Zhou, Ruhong

2018-03-01

Docosahexaenoic acid (DHA) is one of the omega-3 polyunsaturated fatty acids, which has shown promising applications in lowering Aβ peptide neurotoxicity in vitro by preventing aggregation of Aβ peptides and relieving accumulation of Aβ fibrils. Unfortunately, the underlying molecular mechanisms of how DHA interferes with the aggregation of Aβ peptides remain largely enigmatic. Herein, aggregation behaviors of amyloid-β(Aβ)16-21 peptides (KLVFFA) with or without the presence of a DHA molecule were comparatively studied using extensive all-atom molecular dynamics simulations. We found that DHA could effectively suppress the aggregation of KLVFFA peptides by redirecting peptides to unstructured oligomers. The highly hydrophobic and flexible nature of DHA made it randomly but tightly entangled with Leu-17, Phe-19, and Phe-20 residues to form unstructured but stable complexes. These lower-ordered unstructured oligomers could eventually pass through energy barriers to form ordered β-sheet structures through large conformational fluctuations. This study depicts a microscopic picture for understanding the role and mechanism of DHA in inhibition of aggregation of Aβ peptides, which is generally believed as one of the important pathogenic mechanisms of Alzheimer's disease.

Molecular Level Investigation of Staphylococci’s Resistance Mechanisms to Antibiotics

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Lavinia Lorena PRUTEANU

2017-09-01

Full Text Available Polymerase chain reaction (PCR techniques development allows elaboration of many assays for identification of bacteria’s resistance mechanisms to antibiotics. Following this idea, the results of molecular level investigation of bacteria’s resistance mechanisms to antibiotics may give many opportunities to find more rapid methods for identifying the genes which are responsible for antibiotic resistance induction. The aim of this study was to investigate antibiotic resistance genes in Staphylococcus bacteria on molecular level. As classes of antibiotics it was used macrolides-lincosamides-streptogramin B (MLSB and beta-lactams. In the proposed study the bacterial strains are represented by 50 isolates of Staphylococcus. The bacterial strains were analyzed using polymerase chain reaction to identify the nuc, tuf, tst, sea, pathogenic activity genes. After this, the bacteria were tested for ermA, ermB, ermC genes and for mecA, femA which are involved in resistance to macrolides, lincosamides, streptogramin B and to beta-lactams, respectively. The presence or the absence of these genes confirms that tested strains are resistant to specific antibiotic or not. Bacteria pathogenic activity was emphasized by genes as follows: sea (enterotoxin which was found at all isolates, tst (toxic shock toxin gene was not detected in any of isolates and tuf gene (elongation factor was obtained with one pair of primers. Resistance to beta-lactams was evidenced by the presence of mecA in all isolates and femA in some strains. Each of ermC, ermA and ermB, macrolides-lincosamides-streptogramin B resistance genes, were detected.

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

Science.gov (United States)

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

2016-07-01

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

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

Science.gov (United States)

Wu, Chia-Chou; Chen, Bor-Sen

2016-01-01

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

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

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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.

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.

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

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)

Left ventricular remodeling in the post-infarction heart: a review of cellular, molecular mechanisms, and therapeutic modalities.

Science.gov (United States)

Gajarsa, Jason J; Kloner, Robert A

2011-01-01

As more patients survive myocardial infarctions, the incidence of heart failure increases. After an infarction, the human heart undergoes a series of structural changes, which are governed by cellular and molecular mechanisms in a pathological metamorphosis termed "remodeling." This review will discuss the current developments in our understanding of these molecular and cellular events in remodeling and the various pharmacological, cellular and device therapies used to treat, and potentially retard, this condition. Specifically, this paper will examine the neurohormonal activity of the renin-angiotensin-aldosterone axis and its molecular effects on the heart. The emerging understanding of the extra-cellular matrix and the various active molecules within it, such as the matrix metalloproteinases, elicits new appreciation for their role in cardiac remodeling and as possible future therapeutic targets. Cell therapy with stem cells is another recent therapy with great potential in improving post-infarcted hearts. Lastly, the cellular and molecular effects of left ventricular assist devices on remodeling will be reviewed. Our increasing knowledge of the cellular and molecular mechanisms underlying cardiac remodeling enables us not only to better understand how our more successful therapies, like angiotensin-converting enzyme inhibitors, work, but also to explore new therapies of the future.

Quantum mechanical study of molecular collisions at ultra-low energy: applications to alkali and alkaline-earth systems

International Nuclear Information System (INIS)

Quemener, G.

2006-10-01

In order to investigate the collisional processes which occur during the formation of molecular Bose-Einstein condensates, a time-independent quantum mechanical formalism, based on hyperspherical coordinates, has been applied to the study of atom-diatom dynamics at ultra-low energies. We present theoretical results for three alkali systems, each composed of lithium, sodium or potassium atoms, and for an alkaline-earth system composed of calcium atoms. We also study dynamics at large and positive atom-atom scattering length. Evidence for the suppression of inelastic processes in a fermionic system is given, as well as a linear relation between the atom-diatom scattering length and the atom-atom scattering length. (author)

[Interactions of DNA bases with individual water molecules. Molecular mechanics and quantum mechanics computation results vs. experimental data].

Science.gov (United States)

Gonzalez, E; Lino, J; Deriabina, A; Herrera, J N F; Poltev, V I

2013-01-01

To elucidate details of the DNA-water interactions we performed the calculations and systemaitic search for minima of interaction energy of the systems consisting of one of DNA bases and one or two water molecules. The results of calculations using two force fields of molecular mechanics (MM) and correlated ab initio method MP2/6-31G(d, p) of quantum mechanics (QM) have been compared with one another and with experimental data. The calculations demonstrated a qualitative agreement between geometry characteristics of the most of local energy minima obtained via different methods. The deepest minima revealed by MM and QM methods correspond to water molecule position between two neighbor hydrophilic centers of the base and to the formation by water molecule of hydrogen bonds with them. Nevertheless, the relative depth of some minima and peculiarities of mutual water-base positions in' these minima depend on the method used. The analysis revealed insignificance of some differences in the results of calculations performed via different methods and the importance of other ones for the description of DNA hydration. The calculations via MM methods enable us to reproduce quantitatively all the experimental data on the enthalpies of complex formation of single water molecule with the set of mono-, di-, and trimethylated bases, as well as on water molecule locations near base hydrophilic atoms in the crystals of DNA duplex fragments, while some of these data cannot be rationalized by QM calculations.

Exploring the Interaction Mechanism Between Cyclopeptide DC3 and Androgen Receptor Using Molecular Dynamics Simulations and Free Energy Calculations

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Huimin Zhang

2018-04-01

Full Text Available Androgen receptor (AR is a key target in the discovery of anti-PCa (Prostate Cancer drugs. Recently, a novel cyclopeptide Diffusa Cyclotide-3 (DC3, isolated from Hedyotisdiffusa, has been experimentally demonstrated to inhibit the survival and growth of LNCap cells, which typically express T877A-mutated AR, the most frequently detected point mutation of AR in castration-resistant prostate cancer (CRPC. But the interaction mechanism between DC3 and AR is not clear. Here in this study we aim to explore the possible binding mode of DC3 to T877A-mutated AR from molecular perspective. Firstly, homology modeling was employed to construct the three-dimensional structure of the cyclopeptide DC3 using 2kux.1.A as the template. Then molecular docking, molecular dynamics (MD simulations, and molecular mechanics/generalized Born surface area (MM-GBSA methods were performed to determine the bind site and explore the detailed interaction mechanism of DC3-AR complex. The obtained results suggested that the site formed by H11, loop888-893, and H12 (site 2 was the most possible position of DC3 binding to AR. Besides, hydrogen bonds, hydrophobic, and electrostatic interactions play dominant roles in the recognition and combination of DC3-AR complex. The essential residues dominant in each interaction were specifically revealed. This work facilitates our understanding of the interaction mechanism of DC3 binding to AR at the molecular level and contributes to the rational cyclopeptide drug design for prostate cancer.

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.

Improvements in or relating to rotary drive mechanisms

International Nuclear Information System (INIS)

Lodge, J.A.

1981-01-01

The invention relates to rotary drive mechanisms and relates especially, though not exclusively, to such mechanisms for use in rotating a source of penetrating radiation, such as X-radiation, in steps around a body, in the course of a computerised tomographic (CAT) examination of the body. (author)

The buzz on caffeine in invertebrates: effects on behavior and molecular mechanisms

OpenAIRE

Mustard, Julie A.

2013-01-01

A number of recent studies from as diverse fields as plant-pollinator interactions, analyses of caffeine as an environmental pollutant, and the ability of caffeine to provide protection against neurodegenerative diseases have generated interest in understanding the actions of caffeine in invertebrates. This review summarizes what is currently known about the effects of caffeine on behavior and its molecular mechanisms in invertebrates. Caffeine appears to have similar effects on locomotion an...

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

KAUST Repository

Jiang, Hanlun

2016-12-06

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

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

Science.gov (United States)

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

2017-01-01

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

Molecular Mechanism of the Early Stage of Amyloidogenic Hexapeptides (NFGAIL) Aggregation

International Nuclear Information System (INIS)

Shi Bi-Yun; Zhou Bo; Cai Zhuo-Wei; Yang Zai-Xing; Xiu Peng

2013-01-01

Peptides/proteins aggregation can give rise to pathological conditions of many human diseases. Small partially ordered oligomers formed in the early stage of aggregation, rather than mature fibrils, are thought to be the main toxicity agent for the living cell. Thus, understanding the pathway and the underlying physical mechanism in the early stage of aggregation is very important for prevention and treatment of these protein functional diseases. Herein we use all-atom molecular dynamics simulations to study the aggregation of four NFGAIL hexapeptides (NFGAIL peptide is a core segment of human islet amyloid polypeptide and exhibits similar aggregation kinetics as the full-length polypeptide). We observe that the peptide monomers in water mainly adopt non-structural coil configurations; the four peptides which are randomly placed in water aggregate spontaneously to partially ordered oligomer (β-sheets) through dimerization or trimerization, with the dimerization predominated. Both parallel and anti-parallel β-sheets are observed. The hydrophobic interactions drive the initial peptides associations, and the subsequent conformational fluctuations promote the formation of more hydrogen bonds between the dangling hydrogen sites in the main chains of peptides. (interdisciplinary physics and related areas of science and technology)

Investigation of the CH3Cl + CN(-) reaction in water: Multilevel quantum mechanics/molecular mechanics study.

Science.gov (United States)

Xu, Yulong; Zhang, Jingxue; Wang, Dunyou

2015-06-28

The CH3Cl + CN(-) reaction in water was studied using a multilevel quantum mechanics/molecular mechanics (MM) method with the multilevels, electrostatic potential, density functional theory (DFT) and coupled-cluster single double triple (CCSD(T)), for the solute region. The detailed, back-side attack SN2 reaction mechanism was mapped along the reaction pathway. The potentials of mean force were calculated under both the DFT and CCSD(T) levels for the reaction region. The CCSD(T)/MM level of theory presents a free energy activation barrier height at 20.3 kcal/mol, which agrees very well with the experiment value at 21.6 kcal/mol. The results show that the aqueous solution has a dominant role in shaping the potential of mean force. The solvation effect and the polarization effect together increase the activation barrier height by ∼11.4 kcal/mol: the solvation effect plays a major role by providing about 75% of the contribution, while polarization effect only contributes 25% to the activation barrier height. Our calculated potential of mean force under the CCSD(T)/MM also has a good agreement with the one estimated using data from previous gas-phase studies.

Mechanical properties of pillared-graphene nanostructures using molecular dynamics simulations

International Nuclear Information System (INIS)

Wang, Chih-Hao; Fang, Te-Hua; Sun, Wei-Li

2014-01-01

The deformation behaviour and mechanical properties of three-dimensional (3D) pillared graphene are investigated using molecular dynamics simulations. The Tersoff–Brenner many-body potential model is employed to evaluate the interactions between 3D pillared-graphene carbon atoms and nanotube carbons. The Lennard-Jones potential model is used to compute the interactions between a conical indenter and 3D pillared-graphene carbon atoms. The effects of the size and geometric structure of 3D pillared-graphene are evaluated in terms of the indentation force and contact stiffness. The simulation results for an armchair nanotube of 3D pillared graphene show that the contact stiffness increases with increasing chiral vector of the 3D-pillared graphene. However, the adhesive force sharply decreases with increasing chiral vector of the 3D-pillared graphene. A zigzag nanotube of 3D-pillared graphene exhibits better mechanical properties compared with those of the armchair nanotube. (paper)

Ab initio molecular-orbital study on electron correlation effects in CuO6 clusters relating to high-Tc superconductivity

International Nuclear Information System (INIS)

Yamamoto, S.; Yamaguchi, K.; Nasu, K.

1990-01-01