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Sample records for family molecular mechanism

  1. Elucidating the Activation Mechanism of the Insulin-Family Proteins with Molecular Dynamics Simulations.

    Science.gov (United States)

    Papaioannou, Anastasios; Kuyucak, Serdar; Kuncic, Zdenka

    2016-01-01

    The insulin-family proteins bind to their own receptors, but insulin-like growth factor II (IGF-II) can also bind to the A isoform of the insulin receptor (IR-A), activating unique and alternative signaling pathways from those of insulin. Although extensive studies of insulin have revealed that its activation is associated with the opening of the B chain-C terminal (BC-CT), the activation mechanism of the insulin-like growth factors (IGFs) still remains unknown. Here, we present the first comprehensive study of the insulin-family proteins comparing their activation process and mechanism using molecular dynamics simulations to reveal new insights into their specificity to the insulin receptor. We have found that all the proteins appear to exhibit similar stochastic dynamics in their conformational change to an active state. For the IGFs, our simulations show that activation involves two opening locations: the opening of the BC-CT section away from the core, similar to insulin; and the additional opening of the BC-CT section away from the C domain. Furthermore, we have found that these two openings occur simultaneously in IGF-I, but not in IGF-II, where they can occur independently. This suggests that the BC-CT section and the C domain behave as a unified domain in IGF-I, but as two independent domains in IGF-II during the activation process, implying that the IGFs undergo different activation mechanisms for receptor binding. The probabilities of the active and inactive states of the proteins suggest that IGF-II is hyperactive compared to IGF-I. The hinge residue and the hydrophobic interactions in the core are found to play a critical role in the stability and activity of IGFs. Overall, our simulations have elucidated the crucial differences and similarities in the activation mechanisms of the insulin-family proteins, providing new insights into the molecular mechanisms responsible for the observed differences between IGF-I and IGF-II in receptor binding.

  2. Elucidating the Activation Mechanism of the Insulin-Family Proteins with Molecular Dynamics Simulations

    Science.gov (United States)

    Papaioannou, Anastasios; Kuyucak, Serdar; Kuncic, Zdenka

    2016-01-01

    The insulin-family proteins bind to their own receptors, but insulin-like growth factor II (IGF-II) can also bind to the A isoform of the insulin receptor (IR-A), activating unique and alternative signaling pathways from those of insulin. Although extensive studies of insulin have revealed that its activation is associated with the opening of the B chain-C terminal (BC-CT), the activation mechanism of the insulin-like growth factors (IGFs) still remains unknown. Here, we present the first comprehensive study of the insulin-family proteins comparing their activation process and mechanism using molecular dynamics simulations to reveal new insights into their specificity to the insulin receptor. We have found that all the proteins appear to exhibit similar stochastic dynamics in their conformational change to an active state. For the IGFs, our simulations show that activation involves two opening locations: the opening of the BC-CT section away from the core, similar to insulin; and the additional opening of the BC-CT section away from the C domain. Furthermore, we have found that these two openings occur simultaneously in IGF-I, but not in IGF-II, where they can occur independently. This suggests that the BC-CT section and the C domain behave as a unified domain in IGF-I, but as two independent domains in IGF-II during the activation process, implying that the IGFs undergo different activation mechanisms for receptor binding. The probabilities of the active and inactive states of the proteins suggest that IGF-II is hyperactive compared to IGF-I. The hinge residue and the hydrophobic interactions in the core are found to play a critical role in the stability and activity of IGFs. Overall, our simulations have elucidated the crucial differences and similarities in the activation mechanisms of the insulin-family proteins, providing new insights into the molecular mechanisms responsible for the observed differences between IGF-I and IGF-II in receptor binding. PMID

  3. Molecular characterization of a family 5 glycoside hydrolase suggests an induced-fit enzymatic mechanism.

    Science.gov (United States)

    Liberato, Marcelo V; Silveira, Rodrigo L; Prates, Érica T; de Araujo, Evandro A; Pellegrini, Vanessa O A; Camilo, Cesar M; Kadowaki, Marco A; Neto, Mario de O; Popov, Alexander; Skaf, Munir S; Polikarpov, Igor

    2016-04-01

    Glycoside hydrolases (GHs) play fundamental roles in the decomposition of lignocellulosic biomaterials. Here, we report the full-length structure of a cellulase from Bacillus licheniformis (BlCel5B), a member of the GH5 subfamily 4 that is entirely dependent on its two ancillary modules (Ig-like module and CBM46) for catalytic activity. Using X-ray crystallography, small-angle X-ray scattering and molecular dynamics simulations, we propose that the C-terminal CBM46 caps the distal N-terminal catalytic domain (CD) to establish a fully functional active site via a combination of large-scale multidomain conformational selection and induced-fit mechanisms. The Ig-like module is pivoting the packing and unpacking motions of CBM46 relative to CD in the assembly of the binding subsite. This is the first example of a multidomain GH relying on large amplitude motions of the CBM46 for assembly of the catalytically competent form of the enzyme.

  4. Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms.

    Science.gov (United States)

    Yeo, Giles S H; Lank, Emma J; Farooqi, I Sadaf; Keogh, Julia; Challis, Benjamin G; O'Rahilly, Stephen

    2003-03-01

    Mutations in the melanocortin-4 receptor gene (MC4R) represent the commonest monogenic cause of human obesity. However, information regarding the precise effects of such mutations on receptor function is very limited. We examined the functional properties of 12 different mutations in human MC4R that result in severe, familial, early-onset obesity. Of the nine missense mutants studied, four were completely unable to generate cAMP in response to ligand and five were partially impaired. Four showed evidence of impaired cell surface expression and six of reduced binding affinity for ligand. One mutation in the C-terminal tail, I316S, showed reduced affinity for alpha-MSH but retained normal affinity for the antagonist AgRP. None of the mutations inhibited signaling through co-transfected wild-type receptors. Thus, in the most comprehensive study to date of the functional properties of naturally occurring MC4R mutations we have (1) established that defective expression on the cell surface is a common mechanism impairing receptor function, (2) identified mutations which specifically affect ligand binding affinity thus aiding the definition of receptor structure-function relationships, (3) provided evidence against the notion that these receptor mutants act as dominant-negatives, and (4) identified a potentially novel molecular mechanism of receptor dysfunction whereby a mutation alters the relative affinities of a receptor for its natural agonist versus antagonist.

  5. Molecular mechanisms associated with increased fetal hemoglobin G gamma-type in part-aboriginal family with beta thalassemia.

    Science.gov (United States)

    Motum, P I; Lammi, A; Trent, R J

    1989-07-01

    A part-Aboriginal family with beta thalassemia and raised hemoglobin F (HbF) was studied at the molecular level to determine if there were identifiable gene changes associated with increased production of HbF. Two beta thalassemia heterozygotes aged eight years and 18 months had raised HbF levels of 2.9% and 22% respectively. HbF was predominantly G gamma in composition. Five family members were typed for restriction fragment length polymorphisms (RFLPs) using nine restriction enzymes and five DNA probes specific for the beta globin cluster on chromosome 11. RFLPs were combined to construct haplotypes for the beta thalassemia and the high HbF defects. A beta globin subhaplotype comprising only 5' RFLP markers (-(+)-(+) +) co-segregated with the high HbF determinant. This has previously been associated with increased G gamma expression in beta thalassemia and sickle cell anemia. An additional Xmnl RFLP 5' to the G gamma gene, which has been described in individuals with elevated G gamma expression, was also demonstrated in those family members with increased G gamma levels. In this study both the 5' beta globin subhaplotype (-(+)-(+) +) and the Xmnl/gamma RFLP are present in the one family but the relative contributions of each cannot be determined.

  6. Molecular diagnosis of familial hypercholesterolaemia.

    Science.gov (United States)

    Graham, Colin A; Latten, Mark J; Hart, Padraig J

    2017-08-01

    Familial hypercholesterolaemia is a hereditary disorder of lipoprotein metabolism which causes a lifelong increase in LDL-C levels resulting in premature coronary heart disease. The present review looks at some of the recent literature on how molecular methods can be used to assist in the definitive diagnosis of familial hypercholesterolaemia in a range of patient groups. Several recent studies have shown that the prevalence of clinical familial hypercholesterolaemia is higher than previously thought at 1/200 to 1/300, and that 2-5% of patients presenting with early myocardial infarction can be found to have a familial hypercholesterolaemia mutation. The present review then examines different approaches to molecular testing for familial hypercholesterolaemia including point mutation panels versus next-generation sequencing gene panels, and the range of genes tested by some of those panels. Finally, we review the recent evidence for polygenic hypercholesterolaemia within clinically defined familial hypercholesterolaemia patient populations. To identify patients with familial hypercholesterolaemia within clinically selected patient groups efficiently, a clinical scoring system should be combined with a molecular testing approach for mutations and for polygenic LDL-C single-nucleotide polymorphisms. Alternatively, a population screening methodology may be appropriate, using mutation testing at an early age before significant atherosclerosis has begun. The precise molecular testing method chosen may depend on the clinical presentation of the patient, and/or the population from which they arise.

  7. Molecular Mechanisms of Preeclampsia

    OpenAIRE

    N. Vitoratos; D. Hassiakos; Iavazzo, C.

    2012-01-01

    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.

  8. Mechanisms of the self-assembly of EAK16-family peptides into fibrillar and globular structures: molecular dynamics simulations from nano- to micro-seconds.

    Science.gov (United States)

    Emamyari, Soheila; Kargar, Faezeh; Sheikh-Hasani, Vahid; Emadi, Saeed; Fazli, Hossein

    2015-05-01

    The self-assembly of EAK16-family peptides in a bulk solution was studied using a combination of all-atom and coarse-grained molecular dynamics simulations. In addition, specified concentrations of EAK16 peptides were induced to form fibrillary or globular assemblies in vitro. The results show that the combination of all-atom molecular dynamics simulations on the single- and double-chain levels and coarse-grained simulations on the many-chain level predicts the experimental observations reasonably well. At neutral pH conditions, EAK16-I and EAK16-II assemble into fibrillary structures, whereas EAK16-IV aggregates into globular assemblies. Mechanisms of the formation of fibrillar and globular assemblies are described using the simulation results.

  9. Anticancer molecular mechanisms of resveratrol

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    Elena Maria Varoni

    2016-04-01

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

  10. Anticancer Molecular Mechanisms of Resveratrol.

    Science.gov (United States)

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

    2016-01-01

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

  11. Understanding molecular structure from molecular mechanics.

    Science.gov (United States)

    Allinger, Norman L

    2011-04-01

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

  12. Familial Dysautonomia: Mechanisms and Models

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    Paula Dietrich

    Full Text Available Abstract Hereditary Sensory and Autonomic Neuropathies (HSANs compose a heterogeneous group of genetic disorders characterized by sensory and autonomic dysfunctions. Familial Dysautonomia (FD, also known as HSAN III, is an autosomal recessive disorder that affects 1/3,600 live births in the Ashkenazi Jewish population. The major features of the disease are already present at birth and are attributed to abnormal development and progressive degeneration of the sensory and autonomic nervous systems. Despite clinical interventions, the disease is inevitably fatal. FD is caused by a point mutation in intron 20 of the IKBKAP gene that results in severe reduction in expression of IKAP, its encoded protein. In vitro and in vivo studies have shown that IKAP is involved in multiple intracellular processes, and suggest that failed target innervation and/or impaired neurotrophic retrograde transport are the primary causes of neuronal cell death in FD. However, FD is far more complex, and appears to affect several other organs and systems in addition to the peripheral nervous system. With the recent generation of mouse models that recapitulate the molecular and pathological features of the disease, it is now possible to further investigate the mechanisms underlying different aspects of the disorder, and to test novel therapeutic strategies.

  13. Molecular mechanisms in cardiomyopathy.

    Science.gov (United States)

    Dadson, Keith; Hauck, Ludger; Billia, Filio

    2017-07-01

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

  14. Tubuliform silk protein: A protein with unique molecular characteristics and mechanical properties in the spider silk fibroin family

    Science.gov (United States)

    Tian, M.; Lewis, R. V.

    2006-02-01

    Orb-web weavers can produce up to six different types of silk and a glue for various functions. Tubuliform silk is unique among them due to its distinct amino acid composition, specific time of production, and atypical mechanical properties. To study the protein composing this silk, tubuliform gland cDNA libraries were constructed from three orb-weaving spiders Argiope aurantia, Araneus gemmoides, and Nephila clavipes. Amino acid composition comparison between the predicted tubuliform silk protein sequence (TuSp1) and the corresponding gland protein confirms that TuSp1 is the major component in tubuliform gland in three spiders. Sequence analysis suggests that TuSp1 shares no significant similarity with its paralogues, while it has conserved sequence motifs with the most primitive spider, Euagrus chisoseus silk protein. The presence of large side-chain amino acids in TuSp1 sequence is consistent with the frustrated β-sheet crystalline structure of tubuliform silk observed in transmission electron microscopy. Repeat unit comparison within species as well as among three spiders exhibits high sequence conservation. Parsimony analysis based on carboxy terminal sequence shows that Argiope and Araneus are more closely related than either is to Nephila which is consistent with phylogenetic analysis based on morphological evidence.

  15. Molecular mechanisms of meditation.

    Science.gov (United States)

    Jindal, Vishal; Gupta, Sorab; Das, Ritwik

    2013-12-01

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

  16. Molecular mechanisms in gliomagenesis

    DEFF Research Database (Denmark)

    Hulleman, Esther; Helin, Kristian

    2005-01-01

    brain development, such as the differentiation of neural stem cells (NSCs) into astrocytes, might contribute to GBM formation. These pathways include growth factor-induced signal transduction routes and processes that control cell cycle progression, such as the p16-CDK4-RB and the ARF-MDM2-p53 pathways....... The expression of several of the components of these signaling cascades has been found altered in GBM, and recent data indicate that combinations of mutations in these pathways may contribute to GBM formation, although the exact mechanisms are still to be uncovered. Use of novel techniques including large...

  17. Molecular Mechanisms of Parturition

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    F. Ferré

    1997-01-01

    Full Text Available The initial signal for triggering human parturition might be fetal but of trophoblastic origin. Concomitantly, this placental signal would have as its target not only the uterus but also the fetus by activating its hypothalamo-pituitary-adrenocortical axis. The latter would represent a second fetal signal which, at the fetomaternal interface, would amplify and define in time the mechanisms responsible for the onset of labor, implying changes in the myometrial and cervical extracellular matrix associated with the accession of the contractile phenotype for myometrial cells. At each phase of these processes in the utero-feto-placental system, the nature of these signals remains to be identified. Is there a single substance, or rather, and more likely, a combination of several?

  18. Molecular mechanisms of rosacea pathogenesis

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    Davydova A.M.

    2013-09-01

    Full Text Available The article presents possible molecular mechanisms for rosacea pathogenesis from current domestic and foreign clinical observations and laboratory research: regulation and expression defects of antimicrobial peptides, vascular endothelial growth factor, the effect of serine proteases, oxidative stress, reactive oxygen species and ferritin on the occurrence and course of rosacea. New developments in molecular biology and genetics are advanced for researching the interaction of multiple factors involved in rosacea pathogenesis, as well as providing the bases for potentially new therapies.

  19. 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. 

  20. Target Molecular Simulations of RecA Family Protein Filaments

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    Yeng-Tseng Wang

    2012-06-01

    Full Text Available Modeling of the RadA family mechanism is crucial to understanding the DNA SOS repair process. In a 2007 report, the archaeal RadA proteins function as rotary motors (linker region: I71-K88 such as shown in Figure 1. Molecular simulations approaches help to shed further light onto this phenomenon. We find 11 rotary residues (R72, T75-K81, M84, V86 and K87 and five zero rotary residues (I71, K74, E82, R83 and K88 in the simulations. Inclusion of our simulations may help to understand the RadA family mechanism.

  1. Superspreading: mechanisms and molecular design.

    Science.gov (United States)

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

    2015-03-03

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

  2. Molecular mechanisms underlying bacterial persisters

    DEFF Research Database (Denmark)

    Maisonneuve, Etienne; Gerdes, Kenn

    2014-01-01

    All bacteria form persisters, cells that are multidrug tolerant and therefore able to survive antibiotic treatment. Due to the low frequencies of persisters in growing bacterial cultures and the complex underlying molecular mechanisms, the phenomenon has been challenging to study. However, recent...... technological advances in microfluidics and reporter genes have improved this scenario. Here, we summarize recent progress in the field, revealing the ubiquitous bacterial stress alarmone ppGpp as an emerging central regulator of multidrug tolerance and persistence, both in stochastically and environmentally...... induced persistence. In several different organisms, toxin-antitoxin modules function as effectors of ppGpp-induced persistence....

  3. 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

  4. Molecular mechanisms of cryptococcal meningitis.

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

    2012-01-01

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

  5. Molecular Mechanisms of Antisense Oligonucleotides.

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    Crooke, Stanley T

    2017-04-01

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

  6. Molecular Mechanisms of Bacterial Pathogenicity

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    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.

  7. 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.

  8. Oligomerization mechanisms of an H-NS family protein, Pmr, encoded on the plasmid pCAR1 provide a molecular basis for functions of H-NS family members.

    Science.gov (United States)

    Suzuki, Chiho; Kawazuma, Kohei; Horita, Shoichiro; Terada, Tohru; Tanokura, Masaru; Okada, Kazunori; Yamane, Hisakazu; Nojiri, Hideaki

    2014-01-01

    Enterobacterial H-NS-like proteins and Pseudomonas MvaT-like proteins share low homology at the amino acid sequence level, but both can function as xenogeneic silencers and are included in the H-NS family of proteins. H-NS family members have dimerization/oligomerization and DNA-binding domains connected by a flexible linker and form large nucleoprotein complexes using both domains. Pmr, an MvaT-like protein encoded on the IncP-7 carbazole-degradative plasmid pCAR1, is a key regulator of an interaction between pCAR1 and its host Pseudomonas putida KT2440. KT2440 has two transcribed genes that encode the MvaT-like proteins TurA and TurB. Our previous transcriptome analyses suggested that the functions of Pmr, TurA and TurB are non-equivalent, although the detailed underlying mechanisms remain unclear. In this study, we focused on the protein-protein interactions of Pmr, and assessed the homo-oligomerization capacity of various substituted and truncated Pmr derivatives by protein-protein cross-linking analysis. Six of the seven residues identified as important for homo-oligomerization in Pmr were located near the N-terminus, and the putative flexible linker or the region near that was not involved in homo-oligomerization, suggesting that Pmr homo-oligomerization is different from that of enterobacterial H-NS and that the functional mechanism differs between H-NS-like and MvaT-like proteins. In addition, we assessed homo- and hetero-oligomerization of Pmr by surface plasmon resonance analysis and found that the coupling ratio of TurB-Pmr oligomers is smaller than that of Pmr-Pmr or TurA-Pmr oligomers. These results raised the possibility that composition of the hetero-oligomers of Pmr, TurA, and TurB could explain why the different gene sets were affected by either pmr, turA, or turB disruption in our previous studies.

  9. Geometrical families of mechanically stable granular packings

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    Gao, Guo-Jie; Blawzdziewicz, Jerzy; O'Hern, Corey S.

    2009-12-01

    We enumerate and classify nearly all of the possible mechanically stable (MS) packings of bidipserse mixtures of frictionless disks in small sheared systems. We find that MS packings form continuous geometrical families, where each family is defined by its particular network of particle contacts. We also monitor the dynamics of MS packings along geometrical families by applying quasistatic simple shear strain at zero pressure. For small numbers of particles (N16 , we observe an increase in the period and random splittings of the trajectories caused by bifurcations in configuration space. We argue that the ratio of the splitting and contraction rates in large systems will determine the distribution of MS-packing geometrical families visited in steady state. This work is part of our long-term research program to develop a master-equation formalism to describe macroscopic slowly driven granular systems in terms of collections of small subsystems.

  10. Molecular mechanisms of synaptic plasticity and memory.

    Science.gov (United States)

    Elgersma, Y; Silva, A J

    1999-04-01

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

  11. Molecular design and QSARs/QSPRs with molecular descriptors family.

    Science.gov (United States)

    Bolboacă, Sorana D; Jäntschi, Lorentz; Diudea, Mircea V

    2013-06-01

    The aim of the present paper is to present the methodology of the molecular descriptors family (MDF) as an integrative tool in molecular modeling and its abilities as a multivariate QSAR/QSPR modeling tool. An algorithm for extracting useful information from the topological and geometrical representation of chemical compounds was developed and integrated to calculate MDF members. The MDF methodology was implemented and the software is available online (http://l.academicdirect.org/Chemistry/SARs/MDF_SARs/). This integrative tool was developed in order to maximize performance, functionality, efficiency and portability. The MDF methodology is able to provide reliable and valid multiple linear regression models. Furthermore, in many cases, the MDF models were better than the published results in the literature in terms of correlation coefficients (statistically significant Steiger's Z test at a significance level of 5%) and/or in terms of values of information criteria and Kubinyi function. The MDF methodology developed and implemented as a platform for investigating and characterizing quantitative relationships between the chemical structure and the activity/property of active compounds was used on more than 50 study cases. In almost all cases, the methodology allowed obtaining of QSAR/QSPR models improved in explanatory power of structure-activity and structure-property relationships. The algorithms applied in the computation of geometric and topological descriptors (useful in modeling physicochemical or biological properties of molecules) and those used in searching for reliable and valid multiple linear regression models certain enrich the pool of low-cost low-time drug design tools.

  12. Molecular mechanisms of NCAM function

    DEFF Research Database (Denmark)

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

    2004-01-01

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

  13. Polarization effects in molecular mechanical force fields

    Science.gov (United States)

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

    2014-01-01

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

  14. Polarization effects in molecular mechanical force fields

    Energy Technology Data Exchange (ETDEWEB)

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

    2009-08-19

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

  15. Quantum mechanics of molecular structures

    CERN Document Server

    Yamanouchi, Kaoru

    2012-01-01

    At a level accessible to advanced undergraduates, this textbook explains the fundamental role of quantum mechanics in determining the structure, dynamics, and other properties of molecules. Readers will come to understand the quantum-mechanical basis for harmonic oscillators, angular momenta and scattering processes. Exercises are provided to help readers deepen their grasp of the essential phenomena.

  16. Molecular deformation mechanisms in polyethylene

    CERN Document Server

    Coutry, S

    2001-01-01

    adjacent labelled stems is significantly larger when the DPE guest is a copolymer molecule. Our comparative studies on various types of polyethylene lead to the conclusion that their deformation behaviour under drawing has the same basis, with additional effects imputed to the presence of tie-molecules and branches. Three major points were identified in this thesis. The changes produced by drawing imply (1) the crystallisation of some of the amorphous polymer and the subsequent orientation of the newly formed crystals, (2) the re-orientation of the crystalline ribbons and (3) the beginning of crystallite break-up. However, additional effects were observed for the high molecular weight linear sample and the copolymer sample and were attributed, respectively, to the presence of tie-molecules and of branches. It was concluded that both the tie-molecules and the branches are restricting the molecular movement during deformation, and that the branches may be acting as 'anchors'. This work is concerned with details...

  17. Molecular mechanisms of antibiotic resistance.

    Science.gov (United States)

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

    2015-01-01

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

  18. Molecular mechanism of insulin resistance

    Indian Academy of Sciences (India)

    Samir Bhattacharya; Debleena Dey; Sib Sankar Roy

    2007-03-01

    Free fatty acids are known to play a key role in promoting loss of insulin sensitivity, thereby causing insulin resistance and type 2 diabetes. However, the underlying mechanism involved is still unclear. In searching for the cause of the mechanism, it has been found that palmitate inhibits insulin receptor (IR) gene expression, leading to a reduced amount of IR protein in insulin target cells. PDK1-independent phosphorylation of PKCε causes this reduction in insulin receptor gene expression. One of the pathways through which fatty acid can induce insulin resistance in insulin target cells is suggested by these studies. We provide an overview of this important area, emphasizing the current status.

  19. Molecular mechanisms of insulin resistance

    African Journals Online (AJOL)

    insulin action from receptor to the alteration of blood glucose. Hence, in order to ... and regulation of the insulin receptor in our efforts to unravel the cause of this ... defined mechanisms of signal transduction. Structure ..... found in muscle and fat is the most important and mediates ..... glycogen metabolism in skeletal muscle.

  20. Molecular mechanisms underlying the Arabidopsis circadian clock.

    Science.gov (United States)

    Nakamichi, Norihito

    2011-10-01

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

  1. Molecular mechanism of sweetness sensation.

    Science.gov (United States)

    DuBois, Grant E

    2016-10-01

    The current understanding of peripheral molecular events involved in sweet taste sensation in humans is reviewed. Included are discussions of the sweetener receptor T1R2/T1R3, its agonists, antagonists, positive allosteric modulators, the transduction of its activation in taste bud cells and the coding of its signaling to the CNS. Areas of incomplete understanding include 1) signal communication with afferent nerve fibers, 2) contrasting concentration/response (C/R) functions for high-potency (HP) sweeteners (hyperbolic) and carbohydrate (CHO) sweeteners (linear), 3) contrasting temporal profiles for HP sweeteners (delayed onset and extinction) and CHO sweeteners (rapid onset and extinction) and 4) contrasting adaptation behaviors for HP sweeteners (moderate to strong adaptation) and CHO sweeteners (low adaptation). Evidence based on the sweet water aftertastes of several novel sweetness inhibitors is presented providing new support for constitutive activity in T1R2/T1R3. And a model is developed to rationalize the linear C/R functions of CHO sweeteners and hyperbolic C/R functions of HP sweeteners, where the former may activate T1R2/T1R3 by both binding and constitutive activity modulation (i.e., without binding) and the latter activate T1R2/T1R3 only by binding. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Molecular mechanisms of TRAIL-induced apoptosis of cancer cells

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    @@Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) is a recently identified member of the tumor necrosis factor (TNF) family[1]. Numerous studies indicate that TRAIL can induce apoptosis of cancer cells but not of normal cells, pointing to the possibility of de-veloping TRAIL into a cancer drug[2-4]. This review will summary the molecular mechanisms of TRAIL-induced apoptosis and discuss the questions to be resolved in this field.

  3. Molecular Mechanisms of Appetite Regulation

    Directory of Open Access Journals (Sweden)

    Ji Hee Yu

    2012-12-01

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

  4. Molecular mechanisms of appetite regulation.

    Science.gov (United States)

    Yu, Ji Hee; Kim, Min-Seon

    2012-12-01

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

  5. Molecular Mechanisms Underlying Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Christian Trepo

    2009-11-01

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

  6. Molecular mechanisms of Ebola pathogenesis.

    Science.gov (United States)

    Rivera, Andrea; Messaoudi, Ilhem

    2016-11-01

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

  7. Quantum Mechanics/Molecular Mechanics Modeling of Drug Metabolism

    DEFF Research Database (Denmark)

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

    2016-01-01

    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...

  8. Molecular mechanisms of DNA photodamage

    Energy Technology Data Exchange (ETDEWEB)

    Starrs, S.M

    2000-05-01

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

  9. Molecular Mechanisms Underlying the Arabidopsis Circadian Clock

    OpenAIRE

    Nakamichi, Norihito

    2011-01-01

    A wide range of biological processes exhibit circadian rhythm, enabling plants to adapt to the environmental day–night cycle. This rhythm is generated by the so-called ‘circadian clock’. Although a number of genetic approaches have identified >25 clock-associated genes involved in the Arabidopsis clock mechanism, the molecular functions of a large part of these genes are not known. Recent comprehensive studies have revealed the molecular functions of several key clock-associated proteins. Thi...

  10. Modelling the molecular mechanisms of aging

    Science.gov (United States)

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

    2017-01-01

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

  11. Pathogenesis and Molecular Mechanisms of Zika Virus.

    Science.gov (United States)

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

    2016-09-01

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

  12. Modelling the molecular mechanisms of aging.

    Science.gov (United States)

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

    2017-02-28

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

  13. Silica Synthesis by Sponges: Unanticipated Molecular Mechanism

    Science.gov (United States)

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

    2001-12-01

    Oceanic diatoms, sponges and other organisms synthesize gigatons per year of silica from silicic acid, ultimately obtained from the weathering of rock. This biogenic silica exhibits a remarkable diversity of structures, many of which reveal a precision of nanoarchitectural control that exceeds the capabilities of human engineering. In contrast to the conditions of anthropogenic and industrial manufacture, the biological synthesis of silica occurs under mild physiological conditions of low temperatures and pressures and near-neutral pH. In addition to the differentiation between biological and abiotic processes governing silica formation, the biomolecular mechanisms controlling synthesis of these materials may offer insights for the development of new, environmentally benign routes for synthesis of nanostructurally controlled silicas and high-performance polysiloxane composites. We found that the needle-like silica spicules made by the marine sponge, Tethya aurantia, each contain an occluded axial filament of protein composed predominantly of repeating assemblies of three similar subunits we named "silicateins." To our surprise, analysis of the purified protein subunits and the cloned silicatein DNAs revealed that the silicateins are highly homologous to a family of hydrolytic enzymes. As predicted from this finding, we discovered that the silicatein filaments are more than simple, passive templates; they actively catalyze and spatially direct polycondensation to form silica, (as well as the phenyl- and methyl-silsesquioxane) from the corresponding silicon alkoxides at neutral pH and low temperature. Catalytic activity also is exhibited by the silicatein subunits obtained by disaggregation of the protein filaments and those produced from recombinant DNA templates cloned in bacteria. This catalytic activity accelerates the rate-limiting hydrolysis of the silicon alkoxide precursors. Genetic engineering, used to produce variants of the silicatein molecule with

  14. Molecular mechanisms of drug-induced thrombocytopenia

    NARCIS (Netherlands)

    Burgess, Janette K.

    2001-01-01

    A wide range of drugs can induce thrombocytopenia. Molecular mechanisms for the formation of specific epitopes for all the drug-dependent antibodies appear to be very similar. A restricted set of glycoproteins on the platelet surface interacts with the drugs to form neoepitopes, to which the drug-de

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

    Science.gov (United States)

    Liao, Jung-Chi

    2011-12-01

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

  16. [Cellular and molecular mechanisms of memory].

    Science.gov (United States)

    Laroche, Serge

    2010-01-01

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

  17. Ocular diseases: immunological and molecular mechanisms

    Directory of Open Access Journals (Sweden)

    Jing Song

    2016-05-01

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

  18. Teratogenic effects of thalidomide: molecular mechanisms.

    Science.gov (United States)

    Ito, Takumi; Ando, Hideki; Handa, Hiroshi

    2011-05-01

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

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

    Science.gov (United States)

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

    2016-09-13

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

  20. 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.

  1. Molecular mechanism of Endosulfan action in mammals

    Indian Academy of Sciences (India)

    ROBIN SEBASTIAN; SATHEES C RAGHAVAN

    2017-03-01

    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 understood. In two recentstudies, our group investigated the physiological and molecular aspects of endosulfan action using in vitro, ex vivo andin vivo analyses. The results showed that apart from reducing fertility levels in male animals, Endosulfan inducedDNA damage that triggers compromised DNA damage response leading to undesirable processing of broken DNAends. In this review, pesticide use especially of Endosulfan in the Indian scenario is summarized and the importance ofour findings, especially the rationalized use of pesticides in the future, is emphasized.

  2. Molecular Mechanisms of Inherited Demyelinating Neuropathies

    Science.gov (United States)

    SCHERER, STEVEN S.; WRABETZ, LAWRENCE

    2008-01-01

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

  3. Molecular mechanism and regulation of autophagy

    Institute of Scientific and Technical Information of China (English)

    Ya-ping YANG; Zhong-qin LIANG; Zhen-lun GU; Zheng-hong QIN

    2005-01-01

    Autophagy is a major cellular pathway for the degradation of long-lived proteins and cytoplasmic organelles in eukaryotic cells. A large number of intracellular/extracellular stimuli, including amino acid starvation and invasion of microorganisms, are able to induce the autophagic response in cells. The discovery of the ATG genes in yeast has greatly advanced our understanding of the molecular mechanisms participating in autophagy and the genes involved in regulating the autophagic pathway. Many yeast genes have mammalian homologs,suggesting that the basic machinery for autophagy has been evolutionarily conserved along the eukaryotic phylum. The regulation of autophagy is a very complex process. Many signaling pathways, including target of rapamycin (TOR) or mammalian target of rapamycin (mTOR), phosphatidylinositol 3-kinase-I (PI3K-I)/PKB, GTPases, calcium and protein synthesis all play important roles in regulating autophagy. The molecular mechanisms and regulation of autophagy are discussed in this review.

  4. Molecular mechanism for the umami taste synergism.

    Science.gov (United States)

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

    2008-12-30

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

  5. Molecular mechanism of the sweet taste enhancers.

    Science.gov (United States)

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

    2010-03-01

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

  6. Estrogenic endocrine disruptors: Molecular mechanisms of action.

    Science.gov (United States)

    Kiyama, Ryoiti; Wada-Kiyama, Yuko

    2015-10-01

    A comprehensive summary of more than 450 estrogenic chemicals including estrogenic endocrine disruptors is provided here to understand the complex and profound impact of estrogen action. First, estrogenic chemicals are categorized by structure as well as their applications, usage and effects. Second, estrogenic signaling is examined by the molecular mechanism based on the receptors, signaling pathways, crosstalk/bypassing and autocrine/paracrine/homeostatic networks involved in the signaling. Third, evaluation of estrogen action is discussed by focusing on the technologies and protocols of the assays for assessing estrogenicity. Understanding the molecular mechanisms of estrogen action is important to assess the action of endocrine disruptors and will be used for risk management based on pathway-based toxicity testing.

  7. Molecular mechanisms of metastasis in prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Noel W.Clarke; Claire A.Hart; Mick D.Brown

    2009-01-01

    Prostate cancer (PCa) preferentially metastasizes to the bone marrow stroma of the axial skeleton.This activity is the principal cause of PCa morbidity and mortality.The exact mechanism of PCa metastasis is currently unknown,although considerable progress has been made in determining the key players in this process.In this review,we present the current understanding of the molecular processes driving PCa metastasis to the bone.

  8. Estrogen : molecular mechanisms of antidiabetic action

    OpenAIRE

    Al-Qahtani, Saad Misfer

    2016-01-01

    The pathogenesis of metabolic syndrome is multifactorial and hormones play an essential role in its development. Estrogen loss in postmenopausal women has been linked to several features of metabolic syndrome, while estrogen replacement therapy reverses these pathological and metabolic features. However, estrogen replacement therapy is associated with adverse effects including breast cancer and coagulopathy. Therefore, identification of the molecular mechanisms of estrogen’s beneficial effect...

  9. Identification of new molecular alterations in Fatal Familial Insomnia.

    Science.gov (United States)

    Fatal familial insomnia (FFI) is an autosomal dominant prion disease caused by a D178N mutation in PRNP in combination with methionine (Met) at codon 129 in the mutated allele of the same gene (D178N-129M haplotype). The present study analyzes pathological and molecular features in seven FFI cases c...

  10. MOLECULAR MECHANISMS OF FEAR LEARNING AND MEMORY

    Science.gov (United States)

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

    2011-01-01

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

  11. Molecular evolution of the polyamine oxidase gene family in Metazoa

    Directory of Open Access Journals (Sweden)

    Polticelli Fabio

    2012-06-01

    monophyletic clades including, respectively, all the SMOs and APAOs from vertebrates. The two vertebrate monophyletic clades clustered strictly mirroring the organismal phylogeny of fishes, amphibians, reptiles, birds, and mammals. Evidences from comparative genomic analysis, structural evolution and functional divergence in a phylogenetic framework across Metazoa suggested an evolutionary scenario where the ancestor PAO coding sequence, present in invertebrates as an orthologous gene, has been duplicated in the vertebrate branch to originate the paralogous SMO and APAO genes. A further genome evolution event concerns the SMO gene of placental, but not marsupial and monotremate, mammals which increased its functional variation following an alternative splicing (AS mechanism. Conclusions In this study the explicit integration in a phylogenomic framework of phylogenetic tree construction, structure prediction, and biochemical function data/prediction, allowed inferring the molecular evolutionary history of the PAO gene family and to disambiguate paralogous genes related by duplication event (SMO and APAO and orthologous genes related by speciation events (PAOs, SMOs/APAOs. Further, while in vertebrates experimental data corroborate SMO and APAO molecular function predictions, in invertebrates the finding of a supported phylogenetic clusters of insect PAOs and the co-occurrence of two PAO variants in the amphioxus urgently claim the need for future structure-function studies.

  12. 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

    2009-09-01

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

  13. Molecular mechanisms for protein-encoded inheritance

    Energy Technology Data Exchange (ETDEWEB)

    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; (Cornell); (HHMI)

    2009-12-01

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

  14. Molecular Mechanisms in Exercise-Induced Cardioprotection

    Directory of Open Access Journals (Sweden)

    Saeid Golbidi

    2011-01-01

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

  15. Molecular model with quantum mechanical bonding information.

    Science.gov (United States)

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

    2011-11-17

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

  16. Molecular evolution of the crustacean hyperglycemic hormone family in ecdysozoans

    Science.gov (United States)

    2010-01-01

    Background Crustacean Hyperglycemic Hormone (CHH) family peptides are neurohormones known to regulate several important functions in decapod crustaceans such as ionic and energetic metabolism, molting and reproduction. The structural conservation of these peptides, together with the variety of functions they display, led us to investigate their evolutionary history. CHH family peptides exist in insects (Ion Transport Peptides) and may be present in all ecdysozoans as well. In order to extend the evolutionary study to the entire family, CHH family peptides were thus searched in taxa outside decapods, where they have been, to date, poorly investigated. Results CHH family peptides were characterized by molecular cloning in a branchiopod crustacean, Daphnia magna, and in a collembolan, Folsomia candida. Genes encoding such peptides were also rebuilt in silico from genomic sequences of another branchiopod, a chelicerate and two nematodes. These sequences were included in updated datasets to build phylogenies of the CHH family in pancrustaceans. These phylogenies suggest that peptides found in Branchiopoda and Collembola are more closely related to insect ITPs than to crustacean CHHs. Datasets were also used to support a phylogenetic hypothesis about pancrustacean relationships, which, in addition to gene structures, allowed us to propose two evolutionary scenarios of this multigenic family in ecdysozoans. Conclusions Evolutionary scenarios suggest that CHH family genes of ecdysozoans originate from an ancestral two-exon gene, and genes of arthropods from a three-exon one. In malacostracans, the evolution of the CHH family has involved several duplication, insertion or deletion events, leading to neuropeptides with a wide variety of functions, as observed in decapods. This family could thus constitute a promising model to investigate the links between gene duplications and functional divergence. PMID:20184761

  17. Molecular mechanics conformational analysis of tylosin

    Science.gov (United States)

    Ivanov, Petko M.

    1998-01-01

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

  18. 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.

  19. Modeling molecular mechanisms in the axon

    Science.gov (United States)

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

    2017-03-01

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

  20. Molecular mechanisms of sex determination in reptiles.

    Science.gov (United States)

    Rhen, T; Schroeder, A

    2010-01-01

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

  1. Thymic Output: Influence Factors and Molecular Mechanism

    Institute of Scientific and Technical Information of China (English)

    Rong Jin; Jun Zhang; Weifeng Chen

    2006-01-01

    Thymus is a primary lymphoid organ, able to generate mature T cells that eventually colonize secondary lymphoid organs, and is therefore essential for peripheral T cell renewal. Recent data showed that normal thymocyte export can be altered by several influence factors including several chemokines,sphingosinel-phosphate (S1P),transcription factors such as Foxjl, Kruppel-like transcription factor 2 (KLF2) and antigen stimulation, etc. In this review, we summarized the recent reports about study strategies, influence factors and possible molecular mechanisms in thymic output.

  2. Molecular mechanisms of metal hyperaccumulation in plants.

    Science.gov (United States)

    Verbruggen, Nathalie; Hermans, Christian; Schat, Henk

    2009-03-01

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

  3. 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.

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

    Science.gov (United States)

    Shen, Lin; Wu, Jingheng; Yang, Weitao

    2016-10-11

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

  5. 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.

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

    Science.gov (United States)

    Onoprienko, L V

    2011-01-01

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

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

    Science.gov (United States)

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

    2001-01-01

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

  8. Molecular functions and significance of the MTA family in hormone-independent cancer.

    Science.gov (United States)

    Ning, Zhifeng; Gan, Jinfeng; Chen, Chaoying; Zhang, Dianzheng; Zhang, Hao

    2014-12-01

    The members of the metastasis-associated protein (MTA) family play pivotal roles in both physiological and pathophysiological processes, especially in cancer development and metastasis, and their role as master regulators has come to light. Due to the fact that they were first identified as crucial factors in estrogen receptor-mediated breast cancer metastasis, most of the early studies focused on their hormone-dependent functions. However, the accumulating evidence shows that the members of MTA family are deregulated in most, if not all, the cancers studied so far. Therefore, the levels as well as the activities of the MTA family members are widely accepted as potential biomarkers for diagnosis, prognosis, and predictors of overall survival. They function differently in different cancers with specific mechanisms. p53 and HIF-1α appear to be the respectively common upstream and downstream regulator of the MTA family in both development and metastasis of a wide spectrum of cancers. Here, we review the expression and clinical significance of the MTA family, focusing on hormone-independent cancers. To illustrate the molecular mechanisms, we analyze the MTA family-related signaling pathways in different cancers. Finally, targeting the MTA family directly or the pathways involved in the MTA family indirectly could be invaluable strategies in the development of cancer therapeutics.

  9. Molecular Mechanisms Regulating Macrophage Response to Hypoxia

    Directory of Open Access Journals (Sweden)

    Michal Amit Rahat

    2011-09-01

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

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

    Science.gov (United States)

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

    2013-08-14

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

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

    Science.gov (United States)

    Ishiyama, Tatsuya; Takahashi, Hideaki; Morita, Akihiro

    2012-03-28

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

  12. The Family Meeting as a Mechanism of Family Governance: Review of the Experiences of Polish Family Companies

    Directory of Open Access Journals (Sweden)

    Izabela Koładkiewicz

    2014-09-01

    Full Text Available Purpose: The objective of the research was an assessment of the experiences of Polish owners of family companies in organizing family meetings as mechanisms of family governance as well as evaluating the usefulness of solutions developed in this sphere for both family and company. Methodology: The character of the conducted research was qualitative. The main technique used to gather data involved interviews. A total of thirty nine respondents from twenty companies were questioned. Nineteen were representatives of the older generation while twenty represented the younger second generation of owners of family businesses. Findings: Research results indicated the rather extensive use by the examined owner families of family meetings to discuss company matters. Depending on their needs, they developed various models ranging from the ad hoc bringing up of company matters to the transformation of such meetings into formal, family meetings of the management board organized in company offi ces. Regardless of organizational form, family meetings were an important forum for the exchange of information and views on the functioning of the company among family members. The experiences of the examined families of owners in building family governance systems, understood as a complex of structures and mechanisms making possible the maintenance of a balance between tensions stemming from economic and emotional ties among family members, both involved in the company and outside it, remain small. Research limitations: The qualitative character of the research, including the size of the examined sample (twenty family companies represented by thirty nine representatives, means that the generalizations made for the purposes of this study refer only to the experiences and opinions of the interviewed respondents. Originality: The research performed is the fi rst of its kind devoted to family meetings as a component of the system of family governance created in the

  13. Molecular mechanisms of HIV-1 associated neurodegeneration

    Indian Academy of Sciences (India)

    Hakan Ozdener

    2005-06-01

    Since identification of the human immunodeficiency virus-1 (HIV-1), numerous studies suggest a link between neurological impairments, in particular dementia, with acquired immunodeficiency syndrome (AIDS) with alarming occurrence worldwide. Approximately, 60% of HIV-infected people show some form of neurological impairment, and neuropathological changes are found in 90% of autopsied cases. Approximately 30% of untreated HIV-infected persons may develop dementia. The mechanisms behind these pathological changes are still not understood. Mounting data obtained by in vivo and in vitro experiments suggest that neuronal apoptosis is a major feature of HIV associated dementia (HAD), which can occur in the absence of direct infection of neurons. The major pathway of neuronal apoptosis occurs indirectly through release of neurotoxins by activated cells in the central nervous system (CNS) involving the induction of excitotoxicity and oxidative stress. In addition a direct mechanism induced by viral proteins in the pathogenesis of HAD may also play a role. This review focuses on the molecular mechanisms of HIV-associated dementia and possible therapeutic strategies.

  14. Molecular basis for amino acid sensing by family C G-protein-coupled receptors

    DEFF Research Database (Denmark)

    Wellendorph, Petrine; Bräuner-Osborne, Hans

    2009-01-01

    -alpha;-amino acid receptor G-protein-coupled receptor family C, group 6, subtype A (GPRC6A) and seven orphan receptors. Aside from the orphan receptors, the family C GPCRs are dimeric receptors characterized by a large extracellular Venus flytrap domain which bind the endogenous agonists. Except from the GABA(B1......-2) and T1R2-3 receptor, all receptors are either activated or positively modulated by amino acids. In this review, we outline mutational, biophysical and structural studies which have elucidated the interaction of the amino acids with the Venus flytrap domains, molecular mechanisms of receptor selectivity...

  15. Molecular mechanisms of somatostatin receptor trafficking.

    Science.gov (United States)

    Csaba, Zsolt; Peineau, Stéphane; Dournaud, Pascal

    2012-02-01

    The neuropeptide somatostatin (SRIF) is an important modulator of neurotransmission in the central nervous system and acts as a potent inhibitor of hormone and exocrine secretion. In addition, SRIF regulates cell proliferation in normal and tumorous tissues. The six somatostatin receptor subtypes (sst1, sst2A, sst2B, sst3, sst4, and sst5), which belong to the G protein-coupled receptor (GPCR) family, share a common molecular topology: a hydrophobic core of seven transmembrane-spanning α-helices, three intracellular loops, three extracellular loops, an amino-terminus outside the cell, and a carboxyl-terminus inside the cell. For most of the GPCRs, intracytosolic sequences, and more particularly the C-terminus, are believed to interact with proteins that are mandatory for either exporting neosynthesized receptor, anchoring receptor at the plasma membrane, internalization, recycling, or degradation after ligand binding. Accordingly, most of the SRIF receptors can traffic not only in vitro within different cell types but also in vivo. A picture of the pathways and proteins involved in these processes is beginning to emerge.

  16. Molecular mechanisms of the suppression of axon regeneration by KLF transcription factors

    Institute of Scientific and Technical Information of China (English)

    Akintomide Apara; Jeffrey L.Goldberg

    2014-01-01

    Molecular mechanisms of the Kr̈uppel-like family of transcription factors (KLFs) have been studied more in proliferating cells than in post-mitotic cells such as neurons. We recently found that KLFs regulate intrinsic axon growth ability in central nervous system (CNS) neurons in-cluding retinal ganglion cells, and hippocampal and cortical neurons. With at least 15 of 17 KLF family members expressed in neurons and at least 5 structurally unique subfamilies, it is import-ant to determine how this complex family functions in neurons to regulate the intricate genetic programs of axon growth and regeneration. By characterizing the molecular mechanisms of the KLF family in the nervous system, including binding partners and gene targets, and comparing them to deifned mechanisms deifned outside the nervous system, we may better understand how KLFs regulate neurite growth and axon regeneration.

  17. Dissociation mechanisms of photoexcited molecular ions

    CERN Document Server

    Inglis, L C

    2003-01-01

    Photoionisation of gas phase molecules, in the energy range 8 - 40 eV, and the subsequent dissociation mechanisms have been investigated using threshold photoelectron spectroscopy and ion time-of-flight mass spectrometry. The excitation source used was monochromatic radiation, delivered by station 3.2 at the Daresbury Laboratory Synchrotron Radiation Source. These two techniques have also been combined in threshold photoelectron-photoion coincidence experiments, in order to record coincidence time-of-flight mass spectra and thereby determine breakdown curves. Such curves display the ion fragmentation as a function of internal energy. In addition, computer modelling techniques have been employed to gain some understanding of the unimolecular dissociations of energy selected molecular ions by establishing theoretical breakdown graphs, appearance energies, fragmentation pathways and dissociation rates. Ab initio quantum chemistry calculations have been carried out, generating ionisation and appearance energies, ...

  18. Molecular mechanism of TNF signaling and beyond

    Institute of Scientific and Technical Information of China (English)

    Zheng-gang LIU

    2005-01-01

    Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a critical role in diverse cellular events,including cell proliferation, differentiation and apoptosis. TNF is also involved in many types of diseases. In recent years, the molecular mechanisms of TNF functions have been intensively investigated. Studies from many laboratories have demonstrated that the TNF-mediated diverse biological responses are achieved through activating multiple signaling pathways. Especially the activation of transcription factors NF-κB and AP-1 plays a critical role in mediating these cellular responses. Several proteins, including FADD, the death domain kinase RIP and the TNF receptor associated factor TRAF2 have been identified as the key effectors of TNF signaling. Recently, we found that the effector molecules of TNF signaling, such as RIP and TRAF2, are also involved in other cellular responses. These finding suggests that RIP and TRAF2 serve a broader role than as just an effector of TNF signaling.

  19. Molecular mechanisms involved in intestinal iron absorption

    Institute of Scientific and Technical Information of China (English)

    Paul Sharp; Surjit Kaila Srai

    2007-01-01

    Iron is an essential trace metal in the human diet due to its obligate role in a number of metabolic processes.In the diet, iron is present in a number of different forms, generally described as haem (from haemoglobin and myoglobin in animal tissue) and non-haem iron (including ferric oxides and salts, ferritin and lactoferrin).This review describes the molecular mechanisms that co-ordinate the absorption of iron from the diet and its release into the circulation. While many components of the iron transport pathway have been elucidated, a number of key issues still remain to be resolved. Future work in this area will provide a clearer picture regarding the transcellular flux of iron and its regulation by dietary and humoral factors.

  20. Cardiac channelopathies: genetic and molecular mechanisms.

    Science.gov (United States)

    Abriel, Hugues; Zaklyazminskaya, Elena V

    2013-03-15

    Channelopathies are diseases caused by dysfunctional ion channels, due to either genetic or acquired pathological factors. Inherited cardiac arrhythmic syndromes are among the most studied human disorders involving ion channels. Since seminal observations made in 1995, thousands of mutations have been found in many of the different genes that code for cardiac ion channel subunits and proteins that regulate the cardiac ion channels. The main phenotypes observed in patients carrying these mutations are congenital long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), short QT syndrome (SQTS) and variable types of conduction defects (CD). The goal of this review is to present an update of the main genetic and molecular mechanisms, as well as the associated phenotypes of cardiac channelopathies as of 2012. Copyright © 2012 Elsevier B.V. All rights reserved.

  1. Molecular Mechanisms of Neonatal Brain Injury

    Directory of Open Access Journals (Sweden)

    Claire Thornton

    2012-01-01

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

  2. Phenotypic plasticity: molecular mechanisms and adaptive significance.

    Science.gov (United States)

    Kelly, Scott A; Panhuis, Tami M; Stoehr, Andrew M

    2012-04-01

    Phenotypic plasticity can be broadly defined as the ability of one genotype to produce more than one phenotype when exposed to different environments, as the modification of developmental events by the environment, or as the ability of an individual organism to alter its phenotype in response to changes in environmental conditions. Not surprisingly, the study of phenotypic plasticity is innately interdisciplinary and encompasses aspects of behavior, development, ecology, evolution, genetics, genomics, and multiple physiological systems at various levels of biological organization. From an ecological and evolutionary perspective, phenotypic plasticity may be a powerful means of adaptation and dramatic examples of phenotypic plasticity include predator avoidance, insect wing polymorphisms, the timing of metamorphosis in amphibians, osmoregulation in fishes, and alternative reproductive tactics in male vertebrates. From a human health perspective, documented examples of plasticity most commonly include the results of exercise, training, and/or dieting on human morphology and physiology. Regardless of the discipline, phenotypic plasticity has increasingly become the target of a plethora of investigations with the methodological approaches utilized ranging from the molecular to whole organsimal. In this article, we provide a brief historical outlook on phenotypic plasticity; examine its potential adaptive significance; emphasize recent molecular approaches that provide novel insight into underlying mechanisms, and highlight examples in fishes and insects. Finally, we highlight examples of phenotypic plasticity from a human health perspective and underscore the use of mouse models as a powerful tool in understanding the genetic architecture of phenotypic plasticity.

  3. 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.

  4. Molecular Resources from Transcriptomes in the Brassicaceae Family

    Directory of Open Access Journals (Sweden)

    Lua Lopez

    2017-08-01

    Full Text Available The rapidly falling costs and the increasing availability of large DNA sequence data sets facilitate the fast and affordable mining of large molecular markers data sets for comprehensive evolutionary studies. The Brassicaceae (mustards are an important species-rich family in the plant kingdom with taxa distributed worldwide and a complex evolutionary history. We performed Simple Sequence Repeats (SSRs mining using de novo assembled transcriptomes from 19 species across the Brassicaceae in order to study SSR evolution and provide comprehensive sets of molecular markers for genetic studies within the family. Moreover, we selected the genus Cochlearia to test the transferability and polymorphism of these markers among species. Additionally, we annotated Cochlearia pyrenaica transcriptome in order to identify the position of each of the mined SSRs. While we introduce a new set of tools that will further enable evolutionary studies across the Brassicaceae, we also discuss some broader aspects of SSR evolution. Overall, we developed 2012 ready-to-use SSR markers with their respective primers in 19 Brassicaceae species and a high quality annotated transcriptome for C. pyrenaica. As indicated by our transferability test with the genus Cochlearia these SSRs are transferable to species within the genus increasing exponentially the number of targeted species. Also, our polymorphism results showed substantial levels of variability for these markers. Finally, despite its complex evolutionary history, SSR evolution across the Brassicaceae family is highly conserved and we found no deviation from patterns reported in other Angiosperms.

  5. Molecular analysis of precursor lesions in familial pancreatic cancer.

    Directory of Open Access Journals (Sweden)

    Tatjana Crnogorac-Jurcevic

    Full Text Available BACKGROUND: With less than a 5% survival rate pancreatic adenocarcinoma (PDAC is almost uniformly lethal. In order to make a significant impact on survival of patients with this malignancy, it is necessary to diagnose the disease early, when curative surgery is still possible. Detailed knowledge of the natural history of the disease and molecular events leading to its progression is therefore critical. METHODS AND FINDINGS: We have analysed the precursor lesions, PanINs, from prophylactic pancreatectomy specimens of patients from four different kindreds with high risk of familial pancreatic cancer who were treated for histologically proven PanIN-2/3. Thus, the material was procured before pancreatic cancer has developed, rather than from PanINs in a tissue field that already contains cancer. Genome-wide transcriptional profiling using such unique specimens was performed. Bulk frozen sections displaying the most extensive but not microdissected PanIN-2/3 lesions were used in order to obtain the holistic view of both the precursor lesions and their microenvironment. A panel of 76 commonly dysregulated genes that underlie neoplastic progression from normal pancreas to PanINs and PDAC were identified. In addition to shared genes some differences between the PanINs of individual families as well as between the PanINs and PDACs were also seen. This was particularly pronounced in the stromal and immune responses. CONCLUSIONS: Our comprehensive analysis of precursor lesions without the invasive component provides the definitive molecular proof that PanIN lesions beget cancer from a molecular standpoint. We demonstrate the need for accumulation of transcriptomic changes during the progression of PanIN to PDAC, both in the epithelium and in the surrounding stroma. An identified 76-gene signature of PDAC progression presents a rich candidate pool for the development of early diagnostic and/or surveillance markers as well as potential novel preventive

  6. Molecular mechanisms of LRRK2 regulation

    Science.gov (United States)

    Webber, Philip Jeffrey

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

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

    Science.gov (United States)

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

    2013-12-05

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

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

    Science.gov (United States)

    Xie, Zhiguo; Chang, Christopher; Zhou, Zhiguang

    2014-10-01

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

  9. Targeted therapies in epithelial ovarian cancer: Molecular mechanisms of action

    Institute of Scientific and Technical Information of China (English)

    Hiroaki; Itamochi

    2010-01-01

    Ovarian cancer is the leading cause of death in women with gynecological cancer. Most patients are diagnosed at an advanced stage and have a poor prognosis.Currently, surgical tumor debulking, followed by platinum- and taxane-based chemotherapy is the standard treatment for advanced ovarian cancer. However, these patients are at great risk of recurrence and emerging drug resistance. Therefore, novel treatment strategies are required to improve outcomes for women with advanced ovarian cancer. A variety of molecular targeted agents, the majority of which are monoclonal antibodies and small-molecule protein-kinase inhibitors, have been explored in the management of ovarian cancer. The targets of these agents include angiogenesis, the human epidermal growth factor receptor family, ubiquitinproteasome pathway, epigenetic modulators, poly(ADPribose) polymerase (PARP), and mammalian target of rapamycin (mTOR) signaling pathway, which are aberrant in tumor tissue. The antiangiogenic agent, bevacizumab, has been reported as the most effective targeted agent and should be included in the standard chemotherapeutic regimen for advanced ovarian cancer. PARP inhibitors, which are mainly used in breast and ovarian cancer susceptibility gene-mutated patients, and mTOR inhibitors are also attractive treatment strategies, either alone or combination with chemotherapy, for ovarian cancer. Understanding the tumor molecular biology and identification of predictive biomarkers are essential steps for selection of the best treatment strategies. This article reviews the molecular mechanisms of the most promising targeted agents that are under early phase clinical evaluation for ovarian cancer.

  10. 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.

  11. Multiresolution molecular mechanics: Implementation and efficiency

    Science.gov (United States)

    Biyikli, Emre; To, Albert C.

    2017-01-01

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

  12. Deciphering the Molecular Mechanisms of Breast Cancer

    Science.gov (United States)

    2005-03-01

    BRCA1 and BRCA2, by a Signalosome-like Subunit and its Role in DNA Repair. Molecular Cell 12; 1087-1099 (2003). Presentations/Abstracts...BRCA1 and BRCA2, by a Signalosome-like Subunit and its Role in DNA Repair. Molecular Cell 12; 1087-1099. APPENDICIES: CURRICULUM VITAE...Oncogenesis Program Member, Faculty Recruitment Committee Periodic Manuscript Reviews: Cell, Science, Molecular Cell , Molecular and Cellular

  13. RNA profiling reveals familial aggregation of molecular subtypes in non-BRCA1/2 breast cancer families

    DEFF Research Database (Denmark)

    Larsen, Martin J; Thomassen, Mads; Tan, Qihua

    2014-01-01

    BACKGROUND: In more than 70% of families with a strong history of breast and ovarian cancers, pathogenic mutation in BRCA1 or BRCA2 cannot be identified, even though hereditary factors are expected to be involved. It has been proposed that tumors with similar molecular phenotypes also share similar......, in 8 of these families we found that patients from the same family shared the same tumor subtype, showing a tendency of familial aggregation of tumor subtypes (p-value = 1.7e-3). Using our previously developed BRCA1/2-signatures, we identified 7 non-BRCA1/2 tumors with a BRCA1-like molecular phenotype...... cancer but to a particular subtype of breast cancer. This is the first study to provide a biological link between breast cancers from family members of high-risk non-BRCA1/2 families in a systematic manner, suggesting that future genetic analysis may benefit from subgrouping families into molecularly...

  14. Molecular Mechanisms Underlying Psychological Stress and Cancer.

    Science.gov (United States)

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

    2016-01-01

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

  15. Molecular mechanisms controlling legume autoregulation of nodulation.

    Science.gov (United States)

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

    2011-10-01

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

  16. Molecular and cellular mechanisms of adipogenesis

    Directory of Open Access Journals (Sweden)

    Aleksander Dmitrievich Egorov

    2015-03-01

    Full Text Available The main components of metabolic syndrome include insulin resistance, hypertriglyceridemia and arterial hypertension. Obesity is the cause of metabolic syndrome, mainly as a consequence of the endocrine function of adipose tissue. The volume of adipose tissue depends on the size of individual adipocytes and on their number. The number of adipocytes increases as a result of enhanced adipocyte differentiation. The transcriptional cascade that regulates this differentiation has been well studied. The major adipogenic transcription factor peroxisome proliferator-activated receptor gamma is a ligand-activated nuclear receptor with essential roles in adipogenesis. Its ligands are used to treat metabolic syndrome and type 2 diabetes mellitus. The present article describes the basic molecular and cellular mechanisms of adipogenesis and discusses the impact of insulin, glucocorticoids, cyclic adenosine monophosphate-activating agents, nuclear receptors and transcription factors on the process of adipogenesis. New regulatory regions of the genome that are capable of binding multiple transcription factors are described, and the most promising drug targets for the treatment of metabolic syndrome and obesity, including the homeodomain proteins Pbx1 and Prep1, are discussed.

  17. Molecular phylogenetics of the Neotropical fish family Prochilodontidae (Teleostei: Characiformes).

    Science.gov (United States)

    Melo, Bruno F; Sidlauskas, Brian L; Hoekzema, Kendra; Frable, Benjamin W; Vari, Richard P; Oliveira, Claudio

    2016-09-01

    Migratory detritivores of the characiform family Prochilodontidae occur throughout the freshwaters of much of South America. Prochilodontids often form massive populations and many species achieve substantial body sizes; a combination that makes them one of the most commercially important fish groups on the continent. Their economic significance notwithstanding, prochilodontids have never been the subject of a comprehensive molecular phylogenetic analysis. Using three mitochondrial and three nuclear loci spanning all prochilodontid species, we generated a novel phylogenetic hypothesis for the family. Our results strongly support monophyly of the family and the three included genera. A novel, highly supported placement of Ichthyoelephas sister to the clade containing Prochilodus and Semaprochilodus diverges from a previous morphological hypothesis. Most previously hypothesized interspecific relationships are corroborated and some longstanding polytomies within Prochilodus and Semaprochilodus are resolved. The morphologically similar P. brevis, P. lacustris, P. nigricans and P. rubrotaeniatus are embedded within what is herein designated as the P. nigricans group. Species limits and distributions of these species are problematic and the group clearly merits taxonomic revision.

  18. Molecular Mechanisms of Metastasis Suppression in Human Breast Cancer

    Science.gov (United States)

    2000-07-01

    and breast carcinoma metastasis, Wake Forest University Cancer Center, July 28 Molecular mechanisms controlling melanoma and breast carcinoma...Bowman Show, August 17 Molecular regulation of melanoma and breast carcinoma metastasis, Wake Forest University Cancer Center, July 28 Molecular...Institute, April 20, Pathology ofNeoplasia Cumberland Unit, American Cancer Society, April 19; Breast Cancer Research Ministerio de Sanidad y

  19. Molecular evolution of the ependymin protein family: a necessary update

    Directory of Open Access Journals (Sweden)

    García-Arrarás José E

    2007-02-01

    Full Text Available Abstract Background Ependymin (Epd, the predominant protein in the cerebrospinal fluid of teleost fishes, was originally associated with neuroplasticity and regeneration. Ependymin-related proteins (Epdrs have been identified in other vertebrates, including amphibians and mammals. Recently, we reported the identification and characterization of an Epdr in echinoderms, showing that there are ependymin family members in non-vertebrate deuterostomes. We have now explored multiple databases to find Epdrs in different metazoan species. Using these sequences we have performed genome mapping, molecular phylogenetic analyses using Maximum Likelihood and Bayesian methods, and statistical tests of tree topologies, to ascertain the phylogenetic relationship among ependymin proteins. Results Our results demonstrate that ependymin genes are also present in protostomes. In addition, as a result of the putative fish-specific genome duplication event and posterior divergence, the ependymin family can be divided into four groups according to their amino acid composition and branching pattern in the gene tree: 1 a brain-specific group of ependymin sequences that is unique to teleost fishes and encompasses the originally described ependymin; 2 a group expressed in non-brain tissue in fishes; 3 a group expressed in several tissues that appears to be deuterostome-specific, and 4 a group found in invertebrate deuterostomes and protostomes, with a broad pattern of expression and that probably represents the evolutionary origin of the ependymins. Using codon-substitution models to statistically assess the selective pressures acting over the ependymin protein family, we found evidence of episodic positive Darwinian selection and relaxed selective constraints in each one of the postduplication branches of the gene tree. However, purifying selection (with among-site variability appears to be the main influence on the evolution of each subgroup within the family

  20. Molecular evolution of the clustered MIC-3 multigene family of Gossypium species.

    Science.gov (United States)

    Buriev, Zabardast T; Saha, Sukumar; Shermatov, Shukhrat E; Jenkins, Johnie N; Abdukarimov, Abdusattor; Stelly, David M; Abdurakhmonov, Ibrokhim Y

    2011-12-01

    The Gossypium MIC-3 (Meloidogyne Induced Cotton-3) gene family is of great interest for molecular evolutionary studies because of its uniqueness to Gossypium species, multi-gene content, clustered localization, and root-knot nematode resistance-associated features. Molecular evolution of the MIC-3 gene family was studied in 15 tetraploid and diploid Gossypium genotypes that collectively represent seven phylogenetically distinct genomes. Synonymous (d(S)) and non-synonymous (d(N)) nucleotide substitution rates suggest that the second of the two exons of the MIC-3 genes has been under strong positive selection pressure, while the first exon has been under strong purifying selection to preserve function. Based on nucleotide substitution rates, we conclude that MIC-3 genes are evolving by a birth-and-death process and that a 'gene amplification' mechanism has helped to retain all duplicate copies, which best fits with the "bait and switch" model of R-gene evolution. The data indicate MIC-3 gene duplication events occurred at various rates, once per 1 million years (MY) in the allotetraploids, once per ~2 MY in the A/F genome clade, and once per ~8 MY in the D-genome clade. Variations in the MIC-3 gene family seem to reflect evolutionary selection for increased functional stability, while also expanding the capacity to develop novel "switch" pockets for responding to diverse pests and pathogens. Such evolutionary roles are congruent with the hypothesis that members of this unique resistance gene family provide fitness advantages in Gossypium.

  1. Chlorite dismutases - a heme enzyme family for use in bioremediation and generation of molecular oxygen.

    Science.gov (United States)

    Hofbauer, Stefan; Schaffner, Irene; Furtmüller, Paul G; Obinger, Christian

    2014-04-01

    Chlorite is a serious environmental concern, as rising concentrations of this harmful anthropogenic compound have been detected in groundwater, drinking water, and soil. Chlorite dismutases (Clds) are therefore important molecules in bioremediation as Clds catalyze the degradation of chlorite to chloride and molecular oxygen. Clds are heme b-containing oxidoreductases present in numerous bacterial and archaeal phyla. This review presents the phylogeny of functional Clds and Cld-like proteins, and demonstrates the close relationship of this novel enzyme family to the recently discovered dye-decolorizing peroxidases. The available X-ray structures, biophysical and enzymatic properties, as well as a proposed reaction mechanism, are presented and critically discussed. Open questions about structure-function relationships are addressed, including the nature of the catalytically relevant redox and reaction intermediates and the mechanism of inactivation of Clds during turnover. Based on analysis of currently available data, chlorite dismutase from "Candidatus Nitrospira defluvii" is suggested as a model Cld for future application in biotechnology and bioremediation. Additionally, Clds can be used in various applications as local generators of molecular oxygen, a reactivity already exploited by microbes that must perform aerobic metabolic pathways in the absence of molecular oxygen. For biotechnologists in the field of chemical engineering and bioremediation, this review provides the biochemical and biophysical background of the Cld enzyme family as well as critically assesses Cld's technological potential.

  2. Autoinhibitory mechanisms of ERG studied by molecular dynamics simulations

    Science.gov (United States)

    Lu, Yan; Salsbury, Freddie R.

    2015-01-01

    ERG, an ETS-family transcription factor, acts as a regulator of differentiation of early hematopoietic cells. It contains an autoinhibitory domain, which negatively regulates DNA-binding. The mechanism of autoinhibitory is still illusive. To understand the mechanism, we study the dynamical properties of ERG protein by molecular dynamics simulations. These simulations suggest that DNA binding autoinhibition associates with the internal dynamics of ERG. Specifically, we find that (1), The N-C terminal correlation in the inhibited ERG is larger than that in uninhibited ERG that contributes to the autoinhibition of DNA-binding. (2), DNA-binding changes the property of the N-C terminal correlation from being anti-correlated to correlated, that is, changing the relative direction of the correlated motions and (3), For the Ets-domain specifically, the inhibited and uninhibited forms exhibit essentially the same dynamics, but the binding of the DNA decreases the fluctuation of the Ets-domain. We also find from PCA analysis that the three systems, even with quite different dynamics, do have highly similar free energy surfaces, indicating that they share similar conformations.

  3. Statistical mechanics of quasispecies theories of molecular evolution

    Science.gov (United States)

    Munoz Tavera, Enrique

    This thesis presents a statistical mechanical analysis of different formulations of quasispecies theory of molecular evolution. These theories, characterized by two different families of models, the Crow-Kimura and the Eigen model, constitute a microscopie description of evolution. These models are most often used for RNA viruses, where a phase transition is predicted, in agreement with experiments, between an organized or quasispecies phase, and a disordered non-selective phase when the mutation rate exceeds a critical value. The methods of statistical mechanics, in particular field-theoretic methods, are employed to obtain analytic solutions to four problems relevant to biological interest. The first chapter presents the study of evolution under a multiple-peak fitness landscape, with biological applications in the study of the proliferation of viruses or cancer under the control of drugs or the immune system. The second chapter studies the effect of incorporating different forms of horizontal gene transfer and two-parent recombination to the classical formulation of quasispecies models. As an example, we study the effect of the sign of epistasis of the fitness landscape on the advantage or disadvantage of recombination for the mean fitness. The third chapter considers the relaxation of the purine/pyrimidine assumption in the classical formulation of the models, by formulating and solving the parallel and Eigen models in the context of a four-letter alphabet. The fourth and final chapter studies finite population effects, both in the presence and in the absence of horizontal gene transfer.

  4. Molecular Mechanisms of HTLV-1 Cell-to-Cell Transmission

    Directory of Open Access Journals (Sweden)

    Christine Gross

    2016-03-01

    Full Text Available The tumorvirus human T-cell lymphotropic virus type 1 (HTLV-1, a member of the delta-retrovirus family, is transmitted via cell-containing body fluids such as blood products, semen, and breast milk. In vivo, HTLV-1 preferentially infects CD4+ T-cells, and to a lesser extent, CD8+ T-cells, dendritic cells, and monocytes. Efficient infection of CD4+ T-cells requires cell-cell contacts while cell-free virus transmission is inefficient. Two types of cell-cell contacts have been described to be critical for HTLV-1 transmission, tight junctions and cellular conduits. Further, two non-exclusive mechanisms of virus transmission at cell-cell contacts have been proposed: (1 polarized budding of HTLV-1 into synaptic clefts; and (2 cell surface transfer of viral biofilms at virological synapses. In contrast to CD4+ T-cells, dendritic cells can be infected cell-free and, to a greater extent, via viral biofilms in vitro. Cell-to-cell transmission of HTLV-1 requires a coordinated action of steps in the virus infectious cycle with events in the cell-cell adhesion process; therefore, virus propagation from cell-to-cell depends on specific interactions between cellular and viral proteins. Here, we review the molecular mechanisms of HTLV-1 transmission with a focus on the HTLV-1-encoded proteins Tax and p8, their impact on host cell factors mediating cell-cell contacts, cytoskeletal remodeling, and thus, virus propagation.

  5. The cognitive life of mechanical molecular models.

    Science.gov (United States)

    Charbonneau, Mathieu

    2013-12-01

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

  6. Quantum mechanics of molecular rate processes

    CERN Document Server

    Levine, Raphael D

    1999-01-01

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

  7. A Molecular Jump Mechanism of Water Reorientation

    National Research Council Canada - National Science Library

    Damien Laage; James T. Hynes

    2006-01-01

    .... This water reorientation mechanism involves large-amplitude angular jumps, rather than the commonly accepted sequence of small diffusive steps, and therefore calls for reinterpretation of many...

  8. 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 SN1-like reaction mechanism via the formation of a short-lived oxocarbenium ion intermediate. The computational barrier height was 19.5 kcal/mol, which reasonably corresponded with the experimental reaction rate. We also found that two tyrosine residues (Tyr156 and Tyr162) played a vital role in stabilizing the intermediate and the transition states by quantum mechanical interaction with CMP.

  9. Molecular characterization of Iranian patients with possible familial hypercholesterolemia.

    Science.gov (United States)

    Farrokhi, E; Shayesteh, F; Asadi Mobarakeh, S; Roghani Dehkordi, F; Ghatreh Samani, K; Hashemzadeh Chaleshtori, M

    2011-07-01

    Familial hypercholesterolemia (FH) is an autosomal dominant disorder of lipoprotein metabolism caused mainly by mutations in the low-density lipoprotein receptor (LDLR) and apolipoprotein B 100 (APOB) genes. Until now, the molecular basis of FH has been demonstrated in detail in many populations, but there is still very limited Molecular data concerning FH in Iran. The aim of this study was to characterize the LDLR and APOB gene mutations in an Iranian population. A total of 30 non-related Iranian possible FH subjects were studied. Diagnosis of FH was based on the Dutch Lipid Clinic Network diagnostic criteria. All samples were initially tested for three common APOB gene mutations including R3500Q, R3500 W and R3531C using PCR-RFLP assay. Subsequently, promoter and coding region of the LDLR gene was screened by PCR-SSCP analysis and positive results were confirmed by DNA sequencing. Four previously reported polymorphisms 1413G > A, 1725C > T, 1773T > C and 2140 + 5G > A were found in ~17% (5/30) of population studied. Moreover, no variation was found in APOB gene. Our data indicated that LDLR and APOB gene mutations have not contribution to possible FH in Iranian population studied here. However, we examined three common APOB mutations and LDLR in only 30 patients, and to determine the role of these genes in developing FH in Iran, more FH samples and populations needed to be investigated for the mutations of the related genes.

  10. Molecular mechanisms involved in convergent crop domestication.

    Science.gov (United States)

    Lenser, Teresa; Theißen, Günter

    2013-12-01

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

  11. Molecular Mechanisms of Sex Determination in Reptiles

    OpenAIRE

    Rhen, T; Schroeder, A

    2010-01-01

    Charles Darwin first provided a lucid explanation of how gender differences evolve nearly 140 years ago. Yet, a disconnect remains between his theory of sexual selection and the mechanisms that underlie the development of males and females. In particular, comparisons between representatives of different phyla (i.e., flies and mice) reveal distinct genetic mechanisms for sexual differentiation. Such differences are hard to comprehend unless we study organisms that bridge the phylogenetic gap. ...

  12. Molecular mechanics applied to single-walled carbon nanotubes

    Directory of Open Access Journals (Sweden)

    Antonio Ferreira Ávila

    2008-09-01

    Full Text Available Single-walled carbon nanotubes, with stiffness of 1.0 TPa and strength of 60 GPa, are a natural choice for high strength materials. A problem, however, arises when experimental data are compiled. The large variability of experimental data leads to the development of numerical models denominated molecular mechanics, which is a "symbiotic" association of molecular dynamics and solid mechanics. This paper deals with molecular mechanics simulations of single-walled carbon nanotubes. To be able to evaluate the molecular mechanics model, the three major carbon nanotube configurations (armchair, zigzag and chiral were simulated. It was proven that the carbon nanotube configuration has influence on stiffness. By varying the radius, hence the curvature, the Young's modulus changed from 0.95 TPa to 5.5 TPa, and the Poisson's ratio ranged from 0.15 to 0.29. The numerical simulations were in good agreement with those presented in the literature.

  13. A review on the molecular mechanism of plants rooting modulated ...

    African Journals Online (AJOL)

    A review on the molecular mechanism of plants rooting modulated by auxin. ... rooting modulated by auxin. H Han, S Zhang, X Sun ... Phytohormones, especially auxin, played an essential role in regulating roots developments. This review ...

  14. 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)

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

    Science.gov (United States)

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

    2011-05-01

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

  16. Molecular mechanisms of gap junction mutations in myelinating cells.

    Science.gov (United States)

    Sargiannidou, Irene; Markoullis, Kyriaki; Kleopa, Kleopas A

    2010-09-01

    There is an emerging group of neurological disorders that result from genetic mutations affecting gap junction proteins in myelinating cells. The X-linked form of Charcot Marie Tooth disease (CMT1X) is caused by numerous mutations in the GJB1 gene encoding the gap junction protein connexin32 (Cx32), which is expressed in both Schwann cells in the PNS and oligodendrocytes in the CNS. Patients with CMT1X present mainly with a progressive peripheral neuropathy, showing mixed axonal and demyelinating features. In many cases there is also clinical or subclinical involvement of the CNS with acute or chronic phenotypes of encephalopathy. Furthermore, mutations in the GJA12/GJC2 gene encoding the gap junction protein Cx47, which is expressed in oligodendrocytes, have been identified in families with progressive leukodystrophy, known as Pelizaeus-Merzbacher-like disease, as well as in patients with hereditary spastic paraplegia. Recent studies have provided insights into the pattern of gap junction protein expression and function in CNS and PNS myelinating cells. Furthermore, in vitro and in vivo disease models have clarified some of the molecular and cellular mechanisms underlying these disorders. Here we provide an overview of the clinical, genetic, and neurobiological aspects of gap junction disorders affecting the nervous system.

  17. Molecular and cellular mechanisms of pulmonary fibrosis

    Directory of Open Access Journals (Sweden)

    Todd Nevins W

    2012-07-01

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

  18. Molecular mechanisms of STIM/Orai communication

    Science.gov (United States)

    Derler, Isabella; Jardin, Isaac

    2016-01-01

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

  19. Etiologies and molecular mechanisms of communication disorders.

    Science.gov (United States)

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

    2010-09-01

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

  20. Molecular mechanisms of epithelial–mesenchymal transition

    Science.gov (United States)

    Lamouille, Samy; Xu, Jian; Derynck, Rik

    2014-01-01

    The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial–mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix-loop-helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT. PMID:24556840

  1. Mechanism of Molecular Exchange in Copolymer Micelles

    Science.gov (United States)

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

    2010-03-01

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

  2. Male sex determination: insights into molecular mechanisms

    Institute of Scientific and Technical Information of China (English)

    Kathryn McClelland; Josephine Bowles; Peter Koopman

    2012-01-01

    Disorders of sex development often arise from anomalies in the molecular or cellular networks that guide the differentiation of the embryonic gonad into either a testis or an ovary,two functionally distinct organs.The activation of the Y-linked gene Sry(sexdetermining region Y) and its downstream target Sox9 (Sry box-containinggene 9) triggers testis differentiation by stimulating the differentiation of Sertoli cells,which then direct testis morphogenesis.Once engaged,a genetic pathway promotes the testis development while actively suppressing genes involved in ovarian development.This review focuses on the events of testis determination and the struggle to maintain male fate in the face of antagonistic pressure from the underlying female programme.

  3. Fine specificity and molecular competition in SLAM family receptor signalling.

    Science.gov (United States)

    Wilson, Timothy J; Garner, Lee I; Metcalfe, Clive; King, Elliott; Margraf, Stefanie; Brown, Marion H

    2014-01-01

    SLAM family receptors regulate activation and inhibition in immunity through recruitment of activating and inhibitory SH2 domain containing proteins to immunoreceptor tyrosine based switch motifs (ITSMs). Binding of the adaptors, SAP and EAT-2 to ITSMs in the cytoplasmic regions of SLAM family receptors is important for activation. We analysed the fine specificity of SLAM family receptor phosphorylated ITSMs and the conserved tyrosine motif in EAT-2 for SH2 domain containing signalling proteins. Consistent with the literature describing dependence of CRACC (SLAMF7) on EAT-2, CRACC bound EAT-2 (KD = 0.003 μM) with approximately 2 orders of magnitude greater affinity than SAP (KD = 0.44 μM). RNA interference in cytotoxicity assays in NK92 cells showed dependence of CRACC on SAP in addition to EAT-2, indicating selectivity of SAP and EAT-2 may depend on the relative concentrations of the two adaptors. The concentration of SAP was four fold higher than EAT-2 in NK92 cells. Compared with SAP, the significance of EAT-2 recruitment and its downstream effectors are not well characterised. We identified PLCγ1 and PLCγ2 as principal binding partners for the EAT-2 tail. Both PLCγ1 and PLCγ2 are functionally important for cytotoxicity in NK92 cells through CD244 (SLAMF4), NTB-A (SLAMF6) and CRACC. Comparison of the specificity of SH2 domains from activating and inhibitory signalling mediators revealed a hierarchy of affinities for CD244 (SLAMF4) ITSMs. While binding of phosphatase SH2 domains to individual ITSMs of CD244 was weak compared with SAP or EAT-2, binding of tandem SH2 domains of SHP-2 to longer peptides containing tandem phosphorylated ITSMs in human CD244 increased the affinity ten fold. The concentration of the tyrosine phosphatase, SHP-2 was in the order of a magnitude higher than the adaptors, SAP and EAT-2. These data demonstrate a mechanism for direct recruitment of phosphatases in inhibitory signalling by ITSMs, while explaining competitive

  4. Fine Specificity and Molecular Competition in SLAM Family Receptor Signalling

    Science.gov (United States)

    Wilson, Timothy J.; Garner, Lee I.; Metcalfe, Clive; King, Elliott; Margraf, Stefanie; Brown, Marion H.

    2014-01-01

    SLAM family receptors regulate activation and inhibition in immunity through recruitment of activating and inhibitory SH2 domain containing proteins to immunoreceptor tyrosine based switch motifs (ITSMs). Binding of the adaptors, SAP and EAT-2 to ITSMs in the cytoplasmic regions of SLAM family receptors is important for activation. We analysed the fine specificity of SLAM family receptor phosphorylated ITSMs and the conserved tyrosine motif in EAT-2 for SH2 domain containing signalling proteins. Consistent with the literature describing dependence of CRACC (SLAMF7) on EAT-2, CRACC bound EAT-2 (KD = 0.003 μM) with approximately 2 orders of magnitude greater affinity than SAP (KD = 0.44 μM). RNA interference in cytotoxicity assays in NK92 cells showed dependence of CRACC on SAP in addition to EAT-2, indicating selectivity of SAP and EAT-2 may depend on the relative concentrations of the two adaptors. The concentration of SAP was four fold higher than EAT-2 in NK92 cells. Compared with SAP, the significance of EAT-2 recruitment and its downstream effectors are not well characterised. We identified PLCγ1 and PLCγ2 as principal binding partners for the EAT-2 tail. Both PLCγ1 and PLCγ2 are functionally important for cytotoxicity in NK92 cells through CD244 (SLAMF4), NTB-A (SLAMF6) and CRACC. Comparison of the specificity of SH2 domains from activating and inhibitory signalling mediators revealed a hierarchy of affinities for CD244 (SLAMF4) ITSMs. While binding of phosphatase SH2 domains to individual ITSMs of CD244 was weak compared with SAP or EAT-2, binding of tandem SH2 domains of SHP-2 to longer peptides containing tandem phosphorylated ITSMs in human CD244 increased the affinity ten fold. The concentration of the tyrosine phosphatase, SHP-2 was in the order of a magnitude higher than the adaptors, SAP and EAT-2. These data demonstrate a mechanism for direct recruitment of phosphatases in inhibitory signalling by ITSMs, while explaining competitive

  5. Molecular mechanisms in plant abiotic stress response

    Directory of Open Access Journals (Sweden)

    Poltronieri Palmiro

    2011-01-01

    Full Text Available Improved crop varieties are needed to sustain the food supply, to fight climate changes, water scarcity, temperature increase and a high variability of rainfalls. Variability of drought and increase in soil salinity have negative effects on plant growth and abiotic stresses seriously threaten sustainable agricultural production. To overcome the influence of abiotic stresses, new tolerant plant varieties and breeding techniques using assisted selection are sought. A deep understanding of the mechanisms that respond to stress and sustain stress resistance is required. Here is presented an overview of several mechanisms that interact in the stress response. Localised synthesis of plant hormones, second messengers and local effectors of abiotic stress response and survival, the signaling pathways regulated by plant hormones are today better understood. Metabolic networks in drought stress responses, long distance signaling, cross-talk between plant organs finalised to tissue-specific expression of abiotic stress relieving genes have been at the centre of most recent studies.

  6. Vancomycin Molecular Interactions: Antibiotic and Enantioselective Mechanisms

    Science.gov (United States)

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

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

  7. Molecular Mechanisms of Lymphocyte-Mediated Cytotoxicity

    Institute of Scientific and Technical Information of China (English)

    Zusen Fan; Qixiang Zhang

    2005-01-01

    Granule-mediated cytotoxicity is the major mechanism for lymphocytes to kill viruses, intracellular bacteria and tumors. The cytotoxic granules move to the immunological synapse by exocytosis after recognition of a killer cell.The contents of the granules are delivered into target cells with the help of perforin by endocytosis. A group of serine protease granzymes cleave their critical substrates to initiate DNA damage and cell death. The most abundant granzymes are granzyme A and B. They induce cell death through alternate and nonoverlapping pathways. The substrates and functions of the majority of the orphan granzymes have not yet been identified. It is possible that the diversity of granzymes provides fail-safe mechanisms for killing viruses and tumor cells.

  8. Molecular and biochemical mechanisms of preterm labour.

    Science.gov (United States)

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

    2004-12-01

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

  9. Xenon preconditioning: molecular mechanisms and biological effects

    Directory of Open Access Journals (Sweden)

    Liu Wenwu

    2013-01-01

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

  10. Molecular Mechanisms of Mechanosensitivity in Focal Adhesions

    OpenAIRE

    2016-01-01

    Physical environment guides tissue regeneration and morphology in both health and disease. In the past three decades, several experiments illustrated that mechanical cues are captured and transduced to biochemical signals in the cellular level (mechanotransduction) mediated by cell adhesion. Cells adhere to their microenvironment through large protein assemblies known as focal adhesions that directly couple intra- and extra-cellular matrices and play a critical role in many vital cell functio...

  11. Molecular mechanisms for tumour resistance to chemotherapy.

    Science.gov (United States)

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

    2016-08-01

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

  12. Cellular and molecular mechanisms of muscle atrophy

    Science.gov (United States)

    Bonaldo, Paolo; Sandri, Marco

    2013-01-01

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

  13. Cellular and molecular mechanisms of muscle atrophy

    Directory of Open Access Journals (Sweden)

    Paolo Bonaldo

    2013-01-01

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

  14. Parkinson disease: from pathology to molecular disease mechanisms.

    Science.gov (United States)

    Dexter, David T; Jenner, Peter

    2013-09-01

    Parkinson disease (PD) is a complex neurodegenerative disorder with both motor and nonmotor symptoms owing to a spreading process of neuronal loss in the brain. At present, only symptomatic treatment exists and nothing can be done to halt the degenerative process, as its cause remains unclear. Risk factors such as aging, genetic susceptibility, and environmental factors all play a role in the onset of the pathogenic process but how these interlink to cause neuronal loss is not known. There have been major advances in the understanding of mechanisms that contribute to nigral dopaminergic cell death, including mitochondrial dysfunction, oxidative stress, altered protein handling, and inflammation. However, it is not known if the same processes are responsible for neuronal loss in nondopaminergic brain regions. Many of the known mechanisms of cell death are mirrored in toxin-based models of PD, but neuronal loss is rapid and not progressive and limited to dopaminergic cells, and drugs that protect against toxin-induced cell death have not translated into neuroprotective therapies in humans. Gene mutations identified in rare familial forms of PD encode proteins whose functions overlap widely with the known molecular pathways in sporadic disease and these have again expanded our knowledge of the neurodegenerative process but again have so far failed to yield effective models of sporadic disease when translated into animals. We seem to be missing some key parts of the jigsaw, the trigger event starting many years earlier in the disease process, and what we are looking at now is merely part of a downstream process that is the end stage of neuronal death.

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

    Science.gov (United States)

    Gavin, Terrence

    2012-01-01

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

  16. Molecular evolution of the porcine type I interferon family: subtype-specific expression and antiviral activity.

    Directory of Open Access Journals (Sweden)

    Yongming Sang

    Full Text Available Type I interferons (IFNs, key antiviral cytokines, evolve to adapt with ever-changing viral threats during vertebrate speciation. Due to novel pathogenic pressure associated with Suidae speciation and domestication, porcine IFNs evolutionarily engender both molecular and functional diversification, which have not been well addressed in pigs, an important livestock species and animal model for biomedical sciences. Annotation of current swine genome assembly Sscrofa10.2 reveals 57 functional genes and 16 pseudogenes of type I IFNs. Subfamilies of multiple IFNA, IFNW and porcine-specific IFND genes are separated into four clusters with ∼ 60 kb intervals within the IFNB/IFNE bordered region in SSC1, and each cluster contains mingled subtypes of IFNA, IFNW and IFND. Further curation of the 57 functional IFN genes indicates that they include 18 potential artifactual duplicates. We performed phylogenetic construction as well as analyses of gene duplication/conversion and natural selection and showed that porcine type I IFN genes have been undergoing active diversification through both gene duplication and conversion. Extensive analyses of the non-coding sequences proximal to all IFN coding regions identified several genomic repetitive elements significantly associated with different IFN subtypes. Family-wide studies further revealed their molecular diversity with respect to differential expression and restrictive activity on the resurgence of a porcine endogenous retrovirus. Based on predicted 3-D structures of representative animal IFNs and inferred activity, we categorized the general functional propensity underlying the structure-activity relationship. Evidence indicates gene expansion of porcine type I IFNs. Genomic repetitive elements that associated with IFN subtypes may serve as molecular signatures of respective IFN subtypes and genomic mechanisms to mediate IFN gene evolution and expression. In summary, the porcine type I IFN profile has

  17. Molecular mechanisms of male germ cell differentiation.

    Science.gov (United States)

    Hecht, N B

    1998-07-01

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

  18. 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

    For the first time a consistent catalytic mechanism of phospholipase C from Bacillus cereus is reported based on molecular mechanics calculations. We have identified the position of the nucleophilic water molecule, which is directly involved in the hydrolysis of the natural substrate...... 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......). The subsequent collapse of the intermediate, regeneration of the enzyme, and release of the products has to involve a not yet identified second water molecule. The catalytic mechanism reported here is based on a series of molecular mechanics calculations. First, the x-ray structure of phospholipase C from B...

  19. Molecular Mechanisms of Circadian Regulation During Spaceflight

    Science.gov (United States)

    Zanello, S. B.; Boyle, R.

    2012-01-01

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

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

    Science.gov (United States)

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

    2016-08-15

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

  1. Molecular and neuroendocrine mechanisms of cancer cachexia.

    Science.gov (United States)

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

    2015-09-01

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

  2. [Molecular mechanisms of skeletal muscle hypertrophy].

    Science.gov (United States)

    Astratenkova, I V; Rogozkin, V A

    2014-06-01

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

  3. Aquaporin water channels: molecular mechanisms for human diseases.

    Science.gov (United States)

    Agre, Peter; Kozono, David

    2003-11-27

    Although water is the major component of all biological fluids, the molecular pathways for water transport across cell membranes eluded identification until the discovery of the aquaporin family of water channels. The atomic structure of mammalian AQP1 illustrates how this family of proteins is freely permeated by water but not protons (hydronium ions, H3O+). Definition of the subcellular sites of expression predicted their physiological functions and potential clinical disorders. Analysis of several human disease states has confirmed that aquaporins are involved in multiple different illnesses including abnormalities of kidney function, loss of vision, onset of brain edema, starvation, and arsenic toxicity.

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

    Science.gov (United States)

    Minokoshi, Yasuhiko

    2016-03-01

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

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

    Science.gov (United States)

    1989-05-26

    Clasification ) A Molecular Mechanics Analysis of Molecular Recognition By Cyclodextrin Mimics of Alpha-Chymotrypsin. 12. PERSONAL AUTHOR(S) C.A. Venanzil...Field Parameters The AMBER force field was developed by Kollmann and coworkers tc 28293 treat proteins and nucleic acids , as well as small molecules2 9

  6. Molecular Mechanism of Apoptosis and Necrosis

    Directory of Open Access Journals (Sweden)

    Gulfidan Coskun

    2011-06-01

    Full Text Available Organismal homeostasis depends on an intricate balance between cell death and renewal. Apoptosis is a process of programmed cell death that plays a critical role in some normal and pathologic conditions beginning from embryologic development and ends at death. Apoptosis is initiated by morphological changes at the cell membrane, surface organels and nucleus. Apoptosis starts with death signals coming from outside or inside of the cell and continue to activate the mechanisms of apoptosis via cell death receptor or mitochondrial pathways. During apoptosis a group proteases are activated which cause DNA fragmentation, cytoplasmic shrinkage and membrane blebbing. Apoptotic cells divide into apoptotic bodies and then these apoptotic bodies are removed from tissue by phagocytes and adjacent cells In contrast to the “programmed” nature of apoptosis, necrotic cell death has always been believed to be a random, uncontrolled process that leads to death of the cell. Also necrosis, which is an other type of cell death, came to be used to describe pathologic cell death which cause inflamation. [Archives Medical Review Journal 2011; 20(3.000: 145-158

  7. Molecular mechanisms of alcohol associated pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Dahn; L; Clemens; Mark; A; Wells; Katrina; J; Schneider; Shailender; Singh

    2014-01-01

    Alcohol abuse is commonly associated with the development of both acute and chronic pancreatitis. Despite this close association, the fact that only a small percentage of human beings who abuse alcohol develop pancreatitis indicates that alcohol abuse alone is not sufficient to initiate clinical pancreatitis. This contention is further supported by the fact that administration of ethanol to experimental animals does not cause pancreatitis. Because of these findings, it is widely believed that ethanol sensitizes the pancreas to injury and additional factors trigger the development of overt pancreatitis. How ethanol sensitizes the pancreas to pancreatitis is not entirely known. Numerous studies have demonstrated that ethanol and its metabolites have a number of deleterious effects on acinar cells. Important acinar cells properties that are affected by ethanol include: calcium signaling, secretion of zymogens, autophagy, cellular regeneration, the unfolded protein response, and mitochondrial membrane integrity. In addition to the actions of ethanol on acinar cells, it is apparent that ethanol also affects pancreatic stellatecells. Pancreatic stellate cells have a critical role in normal tissue repair and the pathologic fibrotic response. Given that ethanol and its metabolites affect so many pancreatic functions, and that all of these effects occur simultaneously, it is likely that none of these effects is "THE" effect. Instead, it is most likely that the cumulative effect of ethanol on the pancreas predisposes the organ to pancreatitis. The focus of this article is to highlight some of the important mechanisms by which ethanol alters pancreatic functions and may predispose the pancreas to disease.

  8. 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

  9. Insights into the phosphatase and the synthase activities of human bisphosphoglycerate mutase: a quantum mechanics/molecular mechanics simulation.

    Science.gov (United States)

    Chu, Wen-Ting; Zheng, Qing-Chuan; Zhang, Hong-Xing

    2014-03-07

    Bisphosphoglycerate mutase (BPGM) is a multi-activity enzyme. Its main function is to synthesize the 2,3-bisphosphoglycerate, the allosteric effector of hemoglobin. This enzyme can also catalyze the 2,3-bisphosphoglycerate to the 3-phosphoglycerate. In this study, the reaction mechanisms of both the phosphatase and the synthase activities of human bisphosphoglycerate mutase were theoretically calculated by using the quantum mechanics/molecular mechanics method based on the metadynamics and umbrella sampling simulations. The simulation results not only show the free energy curve of the phosphatase and the synthase reactions, but also reveal the important role of some residues in the active site. Additionally, the energy barriers of the two reactions indicate that the activity of the synthase in human bisphosphoglycerate mutase is much higher than that of the phosphatase. The estimated reaction barriers are consistent with the experimental data. Therefore, our work can give important information to understand the catalytic mechanism of the bisphosphoglycerate mutase family.

  10. 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.

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

    CERN Document Server

    Ji, Sungchul

    2012-01-01

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

  12. 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.

  13. Hydrogen bond networks determine emergent mechanical and thermodynamic properties across a protein family

    Directory of Open Access Journals (Sweden)

    Dallakyan Sargis

    2008-08-01

    Full Text Available Abstract Background Gram-negative bacteria use periplasmic-binding proteins (bPBP to transport nutrients through the periplasm. Despite immense diversity within the recognized substrates, all members of the family share a common fold that includes two domains that are separated by a conserved hinge. The hinge allows the protein to cycle between open (apo and closed (ligated conformations. Conformational changes within the proteins depend on a complex interplay of mechanical and thermodynamic response, which is manifested as an increase in thermal stability and decrease of flexibility upon ligand binding. Results We use a distance constraint model (DCM to quantify the give and take between thermodynamic stability and mechanical flexibility across the bPBP family. Quantitative stability/flexibility relationships (QSFR are readily evaluated because the DCM links mechanical and thermodynamic properties. We have previously demonstrated that QSFR is moderately conserved across a mesophilic/thermophilic RNase H pair, whereas the observed variance indicated that different enthalpy-entropy mechanisms allow similar mechanical response at their respective melting temperatures. Our predictions of heat capacity and free energy show marked diversity across the bPBP family. While backbone flexibility metrics are mostly conserved, cooperativity correlation (long-range couplings also demonstrate considerable amount of variation. Upon ligand removal, heat capacity, melting point, and mechanical rigidity are, as expected, lowered. Nevertheless, significant differences are found in molecular cooperativity correlations that can be explained by the detailed nature of the hydrogen bond network. Conclusion Non-trivial mechanical and thermodynamic variation across the family is explained by differences within the underlying H-bond networks. The mechanism is simple; variation within the H-bond networks result in altered mechanical linkage properties that directly affect

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

    Science.gov (United States)

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

    2015-02-01

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

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

    Science.gov (United States)

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

    2012-02-08

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

  16. The Phage-Inducible Chromosomal Islands: A Family of Highly Evolved Molecular Parasites.

    Science.gov (United States)

    Penadés, José R; Christie, Gail E

    2015-11-01

    The phage-inducible chromosomal islands (PICIs) are a family of highly mobile genetic elements that contribute substantively to horizontal gene transfer, host adaptation, and virulence. Initially identified in Staphylococcus aureus, these elements are now thought to occur widely in gram-positive bacteria. They are molecular parasites that exploit certain temperate phages as helpers, using a variety of elegant strategies to manipulate the phage life cycle and promote their own spread, both intra- and intergenerically. At the same time, these PICI-encoded mechanisms severely interfere with helper phage reproduction, thereby enhancing survival of the bacterial population. In this review we discuss the genetics and the life cycle of these elements, with special emphasis on how they interact and interfere with the helper phage machinery for their own benefit. We also analyze the role that these elements play in driving bacterial and viral evolution.

  17. 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.)

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

    Science.gov (United States)

    Abdelalim, Essam M

    2013-12-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1987-01-01

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

  20. Three-dimensional Interlocking Professional Management Mechanism of Agricultural Family-Owned Enterprise

    OpenAIRE

    Zhong-ming, Shen; Cheng-jun, Zhang

    2010-01-01

    The establishment of the three-dimensional interlocking professional management mechanism of agricultural family-owned enterprise was studied through the following three mechanisms; the stimulation and restriction mechanism within the agricultural family-owned enterprises, the credit mechanism of professional manager and the social environment mechanism. The relationship between the agricultural family-owned enterprise, professional manager and the society was studied. In the first place, the...

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

    Science.gov (United States)

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

    2017-03-01

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

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

    Science.gov (United States)

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

    2014-06-05

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

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

    Directory of Open Access Journals (Sweden)

    Audrey E. McCalley

    2014-06-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

  5. Molecular genetics of a Chinese family with spinocerebellar ataxia

    Directory of Open Access Journals (Sweden)

    Dan-dan WU

    2015-10-01

    Full Text Available Objective To study the genotype of the members of a Chinese family with spinocerebellar ataxia (SCA. Methods The peripheral blood samples of 6 patients and 40 asymptomatic people belonged to the family were collected. Referring to the clinical manifestations of the proband and second-generation sequencing results, the CAG trinucleotide repeats of the pathogenic gene ATXN2 were amplified by polymerase chain reaction (PCR. The repeated times of the trinucleotide in normally and abnormally amplified alleles were defined by agarose gel electrophoresis and PCR products sequencing. Results Autosomal dominant heredity was the cause of the SCA in this family. Six out of 46 in the fourth-generation were SCA2 patients, 7 were the carriers of pathogenic allele. The repeated times of CAG trinucleotide were within the normal range in one of the two alleles of ATXN2, but they were in abnormal range in the another one. The repeated times of CAG trinucleotide were 40-46 in abnormal alleles of patients. Conclusion Autosomal dominant heredity SCA2 has been diagnosed in this family caused by the dynamic nutation of CAG trinucleotide repeats, and 7 pathogenic allele carriers in this family were confirmed by genetic diagnosis. DOI: 10.11855/j.issn.0577-7402.2015.08.07

  6. Molecular mechanisms of epithelial host defense in the airways

    NARCIS (Netherlands)

    Vos, Joost Bastiaan

    2007-01-01

    Airway epithelial cells are indispensable for the host defense system in the lungs. Various strategies by which epithelial cells protect the lungs against inhaled pathogens have been described. In spite of that, the molecular mechanisms by which epithelial cells initiate and control the host defense

  7. Molecular mechanisms of novel regulators in cytokine signal transduction

    NARCIS (Netherlands)

    Xiaofei, Zhang

    2013-01-01

    By identifying and studying novel regulators, the studies described in this thesis give substantive insights into the molecular mechanisms and different levels of control of TGF-β/BMP, IL-1β and Wnt signaling pathways. Crucially, our work for the first time demonstrated the monoubiquitination of an

  8. Molecular mechanisms in muscular dystrophy : a gene expression profiling study.

    NARCIS (Netherlands)

    Turk, Rolf

    2006-01-01

    The muscular dystrophies are a group of neuromuscular disorders characterized by progres¬sive muscle weakness and wasting. Although the underlying genetic defects of a large number of muscular dystrophies are now know, the molecular mechanisms resulting in the devastating effects of the disease are

  9. Mechanisms of resistance to HER family targeting antibodies

    Energy Technology Data Exchange (ETDEWEB)

    Kruser, Tim J. [Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI (United States); Wheeler, Deric L., E-mail: dlwheeler@wisc.edu [Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI (United States)

    2010-04-15

    The epidermal growth factor (EGF) family of receptor tyrosine kinases consists of four members: EGFR (HER1/ErbB1), HER2/neu (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). Receptor activation via ligand binding leads to downstream signaling that influence cell proliferation, angiogenesis, invasion and metastasis. Aberrant expression or activity of EGFR and HER2 have been strongly linked to the etiology of several human epithelial cancers including but not limited to head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and breast cancer. With this, intense efforts have been made to inhibit the activity of the EGFR and HER2 by designing antibodies against the ligand binding domains (cetuximab, panitumumab and trastuzumab) or small molecules against the tyrosine kinase domains (erlotinib, gefitinib, and lapatinib). Both approaches have shown considerable clinical promise. However, increasing evidence suggests that the majority of patients do not respond to these therapies, and those who show initial response ultimately become refractory to treatment. While mechanisms of resistance to tyrosine kinase inhibitors have been extensively studied, resistance to monoclonal antibodies is less well understood, both in the laboratory and in the clinical setting. In this review, we discuss resistance to antibody-based therapies against the EGFR and HER2, similarities between these resistance profiles, and strategies to overcome resistance to HER family targeting monoclonal antibody therapy.

  10. Conserved water molecules in family 1 glycosidases: a DXMS and molecular dynamics study.

    Science.gov (United States)

    Teze, David; Hendrickx, Johann; Dion, Michel; Tellier, Charles; Woods, Virgil L; Tran, Vinh; Sanejouand, Yves-Henri

    2013-08-27

    By taking advantage of the wealth of structural data available for family 1 glycoside hydrolases, a study of the conservation of internal water molecules found in this ubiquitous family of enzymes was undertaken. Strikingly, seven water molecules are observed in more than 90% of the known structures. To gain insight into their possible function, the water dynamics inside Thermus thermophilus β-glycosidase was probed using deuterium exchange mass spectroscopy, allowing the pinpointing of peptide L117-A125, which exchanges most of its amide hydrogens quickly in spite of the fact that it is for the most part buried in the crystal structure. To help interpret this result, a molecular dynamics simulation was performed whose analysis suggests that two water channels are involved in the process. The longest one (∼16 Å) extends between the protein surface and W120, whose side chain interacts with E164 (the acid-base residue involved in the catalytic mechanism), whereas the other channel allows for the exchange with the bulk of the highly conserved water molecules belonging to the hydration shell of D121, a deeply buried residue. Our simulation also shows that another chain of highly conserved water molecules, going from the protein surface to the bottom of the active site cleft close to the nucleophile residue involved in the catalytic mechanism, is able to exchange with the bulk on the nanosecond time scale. It is tempting to speculate that at least one of these three water channels could be involved in the function of family 1 glycoside hydrolases.

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

    Science.gov (United States)

    Bayse, Craig A; Merz, Kenneth M

    2014-08-05

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

  12. 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.

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

    Science.gov (United States)

    Vo, Thin; Hardy, Daniel B

    2012-08-01

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

  14. A Modiifed Molecular Structure Mechanics Method for Analysis of Graphene

    Institute of Scientific and Technical Information of China (English)

    HUA Jun; LI Dongbo; ZHAO Dong; LIANG Shengwei; LIU Qinlong; JIA Ruiyan

    2015-01-01

    Based on molecular mechanics and the deformation characteristics of the atomic lattice structure of graphene, a modiifed molecular structure mechanics method was developed to improve the original one, that is, the semi-rigid connections were used to model the bond angle variations between the C-C bonds in graphene. The simulated results show that the equivalent space frame model with semi-rigid connections for graphene proposed in this article is a simple, efifcient, and accurate model to evaluate the equivalent elastic properties of graphene. Though the present computational model of the semi-rigid connected space frame is only applied to characterize the mechanical behaviors of the space lattices of graphene, it has more potential applications in the static and dynamic analyses of graphene and other nanomaterials.

  15. Role of Arg228 in the phosphorylation of galactokinase: the mechanism of GHMP kinases by quantum mechanics/molecular mechanics studies.

    Science.gov (United States)

    Huang, Meilan; Li, Xiaozhou; Zou, Jian-Wei; Timson, David J

    2013-07-16

    GHMP kinases are a group of structurally related small molecule kinases. They have been found in all kingdoms of life and are mostly responsible for catalyzing the ATP-dependent phosphorylation of intermediary metabolites. Although the GHMP kinases are of clinical, pharmaceutical, and biotechnological importance, the mechanism of GHMP kinases is controversial. A catalytic base mechanism was suggested for mevalonate kinase that has a structural feature of the γ-phosphate of ATP close to an aspartate residue; however, for one GHMP family member, homoserine kinase, where the residue acting as general base is absent, a direct phosphorylation mechanism was suggested. Furthermore, it was proposed by some authors that all the GHMP kinases function by a similar mechanism. This controversy in mechanism has limited our ability to exploit these enzymes as drug targets and in biotechnology. Here the phosphorylation reaction mechanism of the human galactokinase, a member of the GHMP kinase family, was investigated using molecular dynamics simulations and density functional theory-based quantum mechanics/molecular mechanics calculations (B3LYP-D/AMBER99). The reaction coordinates were localized by potential energy scan using an adiabatic mapping method. Our results indicate that a highly conserved Glu174 captures Arg105 in the proximity of the α-phosphate of ATP, forming a H-bond network; therefore, the mobility of ATP in the large oxyanion hole is restricted. Arg228 functions to stabilize the negative charge developed at the β,γ-bridging oxygen of the ATP during bond cleavage. The reaction occurs via a direct phosphorylation mechanism, and the Asp186 in the proximity of ATP does not directly participate in the reaction pathway. Because Arg228 is not conserved among GHMP kinases, reagents which form interactions with Arg228, and therefore can interrupt its function in phosphorylation, may be developed into potential selective inhibitors for galactokinase.

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

    Science.gov (United States)

    Eberhardt, Oliver; Wallmersperger, Thomas

    2015-04-01

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

  17. Structural Mechanisms of Allostery and Autoinhibition in JNK Family Kinases

    Energy Technology Data Exchange (ETDEWEB)

    Laughlin, J. D.; Nwachukwu, J. C.; Figuera-Losada, M.; Cherry, L.; Nettles, K. W.; LoGrasso, P. V.

    2012-12-05

    c-Jun N-terminal (JNK) family kinases have a common peptide-docking site used by upstream activating kinases, substrates, scaffold proteins, and phosphatases, where the ensemble of bound proteins determines signaling output. Although there are many JNK structures, little is known about mechanisms of allosteric regulation between the catalytic and peptide-binding sites, and the activation loop, whose phosphorylation is required for catalytic activity. Here, we compare three structures of unliganded JNK3 bound to different peptides. These were compared as a class to structures that differ in binding of peptide, small molecule ligand, or conformation of the kinase activation loop. Peptide binding induced an inhibitory interlobe conformer that was reversed by alterations in the activation loop. Structure class analysis revealed the subtle structural mechanisms for allosteric signaling between the peptide-binding site and activation loop. Biochemical data from isothermal calorimetry, fluorescence energy transfer, and enzyme inhibition demonstrated affinity differences among the three peptides that were consistent with structural observations.

  18. Microscopic and macroscopic polarization within a combined quantum mechanics and molecular mechanics model

    NARCIS (Netherlands)

    Jensen, L; Swart, M; van Duijnen, PT

    2005-01-01

    A polarizable quantum mechanics and molecular mechanics model has been extended to account for the difference between the macroscopic electric field and the actual electric field felt by the solute molecule. This enables the calculation of effective microscopic properties which can be related to mac

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

    Science.gov (United States)

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

    2009-07-21

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

  20. Molecular mechanisms involved in mammalian primary sex determination.

    Science.gov (United States)

    She, Zhen-Yu; Yang, Wan-Xi

    2014-08-01

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

  1. Molecular dynamics simulations of diffusion mechanisms in NiAl

    Energy Technology Data Exchange (ETDEWEB)

    Soule De Bas, B.; Farkas, D

    2003-03-14

    Molecular dynamics simulations of the diffusion process in ordered B2 NiAl at high temperature were performed using an embedded atom interatomic potential. Diffusion occurs through a variety of cyclic mechanisms that accomplish the motion of the vacancy through nearest neighbor jumps restoring order to the alloy at the end of the cycle. The traditionally postulated six-jump cycle is only one of the various cycles observed and some of these are quite complex. A detailed sequential analysis of the observed six-jump cycles was performed and the results are analyzed in terms of the activation energies for individual jumps calculated using molecular statics simulations.

  2. Quantum Mechanical/Molecular Mechanical Studies on Spectral Tuning Mechanisms of Visual Pigments and Other Photoactive Proteins†

    Science.gov (United States)

    Altun, Ahmet; Yokoyama, Shozo; Morokuma, Keiji

    2008-01-01

    The protein environments surrounding the retinal tune electronic absorption maximum from 350 to 630 nm. Hybrid quantum mechanical/molecular mechanical (QM/MM) methods can be used in calculating excitation energies of retinal in its native protein environments and in studying the molecular basis of spectral tuning. We hereby review recent QM/MM results on the phototransduction of bovine rhodopsin, bacteriorhodopsin, sensory rhodopsin II, nonretinal photoactive yellow protein and their mutants. PMID:18331400

  3. Quantum Mechanical/Molecular Mechanical Studies on Spectral Tuning Mechanisms of Visual Pigments and Other Photoactive Proteins†

    OpenAIRE

    Altun, Ahmet; Yokoyama, Shozo; Morokuma, Keiji

    2008-01-01

    The protein environments surrounding the retinal tune electronic absorption maximum from 350 to 630 nm. Hybrid quantum mechanical/molecular mechanical (QM/MM) methods can be used in calculating excitation energies of retinal in its native protein environments and in studying the molecular basis of spectral tuning. We hereby review recent QM/MM results on the phototransduction of bovine rhodopsin, bacteriorhodopsin, sensory rhodopsin II, nonretinal photoactive yellow protein and their mutants.

  4. Genetic classification and molecular mechanisms of primary dystonia

    Institute of Scientific and Technical Information of China (English)

    Xueping Chen; Huifang Shang; Zuming Luo

    2008-01-01

    BACKGROUND: Primary dystonia is a heterogeneous disease, with a complex genetic basis. In previous studies, primary dystonia was classified according to age of onset, involved regions, and other clinical characteristics. With the development of molecular genetics, new virulence genes and sites have been discovered. Therefore, there is a gradual understanding of the various forms of dystonia, based on new viewpoints. There are 15 subtypes of dystonia, based on the molecular level, i.e., DYT1 to DYT15. OBJECTIVE: To analyze the genetic development of dystonia in detail, and to further investigate molecular mechanisms of dystonia. RETRIEVAL STRATEGY: A computer-based online search was conducted in PubMed for English language publications containing the keywords "dystonia and genetic" from January 1980 to March 2007. There were 105 articles in total. Inclusion criteria: ① the contents of the articles should closely address genetic classification and molecular mechanisms of primary dystonia; ② the articles published in recent years or in high-impact journals took preference. Exclusion criteria: duplicated articles. LITERATURE EVALUATION: The selected articles were on genetic classification and molecular genetics mechanism of primary dystonia. Of those, 27 were basic or clinical studies. DATA SYNTHESIS: ① Dystonia is a heterogeneous disease, with a complex genetic basis. According to the classification of the Human Genome Organization, there are 15 dystonia subtypes, based on genetics, i.e., DYT1-DYT15,including primary dystonia, dystonia plus syndrome, degeneration plus dystonia, and paroxysmal dyskinesia plus dystonia. ② To date, the chromosomes of 13 subtypes have been localized; however, DYT2 and DYT4 remain unclear. Six subtypes have been located within virulence genes. Specifically, torsinA gene expression results in the DYT1 genotype; autosomal dominant GTP cyclohydrolase I gene expression and recessive tyrosine hydroxylase expression result in the DYT5

  5. 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.

  6. 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.

  7. Molecular evolution of PKD2 gene family in mammals.

    Science.gov (United States)

    Ye, Chun; Sun, Huan; Guo, Wenhu; Wei, Yuquan; Zhou, Qin

    2009-09-01

    PKD2 gene encodes a critical cation channel protein that plays important roles in various developmental processes and is usually evolutionarily conserved. In the present study, we analyzed the evolutionary patterns of PKD2 and its homologous genes (PKD2L1, PKD2L2) from nine mammalian species. In this study, we demonstrated the orthologs of PKD2 gene family evolved under a dominant purifying selection force. Our results in combination with the reported evidences from functional researches suggested the entire PKD2 gene family are conserved and perform essential biological roles during mammalian evolution. In rodents, PKD2 gene family members appeared to have evolved more rapidly than other mammalian lineages, probably resulting from relaxation of purifying selection. However, positive selection imposed on synonymous sites also potentially contributed to this case. For the paralogs, our results implied that PKD2L2 genes evolved under a weaker purifying selection constraint than PKD2 and PKD2L1 genes. Interestingly, some loop regions of transmembrane domain of PKD2L2 exhibited higher P (N)/P (S) ratios than expected, suggesting these regions are more functional divergent in organisms and worthy of special attention.

  8. A review on the molecular mechanisms involved in insulin resistance induced by organophosphorus pesticides.

    Science.gov (United States)

    Lasram, Mohamed Montassar; Dhouib, Ines Bini; Annabi, Alya; El Fazaa, Saloua; Gharbi, Najoua

    2014-08-01

    There is increasing evidence reporting that organophosphorus pesticides (OPs) impair glucose homeostasis and cause insulin resistance and type 2 diabetes. Insulin resistance is a complex metabolic disorder that defies explanation by a single etiological pathway. Formation of advanced glycation end products, accumulation of lipid metabolites, activation of inflammatory pathways and oxidative stress have all been implicated in the pathogenesis of insulin resistance. Ultimately, these molecular processes activate a series of stress pathways involving a family of serine kinases, which in turn have a negative effect on insulin signaling. Experimental and clinical data suggest an association between these molecular mechanisms and OPs compounds. It was first reported that OPs induce hyperglycemia. Then a concomitant increase of blood glucose and insulin was pointed out. For some years only, we have begun to understand that OPs promote insulin resistance and increase the risk of type 2 diabetes. Overall, this review outlines various mechanisms that lead to the development of insulin resistance by OPs exposure.

  9. 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.

  10. 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.

  11. Preventing Adolescent Depression with the Family Check-Up: Examining Family Conflict as a Mechanism of Change

    Science.gov (United States)

    Fosco, Gregory M.; Van Ryzin, Mark J.; Connell, Arin M.; Stormshak, Elizabeth A.

    2015-01-01

    Family-centered prevention programs are understudied for their effects on adolescent depression, despite considerable evidence that supports their effectiveness for preventing escalation in youth problem behavior and substance use. This study was conducted with 2 overarching goals: (a) replicate previous work that has implicated the Family Check-Up (FCU), a multilevel, gated intervention model embedded in public middle schools, as an effective strategy for preventing growth in adolescent depressive symptoms and (b) test whether changes in family conflict may be an explanatory mechanism for the long-term, protective effects of the FCU with respect to adolescent depression. This trial was conducted with 593 ethnically diverse families who were randomized to intervention (offered the FCU) or middle school as usual. Complier average causal effect (CACE) analysis revealed that engagers in the FCU evidenced less growth in depressive symptoms and family conflict from 6th through 9th grade and post-hoc analyses indicated that the FCU is related to lower rates of Major Depressive Disorder. The second set of analyses examined family conflict as a mechanism of change for families who participated in the FCU. Families who reported short-term intervention benefits had significantly less escalation in family conflict over the middle school years; in turn, growth in family conflict explained risk for adolescent depressive symptoms. PMID:26414418

  12. Preventing adolescent depression with the family check-up: Examining family conflict as a mechanism of change.

    Science.gov (United States)

    Fosco, Gregory M; Van Ryzin, Mark J; Connell, Arin M; Stormshak, Elizabeth A

    2016-02-01

    Family-centered prevention programs are understudied for their effects on adolescent depression, despite considerable evidence that supports their effectiveness for preventing escalation in youth problem behavior and substance use. This study was conducted with 2 overarching goals: (a) replicate previous work that has implicated the Family Check-Up (FCU), a multilevel, gated intervention model embedded in public middle schools, as an effective strategy for preventing growth in adolescent depressive symptoms and (b) test whether changes in family conflict may be an explanatory mechanism for the long-term, protective effects of the FCU with respect to adolescent depression. This trial was conducted with 593 ethnically diverse families who were randomized to intervention (offered the FCU) or middle school as usual. Complier average causal effect (CACE) analysis revealed that engagers in the FCU evidenced less growth in depressive symptoms and family conflict from 6th through 9th grade, and post hoc analyses indicated that the FCU is related to lower rates of major depressive disorder. The second set of analyses examined family conflict as a mechanism of change for families who participated in the FCU. Families who reported short-term intervention benefits had significantly less escalation in family conflict over the middle school years; in turn, growth in family conflict explained risk for adolescent depressive symptoms. (c) 2016 APA, all rights reserved).

  13. Cellular and Molecular Mechanisms of Arrhythmia by Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Ali A. Sovari

    2016-01-01

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

  14. 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

  15. Reaction kinetics, molecular action, and mechanisms of cellulolytic proteins.

    Science.gov (United States)

    Mosier, N S; Hall, P; Ladisch, C M; Ladisch, M R

    1999-01-01

    Cellulolytic proteins form a complex of enzymes that work together to depolymerize cellulose to the soluble products cellobiose and glucose. Fundamental studies on their molecular mechanisms have been facilitated by advances in molecular biology. These studies have shown homology between cellulases from different microorganisms, and common mechanisms between enzymes whose modes of action have sometimes been viewed as being different, as suggested by the distribution of soluble products. A more complete picture of the cellulolytic action of these proteins has emerged and combines the physical and chemical characteristics of solid cellulose substrates with the specialized structure and function of the cellulases that break it down. This chapter combines the fundamentals of cellulose structure with enzyme function in a manner that relates the cellulose binding and biochemical kinetics at the catalytic site of the proteins to the macroscopic behavior of cellulase enzyme systems.

  16. Molecular mechanisms of insulin resistance in chronic hepatitis C

    Institute of Scientific and Technical Information of China (English)

    Mark W Douglas; Jacob George

    2009-01-01

    It is now widely recognized that chronic hepatitis C (CHC) is associated with insulin resistance (IR) and type 2 diabetes, so can be considered a metabolic disease. IR is most strongly associated with hepatitis C virus (HCV) genotype 1, in contrast to hepatic steatosis, which is associated with genotype 3 infection. Apart from the well-described complications of diabetes, IR in CHC predicts faster progression to fibrosis and cirrhosis that may culminate in liver failure and hepatocellular carcinoma. More recently, it has been recognized that IR in CHC predicts a poor response to antiviral therapy. The molecular mechanisms for the association between IR and HCV infection are not well defined. This review will elaborate on the clinical associations between CHC and IR and summarize current knowledge regarding the molecular mechanisms that potentially mediate HCV-associated IR.

  17. Molecular mechanisms of desiccation tolerance in resurrection plants.

    Science.gov (United States)

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

    2012-10-01

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

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

    Science.gov (United States)

    Clark, Melody S; Worland, M Roger

    2008-11-01

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

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

    Science.gov (United States)

    Li, Hongzhi; Fajer, Mikolai; Yang, Wei

    2007-01-14

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

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

    Science.gov (United States)

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

    2010-01-01

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

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

    Science.gov (United States)

    Subramaniyan, Arun K; Sun, C T

    2008-07-16

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

  2. Molecular mechanisms and treatment options for muscle wasting eiseases

    OpenAIRE

    Rüegg, Markus A; Glass, David J.

    2010-01-01

    Loss of muscle mass can be the consequence of pathological changes, as observed in muscular dystrophies; or it can be secondary to cachexia-inducing diseases that cause muscle atrophy, such as cancer, heart disease, or chronic obstructive pulmonary disease; or it can be a consequence of aging or simple disuse. Although muscular dystrophies are rare, muscle loss affects millions of people worldwide.Wediscuss the molecular mechanisms involved in muscular dystrophy and in muscle atrophy and pres...

  3. Molecular Composites: Processing, Post-Treatment and Mechanics

    Science.gov (United States)

    1987-07-01

    Mechanical Analyzer was used. 3.2 Articulated Matricies Several isotropic solutions (2.5, 3.0, and 3.2 wt%) were made from PBT36 and ABPBI in MSA at a fixed...built to address this problem. 22 3.3 Thermoplastic Matricies Thermoplastic matrix molecular composites could potentially be melt processed. This would...provide obvious advantages over PBT which is, of course, limited to solution processing. Several candidates were considered for matricies . The only re

  4. Mechanical characterization of nanoindented graphene via molecular dynamics simulations

    Directory of Open Access Journals (Sweden)

    Wang Tong

    2011-01-01

    Full Text Available Abstract The mechanical behavior of graphene under various indentation depths, velocities, and temperatures is studied using molecular dynamics analysis. The results show that the load, elastic and plastic energies, and relaxation force increased with increasing indentation depth and velocity. Nanoindentation induced pile ups and corrugations of the graphene. Resistance to deformation decreased at higher temperature. Strong adhesion caused topological defects and vacancies during the unloading process.

  5. 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.

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

    Science.gov (United States)

    2007-11-02

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

  7. Molecular mechanisms in muscular dystrophy: a gene expression profiling study.

    OpenAIRE

    2006-01-01

    The muscular dystrophies are a group of neuromuscular disorders characterized by progres¬sive muscle weakness and wasting. Although the underlying genetic defects of a large number of muscular dystrophies are now know, the molecular mechanisms resulting in the devastating effects of the disease are not yet clear. Furthermore, the muscular dystrophies differ in clinical presentation and severity. The processes responsible for this di¬vergence are largely unknown as well. In this thesis, gene e...

  8. Molecular mechanism of signaling by tumor necrosis factor

    Institute of Scientific and Technical Information of China (English)

    ZHA; Jikun(查纪坤); SHU; Hongbing(舒红兵)

    2002-01-01

    Tumor necrosis factor (TNF) is an important cytokine with multiple biological effects,including cell growth,differentiation,apoptosis,immune regulation and induction of inflammation. The effects of TNF are mediated by two receptors,TNF-R1 and TNF-R2. The major signal transduction pathways triggered by TNF include those that lead to apoptosis,activation of transcription factor NF-??B and protein kinase JNK. This review will discuss the molecular mechanisms of these signaling pathways.

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

    Science.gov (United States)

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

    2004-03-22

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

  10. Molecular mechanism of abnormal aggregation of α-synuclein

    Institute of Scientific and Technical Information of China (English)

    HU HongYua; LIN XiaoJing

    2007-01-01

    The abnormal aggregation of α-synuclein (α-Syn) is thought to be closely associated with Parkinson's disease, but the pathogenesis is still unclear. In this review, we survey the latest development in the molecular mechanism of abnormal α-Syn aggregation, especially in the aspects of the core sequences, aggregation inhibitors, structural transformation and filament morphologies. By exploring the mechanism of α-Syn aggregation, we will have a better understanding of the disease pathogenesis, and develop strategies for preventing and treating this severe disease.

  11. A qualitative study of patients' perceptions of the value of molecular diagnosis for familial hypercholesterolemia (FH).

    Science.gov (United States)

    Hallowell, Nina; Jenkins, Nicholas; Douglas, Margaret; Walker, Simon; Finnie, Robert; Porteous, Mary; Lawton, Julia

    2017-01-01

    For many years, familial hypercholesterolemia (FH), an inherited disorder, has been diagnosed using phenotypic features plus family history of early onset cardiovascular disease (CVD), and has been successfully treated using statin therapy. DNA testing is now available and this has been incorporated into familial cascade screening programmes in many parts of Europe. Little is known about patients' perceptions of the value of undergoing molecular diagnosis for FH. In-depth interviews were carried out with patients (n = 38) being treated for FH who were the first in their family to undergo DNA testing for FH. Data were analysed thematically. While interviewees regarded DNA testing as an unexceptional event, it was seen as a positive innovation because it confirmed that their family carried a particular disorder, offered an aetiological explanation for their hypercholesterolemia and provided information about their own and family members' future risks. From the patient perspective, the main benefit of molecular diagnosis lies in its ability to provide information which allows (younger) family members to access genetic screening and, thus, timely treatment. The implications for future developments in genetic services and the need to investigate further the provision of molecular testing in mainstream specialties are briefly discussed.

  12. Molecular mechanisms of Treg-mediated T cell suppression

    Directory of Open Access Journals (Sweden)

    Angelika eSchmidt

    2012-03-01

    Full Text Available CD4+CD25highFoxp3+ regulatory T cells (Tregs can suppress other immune cells and, thus, are critical mediators of peripheral self-tolerance. On the one hand, Tregs prevent autoimmune disease and allergies. On the other hand, Tregs can avert immune reactions against tumors and pathogens. Despite the importance of Tregs, the molecular mechanisms of suppression remain incompletely understood and controversial. Proliferation and cytokine production of CD4+CD25− conventional T cells (Tcons can be inhibited directly by Tregs. In addition, Tregs can indirectly suppress Tcon activation via inhibition of the stimulatory capacity of antigen presenting cells (APCs. Direct suppression of Tcons by Tregs can involve immunosuppressive soluble factors or cell contact. Different mechanisms of suppression have been described, so far with no consensus on one universal mechanism. Controversies might be explained by the fact that different mechanisms may operate depending on the site of the immune reaction and on the type and activation state of the suppressed target cell. Further, inhibition of T cell effector function can occur independently of suppression of proliferation. In this review, we summarize the described molecular mechanisms of suppression with a particular focus on suppression of Tcons and rapid suppression of T cell receptor (TCR-induced calcium (Ca2+, NFAT and NF-κB signaling in Tcons by Tregs.

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

    Directory of Open Access Journals (Sweden)

    Kuan-Hao Tsui

    2012-01-01

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

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

    Science.gov (United States)

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

    2016-01-25

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

  15. Molecular mechanisms of heavy metal hyperaccumulation and phytoremediation.

    Science.gov (United States)

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

    2005-01-01

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

  16. Molecular pathology of familial hypercholesterolemia, related dyslipidemias and therapies beyond the statins.

    Science.gov (United States)

    Faiz, Fathimath; Hooper, Amanda J; van Bockxmeer, Frank M

    2012-01-01

    The development of the statin class of cholesterol-lowering drugs is one of the most significant success stories of modern pharmacotherapy. World-wide there are an estimated 150 million people on statins, with the emerging economies of India and China predicted to contribute significantly to that number. Notwithstanding their success, a significant number of people cannot tolerate statins because of serious side effects; of equal concern, a substantial proportion of high risk patients fail to reach cholesterol-lowering targets. For these subjects there is an urgent need for new cholesterol-lowering agents to be used alone or in combination with statins. The success of statins has been largely underpinned by knowledge of cholesterol homeostasis at a molecular level, knowledge that was first gleaned in the 1980s from Brown and Goldstein's pioneering studies of familial hypercholesterolemia (FH, OMIM 143890). Follow-up work that has identified a number of intracellular and circulating factors, all capable of disrupting LDL clearance, has revealed that the low-density lipoprotein receptor- (LDLR) mediated clearance pathway is substantially more complex than previously thought. These factors were discovered in studies of individuals with very rare inherited conditions that lead to either hypo- or hypercholesterolemia. These investigations, besides providing clearer insight into the molecular mechanisms regulating plasma LDL concentrations, have also revealed a number of novel therapeutic targets independent from statins. Consequently, a number of novel therapeutic approaches that are based on small interfering bio-molecules, including antisense oligonucleotides, are now in clinical development. These are aimed at impairing the assembly, synthesis and secretion of apolipoprotein B-containing lipoproteins and/or accelerating their hepatic catabolism. The aim of this article is to focus on these recent advances in the understanding of the molecular basis of cholesterol

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

    Science.gov (United States)

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

    2013-03-01

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

  18. Structures of pattern recognition receptors reveal molecular mechanisms of autoinhibition, ligand recognition and oligomerization.

    Science.gov (United States)

    Chuenchor, Watchalee; Jin, Tengchuan; Ravilious, Geoffrey; Xiao, T Sam

    2014-02-01

    Pattern recognition receptors (PRRs) are essential sentinels for pathogens or tissue damage and integral components of the innate immune system. Recent structural studies have provided unprecedented insights into the molecular mechanisms of ligand recognition and signal transduction by several PRR families at distinct subcellular compartments. Here we highlight some of the recent discoveries and summarize the common themes that are emerging from these exciting studies. Better mechanistic understanding of the structure and function of the PRRs will improve future prospects of therapeutic targeting of these important innate immune receptors.

  19. The superspreading mechanism unveiled via molecular dynamics simulations

    Science.gov (United States)

    Theodorakis, Panagiotis; Muller, Erich; Craster, Richard; Matar, Omar

    2014-11-01

    Superspreading, by which aqueous droplets laden with specific surfactants wet hydrophobic substrates, is an unusual and dramatic phenomenon. This is attributed to various factors, e.g., a particular surfactant geometry, Marangoni flow, unique solid-fluid interactions, however, direct evidence for a plausible mechanism for superspreading has not yet been provided. Here, we use molecular dynamics simulations of a coarse-grained model with force fields obtained from the SAFT- γ equation of state to capture the superspreading mechanism of water drops with surfactants on model surfaces. Our simulations highlight and monitor the main features of the molecular behavior that lead to the superspreading mechanism, and reproduce and explain the experimentally-observed characteristic maxima of the spreading rate of the droplet vs. surfactant concentration and wettability. We also present a comparison between superspreading and non-superspreading surfactants underlining the main morphological and energetic characteristics of superspreaders. We believe that this is the first time a plausible superspreading mechanism based on a microscopic description is proposed; this will enable the design of surfactants with enhanced spreading ability specifically tailored for applications. EPSRC Grant Number EP/J010502/1.

  20. Structure-Activity Relationships on the Molecular Descriptors Family Project at the End

    Directory of Open Access Journals (Sweden)

    Lorentz JÄNTSCHI

    2007-12-01

    Full Text Available Molecular Descriptors Family (MDF on the Structure-Activity Relationships (SAR, a promising approach in investigation and quantification of the link between 2D and 3D structural information and the activity, and its potential in the analysis of the biological active compounds is summarized. The approach, attempts to correlate molecular descriptors family generated and calculated on a set of biological active compounds with their observed activity. The estimation as well as prediction abilities of the approach are presented. The obtained MDF SAR models can be used to predict the biological activity of unknown substrates in a series of compounds.

  1. MOLECULAR MECHANISM OF URANIUM REDUCTION BY CLOSTRIDIA AND ITS MANIPULATION.

    Energy Technology Data Exchange (ETDEWEB)

    FRANCIS, A.J.; GAO, W.; CHIDAMBARAM, D.; DODGE, C.J.

    2006-11-16

    This research addresses the need for detailed studies of the enzymatic mechanisms for reduction of radionuclides and/or metals by fermentative microorganisms. The overall objective of this research is to elucidate systematically the molecular mechanisms involved in the reduction of uranium by Clostridia. We propose to (1) determine the role of hydrogenases in uranium reduction, (2) purify the enzymes involved in uranium reduction, (3) determine the mechanisms of reduction, e.g., one or two electron transfer reactions, and (4) elucidate the genetic control of the enzymes and cellular factors involved in uranium reduction. This is a collaborative study between BNL and Stanford University involving expertise in biomolecular science, biochemistry, microbiology, and electrochemistry.

  2. Molecular Mechanism of Uranium Reduction by Clostridia and its Manipulation

    Energy Technology Data Exchange (ETDEWEB)

    A. J. Francis; W. Gao, D. Chidambaram; C.J. Dodge

    2006-06-01

    This research addresses the need for detailed studies of the enzymatic mechanisms for reduction of radionuclides and/or metals by fermentative microorganisms. The overall objective of this research is to elucidate systematically the molecular mechanisms involved in the reduction of uranium by Clostridia. We propose to (1) determine the role of hydrogenases in uranium reduction, (22) purify the enzymes involved in uranium reduction, (3) determine the mechanisms of reduction, e.g., one or two electron transfer reactions, and (4) elucidate the genetic control of the enzymes and cellular factors involved in uranium reduction. This is a collaborative study between BNL and Stanford University involving expertise in biomolecular science, biochemistry, microbiology, and electrochemistry.

  3. T cell mediated pathogenesis in EAE: Molecular mechanisms

    Directory of Open Access Journals (Sweden)

    Florian C Kurschus

    2015-06-01

    Full Text Available T cells are major initiators and mediators of disease in multiple sclerosis (MS and in its animal model experimental autoimmune encephalomyelitis (EAE. EAE is an antigen-driven autoimmune model in which immunization against myelin autoantigens elicits strong T cell responses which initiate its pathology with CNS myelin destruction. T cells cause pathogenic events by several mechanisms; some work in a direct fashion in the CNS, such as direct cytokine-induced damage, granzyme-mediated killing, or glutamate-induced neurotoxicity, whereas most are indirect mechanisms, such as activation of other cell types like macrophages, B cells, or neutrophils. This review aims to describe and discuss the molecular effector mechanism by which T cells harm the CNS during EAE.

  4. 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.

  5. 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

  6. 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.

  7. Studies on the molecular mechanisms of seed germination.

    Science.gov (United States)

    Han, Chao; Yang, Pingfang

    2015-05-01

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

  8. 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.

  9. Molecular Evolution of the Glycosyltransferase 6 Gene Family in Primates

    Science.gov (United States)

    Mendonça-Mattos, Patricia Jeanne de Souza; Harada, Maria Lúcia

    2016-01-01

    Glycosyltransferase 6 gene family includes ABO, Ggta1, iGb3S, and GBGT1 genes and by three putative genes restricted to mammals, GT6m6, GTm6, and GT6m7, only the latter is found in primates. GT6 genes may encode functional and nonfunctional proteins. Ggta1 and GBGT1 genes, for instance, are pseudogenes in catarrhine primates, while iGb3S gene is only inactive in human, bonobo, and chimpanzee. Even inactivated, these genes tend to be conversed in primates. As some of the GT6 genes are related to the susceptibility or resistance to parasites, we investigated (i) the selective pressure on the GT6 paralogs genes in primates; (ii) the basis of the conservation of iGb3S in human, chimpanzee, and bonobo; and (iii) the functional potential of the GBGT1 and GT6m7 in catarrhines. We observed that the purifying selection is prevalent and these genes have a low diversity, though ABO and Ggta1 genes have some sites under positive selection. GT6m7, a putative gene associated with aggressive periodontitis, may have regulatory function, but experimental studies are needed to assess its function. The evolutionary conservation of iGb3S in humans, chimpanzee, and bonobo seems to be the result of proximity to genes with important biological functions. PMID:28044107

  10. Molecular Evolution of the TET Gene Family in Mammals

    Directory of Open Access Journals (Sweden)

    Hiromichi Akahori

    2015-12-01

    Full Text Available Ten-eleven translocation (TET proteins, a family of Fe2+- and 2-oxoglutarate-dependent dioxygenases, are involved in DNA demethylation. They also help regulate various cellular functions. Three TET paralogs have been identified (TET1, TET2, and TET3 in humans. This study focuses on the evolution of mammalian TET genes. Distinct patterns in TET1 and TET2 vs. TET3 were revealed by codon-based tests of positive selection. Results indicate that TET1 and TET2 genes have experienced positive selection more frequently than TET3 gene, and that the majority of codon sites evolved under strong negative selection. These findings imply that the selective pressure on TET3 may have been relaxed in several lineages during the course of evolution. Our analysis of convergent amino acid substitutions also supports the different evolutionary dynamics among TET gene subfamily members. All of the five amino acid sites that are inferred to have evolved under positive selection in the catalytic domain of TET2 are localized at the protein’s outer surface. The adaptive changes of these positively selected amino acid sites could be associated with dynamic interactions between other TET-interacting proteins, and positive selection thus appears to shift the regulatory scheme of TET enzyme function.

  11. Molecular Evolution of the Glycosyltransferase 6 Gene Family in Primates

    Directory of Open Access Journals (Sweden)

    Eliane Evanovich

    2016-01-01

    Full Text Available Glycosyltransferase 6 gene family includes ABO, Ggta1, iGb3S, and GBGT1 genes and by three putative genes restricted to mammals, GT6m6, GTm6, and GT6m7, only the latter is found in primates. GT6 genes may encode functional and nonfunctional proteins. Ggta1 and GBGT1 genes, for instance, are pseudogenes in catarrhine primates, while iGb3S gene is only inactive in human, bonobo, and chimpanzee. Even inactivated, these genes tend to be conversed in primates. As some of the GT6 genes are related to the susceptibility or resistance to parasites, we investigated (i the selective pressure on the GT6 paralogs genes in primates; (ii the basis of the conservation of iGb3S in human, chimpanzee, and bonobo; and (iii the functional potential of the GBGT1 and GT6m7 in catarrhines. We observed that the purifying selection is prevalent and these genes have a low diversity, though ABO and Ggta1 genes have some sites under positive selection. GT6m7, a putative gene associated with aggressive periodontitis, may have regulatory function, but experimental studies are needed to assess its function. The evolutionary conservation of iGb3S in humans, chimpanzee, and bonobo seems to be the result of proximity to genes with important biological functions.

  12. Molecular Mechanisms of Cognitive Dysfunction following Traumatic Brain Injury

    Directory of Open Access Journals (Sweden)

    Kendall Rae Walker

    2013-07-01

    Full Text Available 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.

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

    Science.gov (United States)

    van der Kamp, Marc W; Mulholland, Adrian J

    2013-04-23

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

  14. Mechanisms of Helicobacter pylori antibiotic resistance and molecular testing

    Directory of Open Access Journals (Sweden)

    Toshihiro eNishizawa

    2014-10-01

    Full Text Available Antibiotic resistance in Helicobacter pylori (H. pylori is the main factor affecting the efficacy of current treatment methods against infection caused by this organism. The traditional culture methods for testing bacterial susceptibility to antibiotics are expensive and require 10 to 14 days. Since resistance to clarithromycin, fluoroquinolone, and tetracycline seems to be exclusively caused by specific mutations in a small region of the responsible gene, molecular methods offer an attractive alternative to the above-mentioned techniques. The technique of polymerase chain reaction (PCR is an accurate and rapid method for the detection of mutations that confer antibiotic resistance. This review highlights the mechanisms of antibiotic resistance in H. pylori and the molecular methods for antibiotic susceptibility testing.

  15. 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...

  16. Cocoa phytochemicals: recent advances in molecular mechanisms on health.

    Science.gov (United States)

    Kim, Jiyoung; Kim, Jaekyoon; Shim, Jaesung; Lee, Chang Yong; Lee, Ki Won; Lee, Hyong Joo

    2014-01-01

    Recent reports on cocoa are appealing in that a food commonly consumed for pure pleasure might also bring tangible benefits for human health. Cocoa consumption is correlated with reduced health risks of cardiovascular diseases, hypertension, atherosclerosis, and cancer, and the health-promoting effects of cocoa are mediated by cocoa-driven phytochemicals. Cocoa is rich in procyanidins, theobromine, (-)-epicatechin, catechins, and caffeine. Among the phytochemicals present in consumed cocoa, theobromine is most available in human plasma, followed by caffeine, (-)-epicatechin, catechin, and procyanidins. It has been reported that cocoa phytochemicals specifically modulate or interact with specific molecular targets linked to the pathogenesis of chronic human diseases, including cardiovascular diseases, cancer, neurodegenerative diseases, obesity, diabetes, and skin aging. This review summarizes comprehensive recent findings on the beneficial actions of cocoa-driven phytochemicals in molecular mechanisms of human health.

  17. Complement system part I - molecular mechanisms of activation and regulation

    Directory of Open Access Journals (Sweden)

    Nicolas eMerle

    2015-06-01

    Full Text Available Complement is a complex innate immune surveillance system, playing a key role in defense against pathogens and in host homeostasis. The complement system is initiated by conformational changes in recognition molecular complexes upon sensing danger signals. The subsequent cascade of enzymatic reactions is tightly regulated to assure that complement is activated only at specific locations requiring defense against pathogens, thus avoiding host tissue damage. Here we discuss the recent advances describing the molecular and structural basis of activation and regulation of the complement pathways and their implication on physiology and pathology. This article will review the mechanisms of activation of alternative, classical and lectin pathways, the formation of C3 and C5 convertases, the action of anaphylatoxins and the membrane attack complex. We will also discuss the importance of structure-function relationships using the example of atypical hemolytic uremic syndrome. Lastly we will discuss the development and benefits of therapies using complement inhibitors.

  18. Neural tube closure: cellular, molecular and biomechanical mechanisms.

    Science.gov (United States)

    Nikolopoulou, Evanthia; Galea, Gabriel L; Rolo, Ana; Greene, Nicholas D E; Copp, Andrew J

    2017-02-15

    Neural tube closure has been studied for many decades, across a range of vertebrates, as a paradigm of embryonic morphogenesis. Neurulation is of particular interest in view of the severe congenital malformations - 'neural tube defects' - that result when closure fails. The process of neural tube closure is complex and involves cellular events such as convergent extension, apical constriction and interkinetic nuclear migration, as well as precise molecular control via the non-canonical Wnt/planar cell polarity pathway, Shh/BMP signalling, and the transcription factors Grhl2/3, Pax3, Cdx2 and Zic2. More recently, biomechanical inputs into neural tube morphogenesis have also been identified. Here, we review these cellular, molecular and biomechanical mechanisms involved in neural tube closure, based on studies of various vertebrate species, focusing on the most recent advances in the field.

  19. The molecular mechanism for nuclear transport and its application.

    Science.gov (United States)

    Kim, Yun Hak; Han, Myoung-Eun; Oh, Sae-Ock

    2017-06-01

    Transportation between the cytoplasm and the nucleoplasm is critical for many physiological and pathophysiological processes including gene expression, signal transduction, and oncogenesis. So, the molecular mechanism for the transportation needs to be studied not only to understand cell physiological processes but also to develop new diagnostic and therapeutic targets. Recent progress in the research of the nuclear transportation (import and export) via nuclear pore complex and four important factors affecting nuclear transport (nucleoporins, Ran, karyopherins, and nuclear localization signals/nuclear export signals) will be discussed. Moreover, the clinical significance of nuclear transport and its application will be reviewed. This review will provide some critical insight for the molecular design of therapeutics which need to be targeted inside the nucleus.

  20. 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.

  1. Molecular characterization of edestin gene family in Cannabis sativa L.

    Science.gov (United States)

    Docimo, Teresa; Caruso, Immacolata; Ponzoni, Elena; Mattana, Monica; Galasso, Incoronata

    2014-11-01

    Globulins are the predominant class of seed storage proteins in a wide variety of plants. In many plant species globulins are present in several isoforms encoded by gene families. The major seed storage protein of Cannabis sativa L. is the globulin edestin, widely known for its nutritional potential. In this work, we report the isolation of seven cDNAs encoding for edestin from the C. sativa variety Carmagnola. Southern blot hybridization is in agreement with the number of identified edestin genes. All seven sequences showed the characteristic globulin features, but they result to be divergent members/forms of two edestin types. According to their sequence similarity four forms named CsEde1A, CsEde1B, CsEde1C, CsEde1D have been assigned to the edestin type 1 and the three forms CsEde2A, CsEde2B, CsEde2C to the edestin type 2. Analysis of the coding sequences revealed a high percentage of similarity (98-99%) among the different forms belonging to the same type, which decreased significantly to approximately 64% between the forms belonging to different types. Quantitative RT-PCR analysis revealed that both edestin types are expressed in developing hemp seeds and the amount of CsEde1 was 4.44 ± 0.10 higher than CsEde2. Both edestin types exhibited a high percentage of arginine (11-12%), but CsEde2 resulted particularly rich in methionine residues (2.36%) respect to CsEde1 (0.82%). The amino acid composition determined in CsEde1 and CsEde2 types suggests that these seed proteins can be used to improve the nutritional quality of plant food-stuffs.

  2. Molecular mechanisms of dominance evolution in Müllerian mimicry.

    Science.gov (United States)

    Llaurens, V; Joron, M; Billiard, S

    2015-12-01

    Natural selection acting on dominance between adaptive alleles at polymorphic loci can be sufficiently strong for dominance to evolve. However, the molecular mechanisms underlying such evolution are generally unknown. Here, using Müllerian mimicry as a case-study for adaptive morphological variation, we present a theoretical analysis of the invasion of dominance modifiers altering gene expression through different molecular mechanisms. Toxic species involved in Müllerian mimicry exhibit warning coloration, and converge morphologically with other toxic species of the local community, due to positive frequency-dependent selection acting on these colorations. Polymorphism in warning coloration may be maintained by migration-selection balance with fine scale spatial heterogeneity. We modeled a dominance modifier locus altering the expression of the warning coloration locus, targeting one or several alleles, acting in cis or trans, and either enhancing or repressing expression. We confirmed that dominance could evolve when balanced polymorphism was maintained at the color locus. Dominance evolution could result from modifiers enhancing one allele specifically, irrespective of their linkage with the targeted locus. Nonspecific enhancers could also persist in populations, at frequencies tightly depending on their linkage with the targeted locus. Altogether, our results identify which mechanisms of expression alteration could lead to dominance evolution in polymorphic mimicry. © 2015 The Author(s). Evolution © 2015 The Society for the Study of Evolution.

  3. Molecular mechanisms underlying noncoding risk variations in psychiatric genetic studies.

    Science.gov (United States)

    Xiao, X; Chang, H; Li, M

    2017-01-03

    Recent large-scale genetic approaches such as genome-wide association studies have allowed the identification of common genetic variations that contribute to risk architectures of psychiatric disorders. However, most of these susceptibility variants are located in noncoding genomic regions that usually span multiple genes. As a result, pinpointing the precise variant(s) and biological mechanisms accounting for the risk remains challenging. By reviewing recent progresses in genetics, functional genomics and neurobiology of psychiatric disorders, as well as gene expression analyses of brain tissues, here we propose a roadmap to characterize the roles of noncoding risk loci in the pathogenesis of psychiatric illnesses (that is, identifying the underlying molecular mechanisms explaining the genetic risk conferred by those genomic loci, and recognizing putative functional causative variants). This roadmap involves integration of transcriptomic data, epidemiological and bioinformatic methods, as well as in vitro and in vivo experimental approaches. These tools will promote the translation of genetic discoveries to physiological mechanisms, and ultimately guide the development of preventive, therapeutic and prognostic measures for psychiatric disorders.Molecular Psychiatry advance online publication, 3 January 2017; doi:10.1038/mp.2016.241.

  4. Molecular-dynamics study of detonation. II. The reaction mechanism

    Science.gov (United States)

    Rice, Betsy M.; Mattson, William; Grosh, John; Trevino, S. F.

    1996-01-01

    In this work, we investigate mechanisms of chemical reactions that sustain an unsupported detonation. The chemical model of an energetic crystal used in this study consists of heteronuclear diatomic molecules that, at ambient pressure, dissociate endothermically. Subsequent association of the products to form homonuclear diatomic molecules provides the energy release that sustains the detonation. A many-body interaction is used to simulate changes in the electronic bonding as a function of local atomic environment. The consequence of the many-body interaction in this model is that the intramolecular bond is weakened with increasing density. The mechanism of the reaction for this model was extracted by investigating the details of the molecular properties in the reaction zone with two-dimensional molecular dynamics. The mechanism for the initiation of the reaction in this model is pressure-induced atomization. There was no evidence of excitation of vibrational modes to dissociative states. This particular result is directly attributable to the functional form and choice of parameters for this model, but might also have more general applicability.

  5. Molecular mechanical properties of short-sequence peptide enzyme mimics.

    Science.gov (United States)

    Takahashi, Tsukasa; Vo Ngo, Bao C; Xiao, Leyang; Arya, Gaurav; Heller, Michael J

    2016-01-01

    While considerable attempts have been made to recreate the high turnover rates of enzymes using synthetic enzyme mimics, most have failed and only a few have produced minimal reaction rates that can barely be considered catalytic. One particular approach we have focused on is the use of short-sequence peptides that contain key catalytic groups in close proximity. In this study, we designed six different peptides and tested their ability to mimic the catalytic mechanism of the cysteine proteases. Acetylation and deacylation by Ellman's Reagent trapping experiments showed the importance of having phenylalanine groups surrounding the catalytic sites in order to provide greater proximity between the cysteine, histidine, and aspartate amino acid R-groups. We have also carried out all-atom molecular dynamics simulations to determine the distance between these catalytic groups and the overall mechanical flexibility of the peptides. We found strong correlations between the magnitude of fluctuations in the Cys-His distance, which determines the flexibility and interactions between the cysteine thiol and histidine imidazole groups, and the deacylation rate. We found that, in general, shorter Cys-His distance fluctuations led to a higher deacylation rate constant, implying that greater confinement of the two residues will allow a higher frequency of the acetyl exchange between the cysteine thiol and histidine imidazole R-groups. This may be the key to future design of peptide structures with molecular mechanical properties that lead to viable enzyme mimics.

  6. United polarizable multipole water model for molecular mechanics simulation

    Energy Technology Data Exchange (ETDEWEB)

    Qi, Rui; Wang, Qiantao; Ren, Pengyu, E-mail: pren@mail.utexas.edu [Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas 78712 (United States); Wang, Lee-Ping; Pande, Vijay S. [Department of Chemistry, Stanford University, Stanford, California 94305 (United States)

    2015-07-07

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

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

    Science.gov (United States)

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

    2014-07-28

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

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

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Jin; Meguid, S. A., E-mail: meguid@mie.utoronto.ca [Mechanics and Aerospace Design Laboratory, Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, Ontario M5S 3G8 (Canada)

    2014-10-27

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

  9. 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.

  10. 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

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

    Science.gov (United States)

    Yamaguchi, H

    1999-01-01

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

  12. Leber′s hereditary optic neuropathy with molecular characterization in two Indian families

    Directory of Open Access Journals (Sweden)

    Verma I

    2005-01-01

    Full Text Available PURPOSE: Leber′s hereditary optic neuropathy (LHON presents in early adulthood with painless progressive blindness of one or both eyes. Usually there is a positive family history of similar disease on the maternal side. Definitive diagnosis can be established by finding the change in the mitochondrial gene. No molecular studies have been reported from India. MATERIAL AND METHODS: Clinical, ophthalmologic and molecular studies were carried out in two patients from different families and available first degree relatives. The subjects were tested for the three common mutations seen in LHON by molecular techniques of polymerase chain reaction using mutation specific primers. RESULTS: The mutations G3460A and G11778A in the mitochondrial genes MTND1 and MTND4, known to be causative for LHON, were found in one family each. CONCLUSION: Diagnosis of LHON should be considered in familial cases and in young adults with optic atrophy. Confirmation of diagnosis should be sought by molecular gene analysis. Genetic counselling should be offered to all ′at risk′ relatives of a patient harbouring the mutation.

  13. Prediction of solid solution formation in a family of diastereomeric salts. A molecular modeling study

    NARCIS (Netherlands)

    Gervais, C.; Grimbergen, R.F.P.; Markovits, I.; Ariaans, G.J.A.; Kaptein, B.; Bruggink, A.; Broxterman, Q.B.

    2004-01-01

    The possibility of solid solution behavior of diastereomeric salts, containing multiple resolving agents of the same family (Dutch Resolution), is predicted by molecular modeling. Super-cells containing different ratios of resolving agents in the diastereomeric salt are constructed and optimized, an

  14. Estimation of mechanical properties of single wall carbon nanotubes using molecular mechanics approach

    Indian Academy of Sciences (India)

    P Subba Rao; Sunil Anandatheertha; G Narayana Naik; G Gopalakrishnan

    2015-06-01

    Molecular mechanics based finite element analysis is adopted in the current work to evaluate the mechanical properties of Zigzag, Armchair and Chiral Single wall Carbon Nanotubes (SWCNT) of different diameters and chiralities. Three different types of atomic bonds, that is Carbon–Carbon covalent bond and two types of Carbon–Carbon van der Waals bonds are considered in the carbon nanotube system. The stiffness values of these bonds are calculated using the molecular potentials, namely Morse potential function and Lennard-Jones interaction potential function respectively and these stiffness’s are assigned to spring elements in the finite element model of the CNT. The geometry of CNT is built using a macro that is developed for the finite element analysis software. The finite element model of the CNT is constructed, appropriate boundary conditions are applied and the behavior of mechanical properties of CNT is studied.

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

    Science.gov (United States)

    Tang, Anna Y

    2016-08-01

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

  16. Molecular Mechanisms of Two-Component Signal Transduction.

    Science.gov (United States)

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

    2016-09-25

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

  17. Molecular Mechanism 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.

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

    Institute of Scientific and Technical Information of China (English)

    Xiaolong Yang; Tian Xu

    2011-01-01

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

  19. Autophagy - Adaptive Molecular Mechanisms in Condition of Starvation

    Directory of Open Access Journals (Sweden)

    Pedrycz Agnieszka

    2015-09-01

    Full Text Available Autophagy is an extremely old process during which long-lived proteins and cellular organelles are removed by means of lysosomes. Autophagy may be caused by cellular stress mechanisms. Research has proven that autophagy plays a key role in obtaining nutrients and adapting to the conditions of starvation. Owing to this, it takes part in maintaining homeostasis in cytoplasm and cell nucleus. This objective may be achieved through a number of ways. Depending on the manner in which a substrate connects with the lysosome, we can talk about macroautophagy and microautophagy. Additionally, some authors also distinguish a chaperone-mediated autophagy. The article presented below describes molecular mechanisms of each type of autophagy and focuses particularly on macroautophagy, which is the best understood of all the autophagy types.

  20. Systematic analysis of public domain compound potency data identifies selective molecular scaffolds across druggable target families.

    Science.gov (United States)

    Hu, Ye; Wassermann, Anne Mai; Lounkine, Eugen; Bajorath, Jürgen

    2010-01-28

    Molecular scaffolds that yield target family-selective compounds are of high interest in pharmaceutical research. There continues to be considerable debate in the field as to whether chemotypes with a priori selectivity for given target families and/or targets exist and how they might be identified. What do currently available data tell us? We present a systematic and comprehensive selectivity-centric analysis of public domain target-ligand interactions. More than 200 molecular scaffolds are identified in currently available active compounds that are selective for established target families. A subset of these scaffolds is found to produce compounds with high selectivity for individual targets among closely related ones. These scaffolds are currently underrepresented in approved drugs.

  1. 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.

  2. A molecular understanding of the dynamic mechanism of aquaporin osmosis

    CERN Document Server

    Shua, Liangsuo; Qian, Xin; Wanga, Xiyun; Lin, Yixin; Tan, Kai; Shu, Chaohui; Jin, Shiping

    2014-01-01

    AQPs (aquaporins), the rapid water channels of cells, play a key role in maintaining osmotic equilibrium of cells. In this paper, we reported the dynamic mechanism of AQP osmosis at the molecular level. A theoretical model based on molecular dynamics was carried out and verified by the published experimental data. The reflection coefficients ({\\sigma}) of neutral molecules are mainly decided by their relative size with AQPs, and increase with a third power up to a constant value 1. This model also indicated that the reflection coefficient of a complete impermeable solute can be smaller than 1. The H+ concentration of solution can influence the driving force of the AQPs by changing the equivalent diameters of vestibules surrounded by loops with abundant polar amino acids. In this way, pH of solution can regulate water permeability of AQPs. Therefore, an AQP may not only work as a switch to open or close, but as a rapid response molecular valve to control its water flow. The vestibules can prevent the channel b...

  3. Clinicopathological and molecular genetic analysis of 4 typical Chinese HNPCC families

    Institute of Scientific and Technical Information of China (English)

    Qi Cai; Meng-Hong Sun; Hong-Fen Lu; Tai-Ming Zhang; Shan-Jing Mo; Ye Xu; San-Jun Cai; Xiong-Zeng Zhu; Da-Ren Shi

    2001-01-01

    AIM: To study the clinicopathological and molecular genetic characteristics of typical Chinese hereditary nonpolyposis cotorectal cancer (HNPCC) families. METHODS: Four typical Chinese HNPCC families were analyzed using microdissection, microsatellite instability analysis, immunostaining of hMSH2 and hMLH1 proteins and direct DNA sequencing of hMSH2 and hMLH1 genes. RESULTS: All five tumor tissues of 4 probands from the 4typical Chinese HNPCC families showed microsatellite instability at more than two loci (MSI-H or RER +phenotype). Three out of the 4 cases lost hMSH2 protein expression and the other case showed no hMLH1 protein expression. Three pathological germline mutations (2 in hMSH2 and 1 in hMLH1 ), which had not been reported previously, were identified. The same mutations were also found in otler affected members of two HNPCC families,respectively. CONCLUSION: Typical Chinese HNPCC families showed relatively frequent germline mutation of mismstch repair genes. High-level microsateliita instability and loss of expression of mismatch repair genes correlated closely with germline mutation of mismatch repair genes. Microsatellite instability analysis and immunostaining of miamstch repair gens might serve as effective screening methods before direct DNA sequencing. It is necessary to establish clinical criteria and molecular diagnostic strategies more suitable for Chinese HNPCC families.

  4. Molecular mechanism of fluoroquinolones resistance in Mycoplasma hominis clinical isolates

    Directory of Open Access Journals (Sweden)

    Meng Dong-Ya

    2014-01-01

    Full Text Available To evaluate the molecular mechanism of fluoroquinolones resistance in Mycoplasma hominis (MH clinical strains isolated from urogenital specimens. 15 MH clinical isolates with different phenotypes of resistance to fluoroquinolones antibiotics were screened for mutations in the quinolone resistance-determining regions (QRDRs of DNA gyrase (gyrA and gyrB and topoisomerase IV (parC and parE in comparison with the reference strain PG21, which is susceptible to fluoroquinolones antibiotics. 15 MH isolates with three kinds of quinolone resistance phenotypes were obtained. Thirteen out of these quinolone-resistant isolates were found to carry nucleotide substitutions in either gyrA or parC. There were no alterations in gyrB and no mutations were found in the isolates with a phenotype of resistance to Ofloxacin (OFX, intermediate resistant to Levofloxacin (LVX and Sparfloxacin (SFX, and those susceptible to all three tested antibiotics. The molecular mechanism of fluoroquinolone resistance in clinical isolates of MH was reported in this study. The single amino acid mutation in ParC of MH may relate to the resistance to OFX and LVX and the high-level resistance to fluoroquinolones for MH is likely associated with mutations in both DNA gyrase and the ParC subunit of topoisomerase IV.

  5. Molecular mechanism of fluoroquinolones resistance in Mycoplasma hominis clinical isolates.

    Science.gov (United States)

    Meng, Dong-Ya; Sun, Chang-Jian; Yu, Jing-Bo; Ma, Jun; Xue, Wen-Cheng

    2014-01-01

    To evaluate the molecular mechanism of fluoroquinolones resistance in Mycoplasma hominis (MH) clinical strains isolated from urogenital specimens. 15 MH clinical isolates with different phenotypes of resistance to fluoroquinolones antibiotics were screened for mutations in the quinolone resistance-determining regions (QRDRs) of DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE) in comparison with the reference strain PG21, which is susceptible to fluoroquinolones antibiotics. 15 MH isolates with three kinds of quinolone resistance phenotypes were obtained. Thirteen out of these quinolone-resistant isolates were found to carry nucleotide substitutions in either gyrA or parC. There were no alterations in gyrB and no mutations were found in the isolates with a phenotype of resistance to Ofloxacin (OFX), intermediate resistant to Levofloxacin (LVX) and Sparfloxacin (SFX), and those susceptible to all three tested antibiotics. The molecular mechanism of fluoroquinolone resistance in clinical isolates of MH was reported in this study. The single amino acid mutation in ParC of MH may relate to the resistance to OFX and LVX and the high-level resistance to fluoroquinolones for MH is likely associated with mutations in both DNA gyrase and the ParC subunit of topoisomerase IV.

  6. Molecular mechanisms of ROS production and oxidative stress in diabetes.

    Science.gov (United States)

    Newsholme, Philip; Cruzat, Vinicius Fernandes; Keane, Kevin Noel; Carlessi, Rodrigo; de Bittencourt, Paulo Ivo Homem

    2016-12-15

    Oxidative stress and chronic inflammation are known to be associated with the development of metabolic diseases, including diabetes. Oxidative stress, an imbalance between oxidative and antioxidative systems of cells and tissues, is a result of over production of oxidative-free radicals and associated reactive oxygen species (ROS). One outcome of excessive levels of ROS is the modification of the structure and function of cellular proteins and lipids, leading to cellular dysfunction including impaired energy metabolism, altered cell signalling and cell cycle control, impaired cell transport mechanisms and overall dysfunctional biological activity, immune activation and inflammation. Nutritional stress, such as that caused by excess high-fat and/or carbohydrate diets, promotes oxidative stress as evident by increased lipid peroxidation products, protein carbonylation and decreased antioxidant status. In obesity, chronic oxidative stress and associated inflammation are the underlying factors that lead to the development of pathologies such as insulin resistance, dysregulated pathways of metabolism, diabetes and cardiovascular disease through impaired signalling and metabolism resulting in dysfunction to insulin secretion, insulin action and immune responses. However, exercise may counter excessive levels of oxidative stress and thus improve metabolic and inflammatory outcomes. In the present article, we review the cellular and molecular origins and significance of ROS production, the molecular targets and responses describing how oxidative stress affects cell function including mechanisms of insulin secretion and action, from the point of view of possible application of novel diabetic therapies based on redox regulation.

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

    Directory of Open Access Journals (Sweden)

    Alvaro C Ucero

    2010-04-01

    Full Text Available Alvaro C Ucero1,*, Sara Gonçalves2,*, Alberto Benito-Martin1, Beatriz Santamaría1, Adrian M Ramos1, Sergio Berzal1, Marta Ruiz-Ortega1, Jesus Egido1, Alberto Ortiz11Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Fundación Renal Iñigo Alvarez de Toledo, Madrid, Spain; 2Nefrologia e Transplantação Renal, Hospital de Santa Maria EPE, Lisbon, Portugal *Both authors contributed equally to the manuscriptAbstract: Urinary tract obstruction is a frequent cause of renal impairment. The physiopathology of obstructive nephropathy has long been viewed as a mere mechanical problem. However, recent advances in cell and systems biology have disclosed a complex physiopathology involving a high number of molecular mediators of injury that lead to cellular processes of apoptotic cell death, cell injury leading to inflammation and resultant fibrosis. Functional studies in animal models of ureteral obstruction using a variety of techniques that include genetically modified animals have disclosed an important role for the renin-angiotensin system, transforming growth factor-β1 (TGF-β1 and other mediators of inflammation in this process. In addition, high throughput techniques such as proteomics and transcriptomics have identified potential biomarkers that may guide clinical decision-making.Keywords: urinary tract obstruction, renal injury, fluid mechanics, molecular cell biology

  8. Zinc and diabetes--clinical links and molecular mechanisms.

    Science.gov (United States)

    Jansen, Judith; Karges, Wolfram; Rink, Lothar

    2009-06-01

    Zinc is an essential trace element crucial for the function of more than 300 enzymes and it is important for cellular processes like cell division and apoptosis. Hence, the concentration of zinc in the human body is tightly regulated and disturbances of zinc homeostasis have been associated with several diseases including diabetes mellitus, a disease characterized by high blood glucose concentrations as a consequence of decreased secretion or action of insulin. Zinc supplementation of animals and humans has been shown to ameliorate glycemic control in type 1 and 2 diabetes, the two major forms of diabetes mellitus, but the underlying molecular mechanisms have only slowly been elucidated. Zinc seems to exert insulin-like effects by supporting the signal transduction of insulin and by reducing the production of cytokines, which lead to beta-cell death during the inflammatory process in the pancreas in the course of the disease. Furthermore, zinc might play a role in the development of diabetes, since genetic polymorphisms in the gene of zinc transporter 8 and in metallothionein (MT)-encoding genes could be demonstrated to be associated with type 2 diabetes mellitus. The fact that antibodies against this zinc transporter have been detected in type 1 diabetic patients offers new diagnostic possibilities. This article reviews the influence of zinc on the diabetic state including the molecular mechanisms, the role of the zinc transporter 8 and MT for diabetes development and the resulting diagnostic and therapeutic options.

  9. Molecular Fundaments of Mechanical Properties of Spider Silk

    Institute of Scientific and Technical Information of China (English)

    潘志娟; 刘敏; 李春萍; 李栋高; 盛家镛

    2003-01-01

    Dragline,framework and cocoon silk fibers of Araneus Ventricosus were used for this study.To investigate the microstructure mechanisms of stress-strain behavior of spider silk,firstly,amino acid compositions were analyzed and molecular conformations and crystallinity were measured with Raman spectra and X-ray diffraction respectively.The results showed that there were more amino acids with large side groups and polar ones in spider silk than those of Bombyx silk,and the amino acid distribution varied with different spider silk.The molecular structures were mainly α-helix and β-sheet,and random coil and β-turn existed as well.The proportions and arrangement of these conformations of dragline silk were different from framework and cocoon silk fibers.Microstructure was one of important factors of excellent mechanical properties of spider silk.Crystallinity of spider silk was very low,which implied that the roles of crystal on spider silk were not as great as other protein fibers.

  10. Molecular Mechanisms of Phosphorus Metabolism and Transport during Leaf Senescence

    Directory of Open Access Journals (Sweden)

    Kyla A. Stigter

    2015-12-01

    Full Text Available Leaf senescence, being the final developmental stage of the leaf, signifies the transition from a mature, photosynthetically active organ to the attenuation of said function and eventual death of the leaf. During senescence, essential nutrients sequestered in the leaf, such as phosphorus (P, are mobilized and transported to sink tissues, particularly expanding leaves and developing seeds. Phosphorus recycling is crucial, as it helps to ensure that previously acquired P is not lost to the environment, particularly under the naturally occurring condition where most unfertilized soils contain low levels of soluble orthophosphate (Pi, the only form of P that roots can directly assimilate from the soil. Piecing together the molecular mechanisms that underpin the highly variable efficiencies of P remobilization from senescing leaves by different plant species may be critical for devising effective strategies for improving overall crop P-use efficiency. Maximizing Pi remobilization from senescing leaves using selective breeding and/or biotechnological strategies will help to generate P-efficient crops that would minimize the use of unsustainable and polluting Pi-containing fertilizers in agriculture. This review focuses on the molecular mechanisms whereby P is remobilized from senescing leaves and transported to sink tissues, which encompasses the action of hormones, transcription factors, Pi-scavenging enzymes, and Pi transporters.

  11. Molecular dynamics analysis of conserved hydrophobic and hydrophilic bond-interaction networks in ErbB family kinases.

    Science.gov (United States)

    Shih, Andrew J; Telesco, Shannon E; Choi, Sung-Hee; Lemmon, Mark A; Radhakrishnan, Ravi

    2011-06-01

    The EGFR (epidermal growth factor receptor)/ErbB/HER (human EGFR) family of kinases contains four homologous receptor tyrosine kinases that are important regulatory elements in key signalling pathways. To elucidate the atomistic mechanisms of dimerization-dependent activation in the ErbB family, we have performed molecular dynamics simulations of the intracellular kinase domains of three members of the ErbB family (those with known kinase activity), namely EGFR, ErbB2 (HER2) and ErbB4 (HER4), in different molecular contexts: monomer against dimer and wild-type against mutant. Using bioinformatics and fluctuation analyses of the molecular dynamics trajectories, we relate sequence similarities to correspondence of specific bond-interaction networks and collective dynamical modes. We find that in the active conformation of the ErbB kinases, key subdomain motions are co-ordinated through conserved hydrophilic interactions: activating bond-networks consisting of hydrogen bonds and salt bridges. The inactive conformations also demonstrate conserved bonding patterns (albeit less extensive) that sequester key residues and disrupt the activating bond network. Both conformational states have distinct hydrophobic advantages through context-specific hydrophobic interactions. We show that the functional (activating) asymmetric kinase dimer interface forces a corresponding change in the hydrophobic and hydrophilic interactions that characterize the inactivating bond network, resulting in motion of the αC-helix through allostery. Several of the clinically identified activating kinase mutations of EGFR act in a similar fashion to disrupt the inactivating bond network. The present molecular dynamics study reveals a fundamental difference in the sequence of events in EGFR activation compared with that described for the Src kinase Hck.

  12. Towards identification of molecular mechanisms of short stature.

    Science.gov (United States)

    Waldman, Lindsey A; Chia, Dennis J

    2013-11-20

    Growth evaluations are among the most common referrals to pediatric endocrinologists. Although a number of pathologies, both primary endocrine and non-endocrine, can present with short stature, an estimated 80% of evaluations fail to identify a clear etiology, leaving a default designation of idiopathic short stature (ISS). As a group, several features among children with ISS are suggestive of pathophysiology of the GH-IGF-1 axis, including low serum levels of IGF-1 despite normal GH secretion. Candidate gene analysis of rare cases has demonstrated that severe mutations of genes of the GH-IGF-1 axis can present with a profound height phenotype, leading to speculation that a collection of mild mutations or polymorphisms of these genes can explain poor growth in a larger proportion of patients. Recent genome-wide association studies have identified ~180 genomic loci associated with height that together account for approximately 10% of height variation. With only modest representation of the GH-IGF-1 axis, there is little support for the long-held hypothesis that common genetic variants of the hormone pathway provide the molecular mechanism for poor growth in a substantial proportion of individuals. The height-associated common variants are not observed in the anticipated frequency in the shortest individuals, suggesting rare genetic factors with large effect are more plausible in this group. As we advance towards establishing a molecular mechanism for poor growth in a greater percentage of those currently labeled ISS, we highlight two strategies that will likely be offered with increasing frequency: (1) unbiased genetic technologies including array analysis for copy number variation and whole exome/genome sequencing and (2) epigenetic alterations of key genomic loci. Ultimately data from subsets with similar molecular etiologies may emerge that will allow tailored interventions to achieve the best clinical outcome.

  13. 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

  14. Molecular mechanisms in deformation of cross-linked hydrogel nanocomposite.

    Science.gov (United States)

    Mathesan, Santhosh; Rath, Amrita; Ghosh, Pijush

    2016-02-01

    The self-folding behavior in response to external stimuli observed in hydrogels is potentially used in biomedical applications. However, the use of hydrogels is limited because of its reduced mechanical properties. These properties are enhanced when the hydrogels are cross-linked and reinforced with nanoparticles. In this work, molecular dynamics (MD) simulation is applied to perform uniaxial tension and pull out tests to understand the mechanism contributing towards the enhanced mechanical properties. Also, nanomechanical characterization is performed using quasi static nanoindentation experiments to determine the Young's modulus of hydrogels in the presence of nanoparticles. The stress-strain responses for chitosan (CS), chitosan reinforced with hydroxyapatite (HAP) and cross-linked chitosan are obtained from uniaxial tension test. It is observed that the Young's modulus and maximum stress increase as the HAP content increases and also with cross-linking process. Load displacement plot from pullout test is compared for uncross-linked and cross-linked chitosan chains on hydroxyapatite surface. MD simulation reveals that the variation in the dihedral conformation of chitosan chains and the evolution of internal structural variables are associated with mechanical properties. Additional results reveal that the formation of hydrogen bonds and electrostatic interactions is responsible for the above variations in different systems.

  15. 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.

  16. The Lnx family proteins function as molecular scaffolds for Numb family proteins.

    Science.gov (United States)

    Rice, D S; Northcutt, G M; Kurschner, C

    2001-11-01

    Drosophila Numb functions as a cell fate determinant during neurogenesis. We isolated a novel mammalian protein, Lnx2, which interacts with mammalian Numb and Numblike. Lnx2 and the related Lnx1 are multimodular proteins that bind to Numb via their NPXY motifs. In addition, Lnx proteins form oligomers either via their PDZ domains binding to PDZ-binding consensus motifs located in their C-termini or by homophilic oligomerization of their RING fingers. Therefore, Lnx proteins may form large networks by homomeric binding. In situ hybridization analysis revealed complementary patterns of Lnx1 and Lnx2 expression in developing and adult brain, although in several structures they are present in the same cell populations. Moreover, their expression patterns overlap with those of the Numb proteins. Oligomerization of Lnx2 and Numb binding occurs simultaneously. Therefore, our findings suggest that Lnx proteins may serve as molecular scaffolds that localize unrelated, interacting proteins, such as Numb, to specific subcellular sites.

  17. MOLECULAR MECHANISM OF MICROBIAL TECHNETIUM REDUCTION FINAL REPORT

    Energy Technology Data Exchange (ETDEWEB)

    DiChristina, Thomas J. [Georgia Tech

    2013-04-30

    Microbial Tc(VII) reduction is an attractive alternative strategy for bioremediation of technetium-contaminated subsurface environments. Traditional ex situ remediation processes (e.g., adsorption or ion exchange) are often limited by poor extraction efficiency, inhibition by competing ions and production of large volumes of produced waste. Microbial Tc(VII) reduction provides an attractive alternative in situ remediation strategy since the reduced end-product Tc(IV) precipitates as TcO2, a highly insoluble hydrous oxide. Despite its potential benefits, the molecular mechanism of microbial Tc(VII) reduction remains poorly understood. The main goal of the proposed DOENABIR research project is to determine the molecular mechanism of microbial Tc(VII) reduction. Random mutagenesis studies in our lab have resulted in generation of a set of six Tc(VII) reduction-deficient mutants of Shewanella oneidensis. The anaerobic respiratory deficiencies of each Tc(VII) reduction-deficient mutant was determined by anaerobic growth on various combinations of three electron donors and 14 terminal electron acceptors. Results indicated that the electron transport pathways to Tc(VII), NO3 -, Mn(III) and U(VI) share common structural or regulatory components. In addition, we have recently found that wild-type Shewanella are also able to reduce Tc(IV) as electron acceptor, producing Tc(III) as an end-product. The recent genome sequencing of a variety of technetium-reducing bacteria and the anticipated release of several additional genome sequences in the coming year, provides us with an unprecedented opportunity to determine the mechanism of microbial technetium reduction across species and genus lines.

  18. 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.

  19. 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.

  20. 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.

  1. Juvenile neuronal ceroid-lipofuscinosis: clinical and molecular investigation in a large family in Brazil

    Directory of Open Access Journals (Sweden)

    Eugênia Ribeiro Valadares

    2011-02-01

    Full Text Available OBJECTIVE: Juvenile Neuronal Ceroid-Lipofuscinosis (JNCL, CLN 3, Batten Disease (OMIM #204200 belongs to the most common group of neurodegenerative disorders of childhood. We report the clinical data and molecular analysis of a large Brazilian family. METHOD: Family composed of two consanguineous couples and thirty-two children. Clinical data of ten JNCL patients and molecular analyses on 13 participants were obtained. RESULTS: The large 1.02 kb deletion was detected. The most severe phenotype, with autistic behavior, tics and parkinsonism was seen in a 12-year-old female and a milder phenotype in a 14-year-old male. Nyctalopia was the first symptom in one deceased child. The visual loss of six patients has been first observed in the school and not at home. CONCLUSION: The report highlights the phenotypical intrafamily variation in 10 affected children of this family. The molecular investigation of this large family in our metabolic center turned possible the diagnosis, right approach and genetic counseling.

  2. Molecular mechanisms of ETS transcription factor mediated tumorigenesis

    Science.gov (United States)

    Kar, Adwitiya; Gutierrez-Hartmann, Arthur

    2014-01-01

    The ETS family of transcription factors is critical for development, differentiation, proliferation and also has a role in apoptosis and tissue remodeling. Changes in expression of ETS proteins therefore have a significant impact on normal physiology of the cell. Transcriptional consequences of ETS protein deregulation by overexpression, gene fusion, and modulation by RAS/MAPK signaling are linked to alterations in normal cell functions, and lead to unlimited increased proliferation, sustained angiogenesis, invasion and metastasis. Existing data show that ETS proteins control pathways in epithelial cells as well as stromal compartments, and the crosstalk between the two is essential for normal development and cancer. In this review we have focused on ETS factors with a known contribution in cancer development. Instead of focusing on a prototype, we address cancer associated ETS proteins and have highlighted the diverse mechanisms by which they affect carcinogenesis. Finally, we discuss strategies for ETS factor targeting as a potential means for cancer therapeutics. PMID:24066765

  3. Molecular mechanisms of ETS transcription factor-mediated tumorigenesis.

    Science.gov (United States)

    Kar, Adwitiya; Gutierrez-Hartmann, Arthur

    2013-01-01

    The E26 transformation-specific (ETS) family of transcription factors is critical for development, differentiation, proliferation and also has a role in apoptosis and tissue remodeling. Changes in expression of ETS proteins therefore have a significant impact on normal physiology of the cell. Transcriptional consequences of ETS protein deregulation by overexpression, gene fusion, and modulation by RAS/MAPK signaling are linked to alterations in normal cell functions, and lead to unlimited increased proliferation, sustained angiogenesis, invasion and metastasis. Existing data show that ETS proteins control pathways in epithelial cells as well as stromal compartments, and the crosstalk between the two is essential for normal development and cancer. In this review, we have focused on ETS factors with a known contribution in cancer development. Instead of focusing on a prototype, we address cancer associated ETS proteins and have highlighted the diverse mechanisms by which they affect carcinogenesis. Finally, we discuss strategies for ETS factor targeting as a potential means for cancer therapeutics.

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

    Science.gov (United States)

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

    2003-06-01

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

  5. Advances in understanding the molecular mechanism of pancreatic cancer metastasis

    Institute of Scientific and Technical Information of China (English)

    Yong-Xing Du; Zi-Wen Liu; Lei You; Wen-Ming Wu; Yu-Pei Zhao

    2016-01-01

    BACKGROUND: Pancreatic cancer (PC) is usually diagnosed at the late-stage and therefore, has widespread metastasis and a very high mortality rate. The mechanisms underlying PC metastasis are not well understood. Recent advances in genomic sequencing have identiifed groups of gene mutations that affect PC metastasis, but studies elucidating their roles are lacking. The present review was to investigate the molecu-lar mechanisms of PC metastasis. DATA SOURCES: Relevant articles on PC metastasis were searched in MEDLINE via PubMed prior to April 2015. The search was limited in English publications. RESULTS: PC metastatic cascades are multi-factorial events including both intrinsic and extrinsic elements. This review highlights the most important genetic alterations and other mechanisms that account for PC invasion and metastasis, with particular regard to epithelial-mesenchymal transition, inlfammation, stress response, and circulating tumor cells. CONCLUSIONS: Analyses of relevant gene functions and signaling pathways are needed to establish the gene regula-tory network and to deifne the pivotal modulators. Another promising area of study is the genotyping and phenotyping of circulating tumor cells, which could lead to a new era of per-sonalized therapy by identifying speciifc markers and targets.

  6. Small-Molecule Hormones: Molecular Mechanisms of Action

    Directory of Open Access Journals (Sweden)

    Monika Puzianowska-Kuznicka

    2013-01-01

    Full Text Available Small-molecule hormones play crucial roles in the development and in the maintenance of an adult mammalian organism. On the molecular level, they regulate a plethora of biological pathways. Part of their actions depends on their transcription-regulating properties, exerted by highly specific nuclear receptors which are hormone-dependent transcription factors. Nuclear hormone receptors interact with coactivators, corepressors, basal transcription factors, and other transcription factors in order to modulate the activity of target genes in a manner that is dependent on tissue, age and developmental and pathophysiological states. The biological effect of this mechanism becomes apparent not earlier than 30–60 minutes after hormonal stimulus. In addition, small-molecule hormones modify the function of the cell by a number of nongenomic mechanisms, involving interaction with proteins localized in the plasma membrane, in the cytoplasm, as well as with proteins localized in other cellular membranes and in nonnuclear cellular compartments. The identity of such proteins is still under investigation; however, it seems that extranuclear fractions of nuclear hormone receptors commonly serve this function. A direct interaction of small-molecule hormones with membrane phospholipids and with mRNA is also postulated. In these mechanisms, the reaction to hormonal stimulus appears within seconds or minutes.

  7. Molecular dynamics simulations of the buckling of graphyne and its family

    Energy Technology Data Exchange (ETDEWEB)

    Salmalian, K., E-mail: kavehsalmalian@iaul.ac.ir; Rouhi, S.; Mehran, S.

    2015-01-15

    Molecular dynamics simulations are employed to study the instability characteristics of graphyne and its family under compressive loads. The effects of nanosheet side length and aspect ratio on the critical compressive force and critical strain are investigated. It is shown that increasing aspect ratio leads to decreasing the critical compressive force. Besides, the effect of atomic structure on the compressive behavior of nanosheets is explored. It is observed that the zigzag graphynes have larger buckling forces than the armchair graphynes with same geometries. Finally, the buckling behavior of different nanosheets from the graphyne family is studied. It is represented that the nanosheets with more acetylene links have smaller critical compressive forces.

  8. Ethanol-Induced Cerebellar Ataxia: Cellular and Molecular Mechanisms.

    Science.gov (United States)

    Dar, M Saeed

    2015-08-01

    The cerebellum is an important target of ethanol toxicity given that cerebellar ataxia is the most consistent physical manifestation of acute ethanol consumption. Despite the significance of the cerebellum in ethanol-induced cerebellar ataxia (EICA), the cellular and molecular mechanisms underlying EICA are incompletely understood. However, two important findings have shed greater light on this phenomenon. First, ethanol-induced blockade of cerebellar adenosine uptake in rodent models points to a role for adenosinergic A1 modulation of EICA. Second, the consistent observation that intracerebellar administration of nicotine in mice leads to antagonism of EICA provides evidence for a critical role of cerebellar nitric oxide (NO) in EICA reversal. Based on these two important findings, this review discusses the potential molecular events at two key synaptic sites (mossy fiber-granule cell-Golgi cell (MGG synaptic site) and granule cell parallel fiber-Purkinje cell (GPP synaptic site) that lead to EICA. Specifically, ethanol-induced neuronal NOS inhibition at the MGG synaptic site acts as a critical trigger for Golgi cell activation which leads to granule cell deafferentation. Concurrently, ethanol-induced inhibition of adenosine uptake at the GPP synaptic site produces adenosine accumulation which decreases glutamate release and leads to the profound activation of Purkinje cells (PCs). These molecular events at the MGG and GPP synaptic sites are mutually reinforcing and lead to cerebellar dysfunction, decreased excitatory output of deep cerebellar nuclei, and EICA. The critical importance of PCs as the sole output of the cerebellar cortex suggests normalization of PC function could have important therapeutic implications.

  9. The Molecular Genetics and Cellular Mechanisms Underlying Pulmonary Arterial Hypertension

    Directory of Open Access Journals (Sweden)

    Rajiv D. Machado

    2012-01-01

    Full Text Available Pulmonary arterial hypertension (PAH is an incurable disorder clinically characterised by a sustained elevation of mean arterial pressure in the absence of systemic involvement. As the adult circulation is a low pressure, low resistance system, PAH represents a reversal to a foetal state. The small pulmonary arteries of patients exhibit luminal occlusion resultant from the uncontrolled growth of endothelial and smooth muscle cells. This vascular remodelling is comprised of hallmark defects, most notably the plexiform lesion. PAH may be familial in nature but the majority of patients present with spontaneous disease or PAH associated with other complications. In this paper, the molecular genetic basis of the disorder is discussed in detail ranging from the original identification of the major genetic contributant to PAH and moving on to current next-generation technologies that have led to the rapid identification of additional genetic risk factors. The impact of identified mutations on the cell is examined, particularly, the determination of pathways disrupted in disease and critical to pulmonary vascular maintenance. Finally, the application of research in this area to the design and development of novel treatment options for patients is addressed along with the future directions PAH research is progressing towards.

  10. Metabolic actions of FGF21: molecular mechanisms and therapeutic implications

    Directory of Open Access Journals (Sweden)

    Xuan Ge

    2012-08-01

    Full Text Available Fibroblast growth factor 21 (FGF21 is an atypical member of the FGF family that functions as an endocrine factor. In obese animals, elevation of plasma FGF21 levels by either pharmacological or genetic approaches reduces body weight, decreases hyperglycemia and hyperlipidemia, alleviates fatty liver and increases insulin sensitivity. FGF21 exerts its pleiotropic metabolic effects through its actions on multiple targets, including adipose tissue, liver, brain and pancreas. The expression of FGF21 is under the control of both peroxisome proliferator-activated receptor gamma (PPARγ and peroxisome proliferator-activated receptor alpha (PPARα. A growing body of evidence suggests that the metabolic benefits of these two nuclear receptors are mediated in part by induction of FGF21. In humans, plasma levels of FGF21 are elevated in obese subjects and patients with type 2 diabetes, but are reduced in patients with autoimmune diabetes. This review summarizes recent advances in understanding the physiological roles of FGF21 and the molecular pathways underlying its actions, and also discusses the future prospective of developing FGF21 or its agonists as therapeutic agents for obesity-related medical complications.

  11. Generic Transport Mechanisms for Molecular Traffic in Cellular Protrusions

    Science.gov (United States)

    Graf, Isabella R.; Frey, Erwin

    2017-03-01

    Transport of molecular motors along protein filaments in a half-closed geometry is a common feature of biologically relevant processes in cellular protrusions. Using a lattice-gas model we study how the interplay between active and diffusive transport and mass conservation leads to localized domain walls and tip localization of the motors. We identify a mechanism for task sharing between the active motors (maintaining a gradient) and the diffusive motion (transport to the tip), which ensures that energy consumption is low and motor exchange mostly happens at the tip. These features are attributed to strong nearest-neighbor correlations that lead to a strong reduction of active currents, which we calculate analytically using an exact moment identity, and might prove useful for the understanding of correlations and active transport also in more elaborate systems.

  12. 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.

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

    Directory of Open Access Journals (Sweden)

    Shaobin Yu

    2015-01-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

  15. Molecular mechanisms in normal pregnancy and rheumatic diseases.

    Science.gov (United States)

    Vázquez-Del Mercado, M; Martín-Márquez, B T; Petri, M H; Martínez-García, E A; Muñoz-Valle, J F

    2006-01-01

    Pregnancy is a phenomenon that is not totally understood, based on the complex molecular interactions between the mother and the embrio. Once the fecundation is completed the fetus starts to fight for survival. The first challenge is the implantation process and the second one is the interaction with the maternal immune system. This review discusses how the fetus avoids the immune system rejection, and the mechanisms that the maternal immune system adapts in order to be fit for a successful pregnancy. Also, we focus in this paper on the effects of pregnancy in rheumatic diseases, because the myriad clinical outcomes of the disease itself and the obstetric complications dependent of the disease implicated, as for example in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), spondyloarthropaties and antiphospholipid syndrome (APS).

  16. Cellular and molecular mechanisms of antiretroviral effects of HPA23.

    Science.gov (United States)

    Dormont, D; Yeramian, P; Lambert, P; Spire, B; Daveloose, D; Barre-Sinoussi, F C; Chermann, J C

    1988-01-01

    HPA23 is an antimonio-tungstate that exhibits numerous antiviral activities both in vivo and in vitro. It has been described as a competitive inhibitor of human immunodeficiency virus (HIV) reverse transcriptase (RT). Patients treated with daily injections of HPA23 show an inhibition of HIV RT activity in cell culture in 60% of the cases. Using biophysical (electronic spin resonance [ESR]), ultrastructural (microspectroscopic analysis), chemical (spectroscopy), and biological (cell culture) assays, HPA23 cellular and molecular mechanisms may be summarized as follows: 1) competitive inhibition of HIV-RT, 2) no or slight effect on cells infected with HIV in culture, 3) interactions with the cell membranes when long incubations are performed, and 4) antiviral activity possibly mediated by immune modulator effect of the drug.

  17. Molecular mechanisms of water transport in the eye

    DEFF Research Database (Denmark)

    Hamann, Steffen; Hamann, Steffen Ellitsgaard

    2002-01-01

    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......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...

  18. 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.

  19. Conserved Molecular Mechanisms Underlying Homeostasis of the Golgi Complex

    Directory of Open Access Journals (Sweden)

    Cathal Wilson

    2010-01-01

    Full Text Available The Golgi complex performs a central function in the secretory pathway in the sorting and sequential processing of a large number of proteins destined for other endomembrane organelles, the plasma membrane, or secretion from the cell, in addition to lipid metabolism and signaling. The Golgi apparatus can be regarded as a self-organizing system that maintains a relatively stable morphofunctional organization in the face of an enormous flux of lipids and proteins. A large number of the molecular players that operate in these processes have been identified, their functions and interactions defined, but there is still debate about many aspects that regulate protein trafficking and, in particular, the maintenance of these highly dynamic structures and processes. Here, we consider how an evolutionarily conserved underlying mechanism based on retrograde trafficking that uses lipids, COPI, SNAREs, and tethers could maintain such a homeodynamic system.

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

    Science.gov (United States)

    Kschonsak, Marc; Haering, Christian H

    2015-07-01

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

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

    Science.gov (United States)

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

    2012-03-01

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

  2. Molecular mechanism for cavitation in water under tension

    CERN Document Server

    Menzl, Georg; Geiger, Philipp; Caupin, Frédéric; Abascal, Jose L F; Valeriani, Chantal; Dellago, Christoph

    2016-01-01

    Despite its relevance in biology and engineering, the molecular mechanism driving cavitation in water remains unknown. Using computer simulations, we investigate the structure and dynamics of vapor bubbles emerging from metastable water at negative pressures. We find that in the early stages of cavitation, bubbles are irregularly shaped and become more spherical as they grow. Nevertheless, the free energy of bubble formation can be perfectly reproduced in the framework of classical nucleation theory (CNT) if the curvature dependence of the surface tension is taken into account. Comparison of the observed bubble dynamics to the predictions of the macroscopic Rayleigh--Plesset (RP) equation, augmented with thermal fluctuations, demonstrates that the growth of nanoscale bubbles is governed by viscous forces. Combining the dynamical prefactor determined from the RP equation with the free energy of CNT yields an analytical expression for the cavitation rate that reproduces the simulation results very well over a w...

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

    Science.gov (United States)

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

    2010-01-01

    Urinary tract obstruction is a frequent cause of renal impairment. The physiopathology of obstructive nephropathy has long been viewed as a mere mechanical problem. However, recent advances in cell and systems biology have disclosed a complex physiopathology involving a high number of molecular mediators of injury that lead to cellular processes of apoptotic cell death, cell injury leading to inflammation and resultant fibrosis. Functional studies in animal models of ureteral obstruction using a variety of techniques that include genetically modified animals have disclosed an important role for the renin-angiotensin system, transforming growth factor-β1 (TGF-β1) and other mediators of inflammation in this process. In addition, high throughput techniques such as proteomics and transcriptomics have identified potential biomarkers that may guide clinical decision-making. PMID:24198613

  4. A Hybrid Imperative and Functional Molecular Mechanics Application

    Directory of Open Access Journals (Sweden)

    Thomas Deboni

    1996-01-01

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

  5. [Biodegradation mechanism of DDT and chlorpyrifos using molecular simulation].

    Science.gov (United States)

    Lin, Yu-Zhen; Zeng, Guang-Ming; Zhang, Yu; Chen, Ming; Jiang, Min; Zhang, Jia-Chao; Lu, Lun-Hui; Liu, Li-Feng

    2012-03-01

    In order to explore the microscopic degradation mechanism of organic pesticides degrading enzymes, we used molecular docking method to investigate the binding modes of DDT to laccase and chlorpyrifos to organophosphorus hydrolase, and obtained the corresponding complex structures. According to the principle of minimum scoring, the results showed that the MolDock scores were -103.134 and -111.626, re-rank scores were -72.858 and -80.261, respectively. And we used LPC/CSU server search the interactions between organic pesticides and their degrading enzymes. Our results showed that hydrophobic interaction was the strongest contacts in DDT-laccase complex, and both hydrogen bonds and hydrophobic interactions were the strongest contacts when chlorpyrifos-organophosphorus hydrolase complex. The amino acid residues Tyr224 in laccase and Arg254 in organophosphorus hydrolase were detected to play significant roles in catalytic processes.

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

    Science.gov (United States)

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

    2010-04-22

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

  7. Drug-DNA intercalation: from discovery to the molecular mechanism.

    Science.gov (United States)

    Mukherjee, Arnab; Sasikala, Wilbee D

    2013-01-01

    The ability of small molecules to perturb the natural structure and dynamics of nucleic acids is intriguing and has potential applications in cancer therapeutics. Intercalation is a special binding mode where the planar aromatic moiety of a small molecule is inserted between a pair of base pairs, causing structural changes in the DNA and leading to its functional arrest. Enormous progress has been made to understand the nature of the intercalation process since its idealistic conception five decades ago. However, the biological functions were detected even earlier. In this review, we focus mainly on the acridine and anthracycline types of drugs and provide a brief overview of the development in the field through various experimental methods that led to our present understanding of the subject. Subsequently, we discuss the molecular mechanism of the intercalation process, free-energy landscapes, and kinetics that was revealed recently through detailed and rigorous computational studies.

  8. Molecular mechanisms underlying phosphate sensing, signaling, and adaptation in plants

    Institute of Scientific and Technical Information of China (English)

    Zhaoliang Zhang; Hong Liao; William J. Lucas

    2014-01-01

    As an essential plant macronutrient, the low availability of phosphorus (P) in most soils imposes serious limitation on crop production. Plants have evolved complex responsive and adaptive mechanisms for acquisition, remobiliza-tion and recycling of phosphate (Pi) to maintain P homeostasis. Spatio-temporal molecular, physiological, and biochemical Pi deficiency responses developed by plants are the consequence of local and systemic sensing and signaling pathways. Pi deficiency is sensed local y by the root system where hormones serve as important signaling components in terms of develop-mental reprogramming, leading to changes in root system architecture. Root-to-shoot and shoot-to-root signals, delivered through the xylem and phloem, respectively, involving Pi itself, hormones, miRNAs, mRNAs, and sucrose, serve to coordinate Pi deficiency responses at the whole-plant level. A combination of chromatin remodeling, transcriptional and posttranslational events contribute to global y regulating a wide range of Pi deficiency responses. In this review, recent advances are evaluated in terms of progress toward developing a comprehen-sive understanding of the molecular events underlying control over P homeostasis. Application of this knowledge, in terms of developing crop plants having enhanced attributes for P use efficiency, is discussed from the perspective of agricultural sustainability in the face of diminishing global P supplies.

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

    Science.gov (United States)

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

    2010-01-01

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

  10. Molecular Mechanisms of Bipolar Disorder: Progress Made and Future Challenges

    Science.gov (United States)

    Kim, Yeni; Santos, Renata; Gage, Fred H.; Marchetto, Maria C.

    2017-01-01

    Bipolar disorder (BD) is a chronic and progressive psychiatric illness characterized by mood oscillations, with episodes of mania and depression. The impact of BD on patients can be devastating, with up to 15% of patients committing suicide. This disorder is associated with psychiatric and medical comorbidities and patients with a high risk of drug abuse, metabolic and endocrine disorders and vascular disease. Current knowledge of the pathophysiology and molecular mechanisms causing BD is still modest. With no clear biological markers available, early diagnosis is a great challenge to clinicians without previous knowledge of the longitudinal progress of illness. Moreover, despite recommendations from evidence-based guidelines, polypharmacy is still common in clinical treatment of BD, reflecting the gap between research and clinical practice. A major challenge in BD is the development of effective drugs with low toxicity for the patients. In this review article, we focus on the progress made and future challenges we face in determining the pathophysiology and molecular pathways involved in BD, such as circadian and metabolic perturbations, mitochondrial and endoplasmic reticulum (ER) dysfunction, autophagy and glutamatergic neurotransmission; which may lead to the development of new drugs. PMID:28261061

  11. Neuroprotection and its molecular mechanism following spinal cord injury

    Institute of Scientific and Technical Information of China (English)

    Nai-Kui Liu; Xiao-Ming Xu

    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.

  12. 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

  13. Molecular mechanisms underlying phosphate sensing, signaling, and adaptation in plants.

    Science.gov (United States)

    Zhang, Zhaoliang; Liao, Hong; Lucas, William J

    2014-03-01

    As an essential plant macronutrient, the low availability of phosphorus (P) in most soils imposes serious limitation on crop production. Plants have evolved complex responsive and adaptive mechanisms for acquisition, remobilization and recycling of phosphate (Pi) to maintain P homeostasis. Spatio-temporal molecular, physiological, and biochemical Pi deficiency responses developed by plants are the consequence of local and systemic sensing and signaling pathways. Pi deficiency is sensed locally by the root system where hormones serve as important signaling components in terms of developmental reprogramming, leading to changes in root system architecture. Root-to-shoot and shoot-to-root signals, delivered through the xylem and phloem, respectively, involving Pi itself, hormones, miRNAs, mRNAs, and sucrose, serve to coordinate Pi deficiency responses at the whole-plant level. A combination of chromatin remodeling, transcriptional and posttranslational events contribute to globally regulating a wide range of Pi deficiency responses. In this review, recent advances are evaluated in terms of progress toward developing a comprehensive understanding of the molecular events underlying control over P homeostasis. Application of this knowledge, in terms of developing crop plants having enhanced attributes for P use efficiency, is discussed from the perspective of agricultural sustainability in the face of diminishing global P supplies.

  14. 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.

  15. Rupture mechanism of liquid crystal thin films realized by large-scale molecular simulations

    Science.gov (United States)

    Nguyen, Trung Dac; Carrillo, Jan-Michael Y.; Matheson, Michael A.; Brown, W. Michael

    2014-02-01

    The ability of liquid crystal (LC) molecules to respond to changes in their environment makes them an interesting candidate for thin film applications, particularly in bio-sensing, bio-mimicking devices, and optics. Yet the understanding of the (in)stability of this family of thin films has been limited by the inherent challenges encountered by experiment and continuum models. Using unprecedented large-scale molecular dynamics (MD) simulations, we address the rupture origin of LC thin films wetting a solid substrate at length scales similar to those in experiment. Our simulations show the key signatures of spinodal instability in isotropic and nematic films on top of thermal nucleation, and importantly, for the first time, evidence of a common rupture mechanism independent of initial thickness and LC orientational ordering. We further demonstrate that the primary driving force for rupture is closely related to the tendency of the LC mesogens to recover their local environment in the bulk state. Our study not only provides new insights into the rupture mechanism of liquid crystal films, but also sets the stage for future investigations of thin film systems using peta-scale molecular dynamics simulations.The ability of liquid crystal (LC) molecules to respond to changes in their environment makes them an interesting candidate for thin film applications, particularly in bio-sensing, bio-mimicking devices, and optics. Yet the understanding of the (in)stability of this family of thin films has been limited by the inherent challenges encountered by experiment and continuum models. Using unprecedented large-scale molecular dynamics (MD) simulations, we address the rupture origin of LC thin films wetting a solid substrate at length scales similar to those in experiment. Our simulations show the key signatures of spinodal instability in isotropic and nematic films on top of thermal nucleation, and importantly, for the first time, evidence of a common rupture mechanism

  16. The molecular mechanisms of hazardous metals for carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    ChenJK; LeiYX

    2002-01-01

    The available experimental and epidemiological data have shown that nickel (Ni) and cadmium (Dd) and their compounds are carcinogenic to experimental animals and human.These two metals have been classified as human carcinogens bythe International Agency for Research on Cancer (IARC).However,Their underlying molecular mechanisms remain unknown.The objective of this research was to investigate the molecular mechanisms responsible for Ni and Cd carcinogenesis through epidemiological study in human exposure,transformation expreiments in human epithelial cells (16HBE) and BALB/c-3T3 cell lines in vitro,DNA damage detections (comet,DNA-protein crosslinks) as well as telomerase activity and apoptosis assay,and analysis of oncogens,tumor suppressor genes and their mutation (including genomic instability,k-ras,p15,p16,p53,FHIT) in transformed cell lines or tumor cells/tissue.Furthermore,we also detected and analyses the methylation,related novel genes and encoded protein in Cd transformed cells.The results and conclusion are as follows:(1)There is significant relationship between some hazardous metals and lung cancer (OR=8.76),especially for nickel(OR=11.25).(2)Ni and Cd and their compounds could induce malignant transformation in mammalian cell lines and human epithelial cells,and induce tumorigenesis in nude mice.(3)There is obvious DNA damage during cell transformation and tumorigenesis induced by Ni.(4) Significant genomic instability has been shown during cell transformation and tumorigenesis induced by Ni.(5)Detection of k-ras,p15,p16 genes in point mutation have demonstrated no changes during cell transformation and tumorigenesis induced by hazardous medals,suggesting that gene mutation is not the main way to metal carcinogenesis.(6)There are some aberrant DNA methylation in Cdtransformed cell lines.(7)We found two novel Cd-responsive proto-oncogenes and their encoded proteins in Cd-transformed cell lines.

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

    Science.gov (United States)

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

    2011-01-01

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

  18. Molecular Mechanism for LAMP1 Recognition by Lassa Virus

    Science.gov (United States)

    Cohen-Dvashi, Hadas; Cohen, Nadav; Israeli, Hadar

    2015-01-01

    ABSTRACT Lassa virus is a notorious human pathogen that infects many thousands of people each year in West Africa, causing severe viral hemorrhagic fevers and significant mortality. The surface glycoprotein of Lassa virus mediates receptor recognition through its GP1 subunit. Here we report the crystal structure of GP1 from Lassa virus, which is the first representative GP1 structure for Old World arenaviruses. We identify a unique triad of histidines that forms a binding site for LAMP1, a known lysosomal protein recently discovered to be a critical receptor for internalized Lassa virus at acidic pH. We demonstrate that mutation of this histidine triad, which is highly conserved among Old World arenaviruses, impairs LAMP1 recognition. Our biochemical and structural data further suggest that GP1 from Lassa virus may undergo irreversible conformational changes that could serve as an immunological decoy mechanism. Together with a variable region that we identify on the surface of GP1, those could be two distinct mechanisms that Lassa virus utilizes to avoid antibody-based immune response. IMPORTANCE Structural data at atomic resolution for viral proteins is key for understanding their function at the molecular level and can facilitate novel avenues for combating viral infections. Here we used X-ray protein crystallography to decipher the crystal structure of the receptor-binding domain (GP1) from Lassa virus. This is a pathogenic virus that causes significant illness and mortality in West Africa. This structure reveals the overall architecture of GP1 domains from the group of viruses known as the Old World arenaviruses. Using this structural information, we elucidated the mechanisms for pH switch and binding of Lassa virus to LAMP1, a recently identified host receptor that is critical for successful infection. Lastly, our structural analysis suggests two novel immune evasion mechanisms that Lassa virus may utilize to escape antibody-based immune response. PMID

  19. Investigating the work-family conflict and health link: Repetitive thought as a mechanism.

    Science.gov (United States)

    Davis, Kelly D; Gere, Judith; Sliwinski, Martin J

    2016-10-06

    Research is needed to investigate mechanisms linking work-family conflict to poor health in working adults. We took a novel approach to build on extant studies by testing a potential mechanism in these associations - repetitive thought. Data came from a sample of 203 partnered working adults. There were significant direct effects of work-family conflict with lower life satisfaction, positive affect, and perceived health as well as greater fatigue. As for total effects, work-family conflict was significantly associated with all health outcomes - life satisfaction, positive affect, negative affect, fatigue, perceived health, and chronic health conditions - in the expected directions through repetitive thought. This study provides support that repetitive thought is one potential mechanism of how work-family conflict can take a toll on psychological and physical health. Findings are discussed in relation to improving workplace policies to improve the health of working adults managing work-family conflict.

  20. Molecular evolution and expression of the CRAL_TRIO protein family in insects.

    Science.gov (United States)

    Smith, Gilbert; Briscoe, Adriana D

    2015-07-01

    CRAL_TRIO domain proteins are known to bind small lipophilic molecules such as retinal, inositol and Vitamin E and include such gene family members as PINTA, α-tocopherol transfer (ATT) proteins, retinoid binding proteins, and clavesins. In insects, very little is known about either the molecular evolution of this family of proteins or their ligand specificity. Here we characterize insect CRAL_TRIO domain proteins and present the first insect CRAL_TRIO protein phylogeny constructed by performing reciprocal BLAST searches of the reference genomes of Drosophila melanogaster, Anopheles gambiae, Apis mellifera, Tribolium castaneum, Bombyx mori, Manduca sexta and Danaus plexippus. We find several highly conserved amino acid residues in the CRAL_TRIO domain-containing genes across insects and a gene expansion resulting in more than twice as many gene family members in lepidopterans than in other surveyed insect species, but no lepidopteran homolog of the PINTA gene in Drosophila. In addition, we examined the expression pattern of CRAL_TRIO domain genes in Manduca sexta heads using RNA-Seq data. Of the 42 gene family members found in the M. sexta reference genome, we found 30 expressed in the head tissue with similar expression profiles between males and females. Our results suggest this gene family underwent a large expansion in lepidopteran, making the lepidopteran CRAL_TRIO domain family distinct from other holometabolous insect lineages.

  1. Nosocomial infection and its molecular mechanisms of antibiotic resistance.

    Science.gov (United States)

    Xia, Jufeng; Gao, Jianjun; Tang, Wei

    2016-02-01

    Nosocomial infection is a kind of infection, which is spread in various hospital environments, and leads to many serious diseases (e.g. pneumonia, urinary tract infection, gastroenteritis, and puerperal fever), and causes higher mortality than community-acquired infection. Bacteria are predominant among all the nosocomial infection-associated pathogens, thus a large number of antibiotics, such as aminoglycosides, penicillins, cephalosporins, and carbapenems, are adopted in clinical treatment. However, in recent years antibiotic resistance quickly spreads worldwide and causes a critical threat to public health. The predominant bacteria include Methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Acinetobacter baumannii. In these bacteria, resistance emerged from antibiotic resistant genes and many of those can be exchanged between bacteria. With technical advances, molecular mechanisms of resistance have been gradually unveiled. In this review, recent advances in knowledge about mechanisms by which (i) bacteria hydrolyze antibiotics (e.g. extended spectrum β-lactamases, (ii) AmpC β-lactamases, carbapenemases), (iii) avoid antibiotic targeting (e.g. mutated vanA and mecA genes), (iv) prevent antibiotic permeation (e.g. porin deficiency), or (v) excrete intracellular antibiotics (e.g. active efflux pump) are summarized.

  2. Molecular mechanisms controlling the migration of striatal interneurons.

    Science.gov (United States)

    Villar-Cerviño, Verona; Kappeler, Caroline; Nóbrega-Pereira, Sandrina; Henkemeyer, Mark; Rago, Luciano; Nieto, M Angela; Marín, Oscar

    2015-06-10

    In the developing telencephalon, the medial ganglionic eminence (MGE) generates many cortical and virtually all striatal interneurons. While the molecular mechanisms controlling the migration of interneurons to the cortex have been extensively studied, very little is known about the nature of the signals that guide interneurons to the striatum. Here we report that the allocation of MGE-derived interneurons in the developing striatum of the mouse relies on a combination of chemoattractive and chemorepulsive activities. Specifically, interneurons migrate toward the striatum in response to Nrg1/ErbB4 chemoattraction, and avoid migrating into the adjacent cortical territories by a repulsive activity mediated by EphB/ephrinB signaling. Our results also suggest that the responsiveness of MGE-derived striatal interneurons to these cues is at least in part controlled by the postmitotic activity of the transcription factor Nkx2-1. This study therefore reveals parallel mechanisms for the migration of MGE-derived interneurons to the striatum and the cerebral cortex.

  3. Categorical prototyping: incorporating molecular mechanisms into 3D printing

    Science.gov (United States)

    Brommer, Dieter B.; Giesa, Tristan; Spivak, David I.; Buehler, Markus J.

    2016-01-01

    We apply the mathematical framework of category theory to articulate the precise relation between the structure and mechanics of a nanoscale system in a macroscopic domain. We maintain the chosen molecular mechanical properties from the nanoscale to the continuum scale. Therein we demonstrate a procedure to ‘protoype a model’, as category theory enables us to maintain certain information across disparate fields of study, distinct scales, or physical realizations. This process fits naturally with prototyping, as a prototype is not a complete product but rather a reduction to test a subset of properties. To illustrate this point, we use large-scale multi-material printing to examine the scaling of the elastic modulus of 2D carbon allotropes at the macroscale and validate our printed model using experimental testing. The resulting hand-held materials can be examined more readily, and yield insights beyond those available in the original digital representations. We demonstrate this concept by twisting the material, a test beyond the scope of the original model. The method developed can be extended to other methods of additive manufacturing.

  4. Emerging Anticancer Potentials of Goniothalamin and Its Molecular Mechanisms

    Directory of Open Access Journals (Sweden)

    Mohamed Ali Seyed

    2014-01-01

    Full Text Available The treatment of most cancers is still inadequate, despite tremendous steady progress in drug discovery and effective prevention. Nature is an attractive source of new therapeutics. Several medicinal plants and their biomarkers have been widely used for the treatment of cancer with less known scientific basis of their functioning. Although a wide array of plant derived active metabolites play a role in the prevention and treatment of cancer, more extensive scientific evaluation of their mechanisms is still required. Styryl-lactones are a group of secondary metabolites ubiquitous in the genus Goniothalamus that have demonstrated to possess antiproliferative activity against cancer cells. A large body of evidence suggests that this activity is associated with the induction of apoptosis in target cells. In an effort to promote further research on the genus Goniothalamus, this review offers a broad analysis of the current knowledge on Goniothalamin (GTN or 5, 6, dihydro-6-styryl-2-pyronone (C13H12O2, a natural occurring styryl-lactone. Therefore, it includes (i the source of GTN and other metabolites; (ii isolation, purification, and (iii the molecular mechanisms of actions of GTN, especially the anticancer properties, and summarizes the role of GTN which is crucial for drug design, development, and application in future for well-being of humans.

  5. The molecular mechanism of thalidomide analogs in hematologic malignancies.

    Science.gov (United States)

    Lindner, Stefanie; Krönke, Jan

    2016-12-01

    Thalidomide was sold in the 1950s as a sedative and was also used by pregnant women to treat morning sickness. It became notorious for causing severe birth defects and was removed from the market. More than four decades later, thalidomide had a renaissance in the treatment of cancer. Thalidomide and its more potent analogs, lenalidomide and pomalidomide, are nowadays approved treatments for multiple myeloma and myelodysplastic syndrome with deletion of chromosome 5q. In addition, thalidomide and its analogs inhibit release of tumor necrosis factor-α and increase interleukin-2 (IL-2) and interferon-γ release from T cells. The underlying molecular mechanisms for these pleiotropic effects remained obscure until the identification of the cereblon (CRBN) E3 ubiquitin ligase as the primary target of thalidomide and its analogs in 2010. Binding of thalidomide or lenalidomide increases the affinity of CRBN to the transcription factors IKZF1 and IKZF3 and casein kinase 1α (CK1α). Ubiquitination and degradation of these neo-substrates results in IL-2 release and growth arrest of multiple myeloma and MDS cells. The discovery of this previously undescribed mechanism for an approved drug provides a proof-of-concept for the development of new therapeutics that exploit ubiquitin ligases for specific degradation of disease-associated proteins.

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

    Science.gov (United States)

    Reid, Brian; Zhao, Min

    2014-01-01

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

  7. Molecular mechanisms of CRISPR-mediated microbial immunity.

    Science.gov (United States)

    Gasiunas, Giedrius; Sinkunas, Tomas; Siksnys, Virginijus

    2014-02-01

    Bacteriophages (phages) infect bacteria in order to replicate and burst out of the host, killing the cell, when reproduction is completed. Thus, from a bacterial perspective, phages pose a persistent lethal threat to bacterial populations. Not surprisingly, bacteria evolved multiple defense barriers to interfere with nearly every step of phage life cycles. Phages respond to this selection pressure by counter-evolving their genomes to evade bacterial resistance. The antagonistic interaction between bacteria and rapidly diversifying viruses promotes the evolution and dissemination of bacteriophage-resistance mechanisms in bacteria. Recently, an adaptive microbial immune system, named clustered regularly interspaced short palindromic repeats (CRISPR) and which provides acquired immunity against viruses and plasmids, has been identified. Unlike the restriction–modification anti-phage barrier that subjects to cleavage any foreign DNA lacking a protective methyl-tag in the target site, the CRISPR–Cas systems are invader-specific, adaptive, and heritable. In this review, we focus on the molecular mechanisms of interference/immunity provided by different CRISPR–Cas systems.

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

    Lifescience Database Archive (English)

    Full Text Available 18086388 Molecular mechanisms of the anti-inflammatory functions of interferons. Ko...varik P, Sauer I, Schaljo B. Immunobiology. 2007;212(9-10):895-901. Epub 2007 Nov 8. (.png) (.svg) (.html) (.csml) Show Molecular... mechanisms of the anti-inflammatory functions of interferons. PubmedID 18086388 Title Molecular

  9. A regularized and renormalized electrostatic coupling Hamiltonian for hybrid quantum-mechanical-molecular-mechanical calculations.

    Science.gov (United States)

    Biswas, P K; Gogonea, V

    2005-10-22

    We describe a regularized and renormalized electrostatic coupling Hamiltonian for hybrid quantum-mechanical (QM)-molecular-mechanical (MM) calculations. To remedy the nonphysical QM/MM Coulomb interaction at short distances arising from a point electrostatic potential (ESP) charge of the MM atom and also to accommodate the effect of polarized MM atom in the coupling Hamiltonian, we propose a partial-wave expansion of the ESP charge and describe the effect of a s-wave expansion, extended over the covalent radius r(c), of the MM atom. The resulting potential describes that, at short distances, large scale cancellation of Coulomb interaction arises intrinsically from the localized expansion of the MM point charge and the potential self-consistently reduces to 1r(c) at zero distance providing a renormalization to the Coulomb energy near interatomic separations. Employing this renormalized Hamiltonian, we developed an interface between the Car-Parrinello molecular-dynamics program and the classical molecular-dynamics simulation program Groningen machine for chemical simulations. With this hybrid code we performed QM/MM calculations on water dimer, imidazole carbon monoxide (CO) complex, and imidazole-heme-CO complex with CO interacting with another imidazole. The QM/MM results are in excellent agreement with experimental data for the geometry of these complexes and other computational data found in literature.

  10. Molecular mechanisms for interaction of glycine betaine with supra-molecular phycobiliprotein complexes

    Institute of Scientific and Technical Information of China (English)

    XU XiuLing; LI Heng; XIE Jie; ZHAO JingQuan

    2009-01-01

    Glycine betaine (GB) is a biologically important small molecule protecting cells,proteins and enzymes in vivo and in vitro under environmental stresses.Recently,it was found that GB could also relax the structure and inactivate the function of phycobiliproteins and phycobilisome (PBS),a kind of supramolecular complexes,in cyanobacterial cells.The molecular mechanisms for the opposite phenomena are quite ambiguous.Taking PBS and a trimeric or monomeric C-phycocyanin (C-PC) as models,the molecular mechanism for the interaction of GB with supra-molecular complexes or nuclear proteins was investigated.The energetic decoupling of PBS components induced by GB suggests that the PBS core-membrane linking polypeptide was the most sensitive site while the rod-core linker was the next.Biochemistry analysis proves that PBS structure was loosened but not dissociated into the components.On the basis of the results and structure knowledge,it was proposed that GB screened the electrostatic attraction of the opposite charges on a linker and a protein leading to a much looser structure.It was observed that GB induced a spectral blue shift for trimeric C-PC but a red shift for s monomeric C-PC (a nuclear protein),which were ascribed to GB's screening of the electrostatic attraction of a linker to a protein and strengthening of the hydrophobic interaction between C-PC monomers.The trimers and monomers' forming of the same products under high concentration of GB was ascribed to a compromise of the opposite interaction forces.

  11. Molecular mechanisms for interaction of glycine betaine with supra-molecular phycobiliprotein complexes

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Glycine betaine(GB) is a biologically important small molecule protecting cells,proteins and enzymes in vivo and in vitro under environmental stresses.Recently,it was found that GB could also relax the structure and inactivate the function of phycobiliproteins and phycobilisome(PBS),a kind of supramolecular complexes,in cyanobacterial cells.The molecular mechanisms for the opposite phenomena are quite ambiguous.Taking PBS and a trimeric or monomeric C-phycocyanin(C-PC) as models,the molecular mechanism for the interaction of GB with supra-molecular complexes or nuclear proteins was investigated.The energetic decoupling of PBS components induced by GB suggests that the PBS core-membrane linking polypeptide was the most sensitive site while the rod-core linker was the next.Biochemistry analysis proves that PBS structure was loosened but not dissociated into the components.On the basis of the results and structure knowledge,it was proposed that GB screened the electrostatic attraction of the opposite charges on a linker and a protein leading to a much looser structure.It was observed that GB induced a spectral blue shift for trimeric C-PC but a red shift for a monomeric C-PC(a nuclear protein),which were ascribed to GB’s screening of the electrostatic attraction of a linker to a protein and strengthening of the hydrophobic interaction between C-PC monomers.The trimers and monomers’ forming of the same products under high concentration of GB was ascribed to a compromise of the opposite interaction forces.

  12. Molecular evolution and functional divergence of the metallothionein gene family in vertebrates.

    Science.gov (United States)

    Serén, Nina; Glaberman, Scott; Carretero, Miguel A; Chiari, Ylenia

    2014-04-01

    The metallothionein (MT) gene superfamily consists of metal-binding proteins involved in various metal detoxification and storage mechanisms. The evolution of this gene family in vertebrates has mostly been studied in mammals using sparse taxon or gene sampling. Genomic databases and available data on MT protein function and expression allow a better understanding of the evolution and functional divergence of the different MT types. We recovered 77 MT coding sequences from 20 representative vertebrates with annotated complete genomes. We found multiple MT genes, also in reptiles, which were thought to have only one MT type. Phylogenetic and synteny analyses indicate the existence of a eutherian MT1 and MT2, a tetrapod MT3, an amniote MT4, and fish MT. The optimal gene-tree/species-tree reconciliation analyses identified the best root in the fish clade. Functional analyses reveal variation in hydropathic index among protein domains, likely correlated with their distinct flexibility and metal affinity. Analyses of functional divergence identified amino acid sites correlated with functional divergence among MT types. Uncovering the number of genes and sites possibly correlated with functional divergence will help to design cost-effective MT functional and gene expression studies. This will permit further understanding of the distinct roles and specificity of these proteins and to properly target specific MT for different types of functional studies. Therefore, this work presents a critical background on the molecular evolution and functional divergence of vertebrate MTs to carry out further detailed studies on the relationship between heavy metal metabolism and tolerances among vertebrates.

  13. Molecular evolution and selection pressure in alpha-class carbonic anhydrase family members.

    Science.gov (United States)

    McDevitt, Meghan E; Lambert, Lisa A

    2011-12-01

    Carbonic anhydrases (CA) are ubiquitous, and their involvement in diseases such as hypertension, diabetes, and glaucoma is well known. Most members of this family of metalloenzymes convert carbon dioxide to bicarbonate with the help of a Zn(2+) cofactor. While the expression patterns and kinetic activities of many of these isozymes have been studied, little is known about the differences in the conservation patterns of individual residues. To better understand the molecular evolution of the CA gene family, we created multiple sequence alignments and analyzed the selection pressure (dN/dS ratios) on surface and active site residues in 248 mammalian sequences of the 14 known family members. Using the values found for amino acids of known functional importance (i.e. the three histidines that bind the zinc cofactor) as our baseline, we were able to identify other regions of possible structural and functional importance. Copyright © 2011 Elsevier B.V. All rights reserved.

  14. Subjects with molecularly defined familial hypercholesterolemia or familial defective apoB-100 are not being adequately treated.

    Directory of Open Access Journals (Sweden)

    Trond P Leren

    Full Text Available OBJECTIVES: To study whether subjects with a molecular genetic diagnosis of familial hypercholesterolemia (FH or familial defective apoB-100 (FDB are being adequately treated. DESIGN: A questionnaire regarding medical history was sent to 2611 subjects who had been provided with a molecular genetic diagnosis of FH or FDB, and a blood sample was obtained for lipid measurements. RESULTS: 956 (36.6% of the 2611 subjects participated. The mean age for starting lipid-lowering therapy was 33.4 (±12.1 years. Among those below 18 years of age, only 20.4% were on lipid-lowering drugs, whereas 89.1% of those aged 18 and above were on lipid-lowering drugs. The mean levels of total serum cholesterol and LDL-cholesterol were 5.7 (±1.5 mmol/l and 3.9 (±1.3 mmol/l, respectively. Among those who were on lipid-lowering drugs, 29.0% and 12.2% had levels of LDL cholesterol below 3.0 mmol/l and 2.6 mmol/l, respectively. Only 47.3% of the 956 subjects were considered as being adequately treated largely due to a failure to titrate their drug regimens. From the use of cholesterol-years score, lipid-lowering therapy must start before the age of 20 in order to prevent the subjects from contracting premature coronary heart disease. CONCLUSION: The majority of FH/FDB subjects are being diagnosed late in life and are not being adequately treated. In order to prevent them from contracting premature coronary heart disease, it is key that levels of LDL cholesterol are normalized from a young age and that sufficient doses of lipid-lowering drugs are being used.

  15. Sociocultural Mechanisms of Intergenerational Values and Mindset Translation in Modern Family Development and Generational Change

    Science.gov (United States)

    Nemova, Olga A.; Retivina, Veronika V.; Kutepova, Lubov I.; Vinnikova, Irina S.; Kuznetsova, Ekaterina A.

    2016-01-01

    The paper considers the issue of functioning of the mechanism of formation and translation of values of labor in family. Fundamental labor values and main channels of their distribution are revealed based on empiric material. Family influence on motivation of today's Russian youth's labor behavior was determined. An intergenerational comparative…

  16. Molecular mechanisms linking high dose medroxyprogesterone with HIV-1 risk.

    Directory of Open Access Journals (Sweden)

    Susan C Irvin

    Full Text Available Epidemiological studies suggest that medroxyprogesterone acetate (MPA may increase the risk of HIV-1. The current studies were designed to identify potential underlying biological mechanisms.Human vaginal epithelial (VK2/E6E7, peripheral blood mononuclear (PBMC, and polarized endometrial (HEC-1-A cells were treated with a range of concentrations of MPA (0.015-150 μg/ml and the impact on gene expression, protein secretion, and HIV infection was evaluated.Treatment of VK2/E6E7 cells with high doses (>15 μg/ml] of MPA significantly upregulated proinflammatory cytokines, which resulted in a significant increase in HIV p24 levels secreted by latently infected U1 cells following exposure to culture supernatants harvested from MPA compared to mock-treated cells. MPA also increased syndecan expression by VK2/E6E7 cells and cells treated with 15 μg/ml of MPA bound and transferred more HIV-1 to T cells compared to mock-treated cells. Moreover, MPA treatment of epithelial cells and PBMC significantly decreased cell proliferation resulting in disruption of the epithelial barrier and decreased cytokine responses to phytohaemagglutinin, respectively.We identified several molecular mechanisms that could contribute to an association between DMPA and HIV including proinflammatory cytokine and chemokine responses that could activate the HIV promoter and recruit immune targets, increased expression of syndecans to facilitate the transfer of virus from epithelial to immune cells and decreased cell proliferation. The latter could impede the ability to maintain an effective epithelial barrier and adversely impact immune cell function. However, these responses were observed primarily following exposure to high (15-150 μg/ml MPA concentrations. Clinical correlation is needed to determine whether the prolonged MPA exposure associated with contraception activates these mechanisms in vivo.

  17. Molecular mechanisms linking high dose medroxyprogesterone with HIV-1 risk.

    Science.gov (United States)

    Irvin, Susan C; Herold, Betsy C

    2015-01-01

    Epidemiological studies suggest that medroxyprogesterone acetate (MPA) may increase the risk of HIV-1. The current studies were designed to identify potential underlying biological mechanisms. Human vaginal epithelial (VK2/E6E7), peripheral blood mononuclear (PBMC), and polarized endometrial (HEC-1-A) cells were treated with a range of concentrations of MPA (0.015-150 μg/ml) and the impact on gene expression, protein secretion, and HIV infection was evaluated. Treatment of VK2/E6E7 cells with high doses (>15 μg/ml] of MPA significantly upregulated proinflammatory cytokines, which resulted in a significant increase in HIV p24 levels secreted by latently infected U1 cells following exposure to culture supernatants harvested from MPA compared to mock-treated cells. MPA also increased syndecan expression by VK2/E6E7 cells and cells treated with 15 μg/ml of MPA bound and transferred more HIV-1 to T cells compared to mock-treated cells. Moreover, MPA treatment of epithelial cells and PBMC significantly decreased cell proliferation resulting in disruption of the epithelial barrier and decreased cytokine responses to phytohaemagglutinin, respectively. We identified several molecular mechanisms that could contribute to an association between DMPA and HIV including proinflammatory cytokine and chemokine responses that could activate the HIV promoter and recruit immune targets, increased expression of syndecans to facilitate the transfer of virus from epithelial to immune cells and decreased cell proliferation. The latter could impede the ability to maintain an effective epithelial barrier and adversely impact immune cell function. However, these responses were observed primarily following exposure to high (15-150 μg/ml) MPA concentrations. Clinical correlation is needed to determine whether the prolonged MPA exposure associated with contraception activates these mechanisms in vivo.

  18. 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.

  19. Mechanical Characterization of Molecular Assemblies at Oil/Water Interfaces

    Science.gov (United States)

    Yuan, Wa

    The self-assembly of charged molecules in liquid phases and their ability to form functional layers at immiscible interfaces are areas of great interest. However, the implementation of these assemblies is often limited by a lack of understanding of the detailed assembly mechanisms. In order to enhance the performance of interfacial assemblies it is essential to be able to characterize the physical and mechanical properties of assembled layers, as well as develop model systems that will allow us to examine the factors that govern their interaction with the surrounding environment. The key purpose of this thesis is to develop an understanding of some of the important factors influencing interfacial assemblies at immiscible liquid interfaces. The first portion of the work involves mechanical characterization of interfacial layers formed by large amphiphilic molecules. The study of block and gradient copolymers, reveals the effect of copolymer sequence distribution on the ability of these molecules to form interfacial assemblies. Specifically, the unique network structure formed by gradient copolymers at oil/water interfaces enables us to create a robust membrane at the interface by ionic crosslinking. The second part of this thesis explores smaller molecule assemblies at liquid interfaces, including commonly used commercial surfactant (span 80) and nano particles (graphene oxide). Both studies demonstrate an interesting correlation between molecular structure and overall properties of the assembled layers. Factors such as interfacial density, particle sizes and pH can greatly influence the structure of the assembled layers, resulting in interesting phenomena such as spontaneous emulsification, wrinkling and layer collapse. The bulk of the oil/water interface study was performed using axisymmetric drop shape analysis (DSA), which successfully quantifies the mechanical tension in the interfacial layer. This analysis was further extended by a development of a double

  20. Molecular Mechanisms of White Spot Syndrome Virus Infection and Perspectives on Treatments.

    Science.gov (United States)

    Verbruggen, Bas; Bickley, Lisa K; van Aerle, Ronny; Bateman, Kelly S; Stentiford, Grant D; Santos, Eduarda M; Tyler, Charles R

    2016-01-18

    Since its emergence in the 1990s, White Spot Disease (WSD) has had major economic and societal impact in the crustacean aquaculture sector. Over the years shrimp farming alone has experienced billion dollar losses through WSD. The disease is caused by the White Spot Syndrome Virus (WSSV), a large dsDNA virus and the only member of the Nimaviridae family. Susceptibility to WSSV in a wide range of crustacean hosts makes it a major risk factor in the translocation of live animals and in commodity products. Currently there are no effective treatments for this disease. Understanding the molecular basis of disease processes has contributed significantly to the treatment of many human and animal pathogens, and with a similar aim considerable efforts have been directed towards understanding host-pathogen molecular interactions for WSD. Work on the molecular mechanisms of pathogenesis in aquatic crustaceans has been restricted by a lack of sequenced and annotated genomes for host species. Nevertheless, some of the key host-pathogen interactions have been established: between viral envelope proteins and host cell receptors at initiation of infection, involvement of various immune system pathways in response to WSSV, and the roles of various host and virus miRNAs in mitigation or progression of disease. Despite these advances, many fundamental knowledge gaps remain; for example, the roles of the majority of WSSV proteins are still unknown. In this review we assess current knowledge of how WSSV infects and replicates in its host, and critique strategies for WSD treatment.

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

    Science.gov (United States)

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

    2016-02-01

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

  2. Molecular modifiers reveal a mechanism of pathological crystal growth inhibition

    Science.gov (United States)

    Chung, Jihae; Granja, Ignacio; Taylor, Michael G.; Mpourmpakis, Giannis; Asplin, John R.; Rimer, Jeffrey D.

    2016-08-01

    Crystalline materials are crucial to the function of living organisms, in the shells of molluscs, the matrix of bone, the teeth of sea urchins, and the exoskeletons of coccoliths. However, pathological biomineralization can be an undesirable crystallization process associated with human diseases. The crystal growth of biogenic, natural and synthetic materials may be regulated by the action of modifiers, most commonly inhibitors, which range from small ions and molecules to large macromolecules. Inhibitors adsorb on crystal surfaces and impede the addition of solute, thereby reducing the rate of growth. Complex inhibitor-crystal interactions in biomineralization are often not well elucidated. Here we show that two molecular inhibitors of calcium oxalate monohydrate crystallization—citrate and hydroxycitrate—exhibit a mechanism that differs from classical theory in that inhibitor adsorption on crystal surfaces induces dissolution of the crystal under specific conditions rather than a reduced rate of crystal growth. This phenomenon occurs even in supersaturated solutions where inhibitor concentration is three orders of magnitude less than that of the solute. The results of bulk crystallization, in situ atomic force microscopy, and density functional theory studies are qualitatively consistent with a hypothesis that inhibitor-crystal interactions impart localized strain to the crystal lattice and that oxalate and calcium ions are released into solution to alleviate this strain. Calcium oxalate monohydrate is the principal component of human kidney stones and citrate is an often-used therapy, but hydroxycitrate is not. For hydroxycitrate to function as a kidney stone treatment, it must be excreted in urine. We report that hydroxycitrate ingested by non-stone-forming humans at an often-recommended dose leads to substantial urinary excretion. In vitro assays using human urine reveal that the molecular modifier hydroxycitrate is as effective an inhibitor of nucleation

  3. Survivin-T34A: molecular mechanism and therapeutic potential

    Directory of Open Access Journals (Sweden)

    Jonathan R Aspe

    2010-12-01

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

  4. 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

  5. Conformational analysis of methylphenidate: comparison of molecular orbital and molecular mechanics methods

    Science.gov (United States)

    Gilbert, Kathleen M.; Skawinski, William J.; Misra, Milind; Paris, Kristina A.; Naik, Neelam H.; Buono, Ronald A.; Deutsch, Howard M.; Venanzi, Carol A.

    2004-11-01

    Methylphenidate (MP) binds to the cocaine binding site on the dopamine transporter and inhibits reuptake of dopamine, but does not appear to have the same abuse potential as cocaine. This study, part of a comprehensive effort to identify a drug treatment for cocaine abuse, investigates the effect of choice of calculation technique and of solvent model on the conformational potential energy surface (PES) of MP and a rigid methylphenidate (RMP) analogue which exhibits the same dopamine transporter binding affinity as MP. Conformational analysis was carried out by the AM1 and AM1/SM5.4 semiempirical molecular orbital methods, a molecular mechanics method (Tripos force field with the dielectric set equal to that of vacuum or water) and the HF/6-31G* molecular orbital method in vacuum phase. Although all three methods differ somewhat in the local details of the PES, the general trends are the same for neutral and protonated MP. In vacuum phase, protonation has a distinctive effect in decreasing the regions of space available to the local conformational minima. Solvent has little effect on the PES of the neutral molecule and tends to stabilize the protonated species. The random search (RS) conformational analysis technique using the Tripos force field was found to be capable of locating the minima found by the molecular orbital methods using systematic grid search. This suggests that the RS/Tripos force field/vacuum phase protocol is a reasonable choice for locating the local minima of MP. However, the Tripos force field gave significantly larger phenyl ring rotational barriers than the molecular orbital methods for MP and RMP. For both the neutral and protonated cases, all three methods found the phenyl ring rotational barriers for the RMP conformers/invertamers (denoted as cte, tte, and cta) to be: cte, tte> MP > cta. Solvation has negligible effect on the phenyl ring rotational barrier of RMP. The B3LYP/6-31G* density functional method was used to calculate the phenyl

  6. Possible roles of transglutaminases in molecular mechanisms responsible for human neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Nicola Gaetano Gatta

    2016-11-01

    Full Text Available Transglutaminases are a family of Ca2+-dependent enzymes which catalyze post-translational modifications of proteins. The main activity of these enzymes is the cross-linking of glutaminyl residues of a protein/peptide substrate to lysyl residues of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono- or bi-substituted/crosslinked adducts or –OH groups (to form ester linkages. In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Transglutaminase activity has been suggested to be involved in molecular mechanisms responsible for both physiological or pathological processes. In particular, transglutaminase activity has been shown to be responsible for human autoimmune diseases, Celiac Disease is just one of them. Interestingly, neurodegenerative diseases, such as Alzheimer’s Disease, Parkinson’s Disease, supranuclear palsy, Huntington’s Disease and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This review describes the possible molecular mechanisms by which these enzymes could be responsible for such diseases and the possible use of transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity.

  7. [The molecular physiological and genetic mechanisms underlying the superb efficacy of quinolones].

    Science.gov (United States)

    Long, Quan-xin; He, Ying; Xie, Jian-ping

    2012-08-01

    The fluoroquinolones are the most widely used broad-spectrum antibiotics, accounting for 18% of global antibacterial market share. They can kill bacteria rapidly with variety of derivatives available. Different quinolones vary significantly in rate and spectrum of killing, oxygen requirement for metabolism and reliance upon protein synthesis. Further understanding the sophisticated mechanisms of action of this important antibiotic family based on the molecular genetic response of bacteria can facilitate the discovery of better quinolone derivatives. Factors such as SOS response, bacterial toxin-antitoxin system, programmed death, chromosome fragmentation and reactive oxygen have been implicated in the action to some extent. "Two steps characteristic" of quinolones killing is also emphasized, which might inspire future better quinolones modification.

  8. Molecular mechanisms of Ca(2+) signaling in neurons induced by the S100A4 protein

    DEFF Research Database (Denmark)

    Kiryushko, Darya; Novitskaya, Vera; Soroka, Vladislav

    2006-01-01

    The S100A4 protein belongs to the S100 family of vertebrate-specific proteins possessing both intra- and extracellular functions. In the nervous system, high levels of S100A4 expression are observed at sites of neurogenesis and lesions, suggesting a role of the protein in neuronal plasticity....... Extracellular oligomeric S100A4 is a potent promoter of neurite outgrowth and survival from cultured primary neurons; however, the molecular mechanism of this effect has not been established. Here we demonstrate that oligomeric S100A4 increases the intracellular calcium concentration in primary neurons. We...... present evidence that both S100A4-induced Ca(2+) signaling and neurite extension require activation of a cascade including a heterotrimeric G protein(s), phosphoinositide-specific phospholipase C, and diacylglycerol-lipase, resulting in Ca(2+) entry via nonselective cation channels and via T- and L...

  9. DMPD: The interferon regulatory factor family in host defense: mechanism of action. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17502370 The interferon regulatory factor family in host defense: mechanism of acti....html) (.csml) Show The interferon regulatory factor family in host defense: mechanism of action. PubmedID 1...7502370 Title The interferon regulatory factor family in host defense: mechanism

  10. Different mechanisms of action of antimicrobial peptides: insights from fluorescence spectroscopy experiments and molecular dynamics simulations.

    Science.gov (United States)

    Bocchinfuso, Gianfranco; Palleschi, Antonio; Orioni, Barbara; Grande, Giacinto; Formaggio, Fernando; Toniolo, Claudio; Park, Yoonkyung; Hahm, Kyung-Soo; Stella, Lorenzo

    2009-09-01

    Most antimicrobial peptides exert their activity by interacting with bacterial membranes, thus perturbing their permeability. They are investigated as a possible solution to the insurgence of bacteria resistant to the presently available antibiotic drugs. However, several different models have been proposed for their mechanism of membrane perturbation, and the molecular details of this process are still debated. Here, we compare fluorescence spectroscopy experiments and molecular dynamics (MD) simulations regarding the association with lipid bilayers and lipid perturbation for two different amphiphilic helical antimicrobial peptides, PMAP-23 and trichogin GA IV. PMAP-23, a cationic peptide member of the cathelicidin family, is considered to induce membrane permeability according to the Shai-Matsuzaki-Huang "carpet" model, while trichogin GA IV is a neutral peptide, member of the peptaibol family. Although several lines of evidence suggest a "barrel-stave" mechanism of pore formation for the latter peptide, its length is only half the normal thickness of a lipid bilayer. Both fluorescence spectroscopy experiments and MD simulations indicated that PMAP-23 associates with membranes close to their surface and parallel to it, and in this arrangement it causes a severe perturbation to the bilayer, both regarding its surface tension and lipid order. By contrast, trichogin GA IV can undergo a transition from a surface-bound state to a transmembrane orientation. In the first arrangement, it does not cause any strong membrane perturbation, while in the second orientation it might be able to span the bilayer from one side to the other, despite its relatively short length, by causing a significant thinning of the membrane.

  11. Molecular Mechanisms of Microcystin Toxicity in Animal Cells

    Directory of Open Access Journals (Sweden)

    Alexandre Campos

    2010-01-01

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

  12. Molecular mechanisms of heavy metal tolerance and evolution n invertebrates

    Institute of Scientific and Technical Information of China (English)

    Thierry K.S.Janssens; Dick Roelofs; Nico M.van Straalen

    2009-01-01

    Following the genomics revolution,our knowledge of the molecular mechanisms underlying defenses against stress has been greatly expanded.Under strong selective pressure many animals may evolve an enhanced stress tolerance.This can be achieved by altering the structure of proteins(through mutations in the coding regions of genes)or by altering the amount of protein(through changes in transcriptional regulation).The latter type of evolution Can be achieved by substitutions in the promoter of the gene of interest(cis-regulatory change)or by altering the structure or anaount of transcriptional regulator proteins (trans-regulatory change).The metallothionein system is one of the best studied stress response systems in the context of heavy metals.Metallothionein expression is assumed to be regulated by metal transcription factor 1(MTF-1);however,up to now the involvement of MTF-1 has only been proven for some vertebrates and Drosophila.Data on invertebrates such as nematodes and earthworms suggest that other mechanisms of metallothionein induction may be present.A detailed study of Cd tolerance was done for a species of soilliving springtail,Orchesella cincta.The metallothionein gene of this species is overexpressed in metal-exposed field populations.Analysis of the metallothionein promoter has demonstrated extensive polymorphisills that have a functional significance,as shown in bioreporter assays.In a study comparing 20 different populations,the frequency of a high-expresser promoter allele Was positively correlated with the concentration of metals in soil,especially Cd.The springtail study shows that cis-regulatory change of genes involved in the cellular stress response may contribute to evolution of metal tolerance.

  13. Molecular mechanisms governing competitive synaptic wiring in cerebellar Purkinje cells.

    Science.gov (United States)

    Watanabe, Masahiko

    2008-03-01

    Cerebellar Purkinje cells (PCs) play a principal role in motor coordination and motor learning. To fulfill these functions, PCs receive and integrate two types of excitatory inputs, climbing fiber (CF) and parallel fiber (PF). CFs are projection axons from the inferior olive, and convey error signals to PCs. On the other hand, PFs are T-shaped axons of cerebellar granule cells, and convey sensory and motor information carried through the pontocerebellar and spinocerebellar mossy fiber pathways. The most remarkable feature of PC circuits is the highly territorial innervation by these two excitatory afferents. A single climbing CF powerfully and exclusively innervates proximal PC dendrites, whereas hundreds of thousands of PFs innervate distal PC dendrites. Recent studies using gene-manipulated mice have been elucidating that the PC circuitry is formed and maintained by molecular mechanisms that fuel homosynaptic competition among CFs and heterosynaptic competition between CFs and PFs. GluRdelta2 (a PC-specific glutamate receptor) and precerebellin or Cbln1 (a granule cell-derived secretory protein) cooperatively work for selective strengthening of PF-PC synapses, and prevent excessive distal extension of CFs that eventually causes multiple innervation at distal dendrites. In contrast, P/Q-type Ca2+ channels, which mediate Ca2+ influx upon CF activity, selectively strengthen the innervation by a single main CF, and expel PFs and other CFs from proximal dendrites that it innervates. Therefore, we now understand that owing to these mechanisms, territorial innervation by CFs and PFs is properly structured and mono-innervation by CFs is established. Several key issues for future study are also discussed.

  14. Multiresolution molecular mechanics: Surface effects in nanoscale materials

    Science.gov (United States)

    Yang, Qingcheng; To, Albert C.

    2017-05-01

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

  15. 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...

  16. A Quantum-Mechanics Molecular-Mechanics scheme for extended systems

    CERN Document Server

    Hunt, Diego; Scherlis, Damian A

    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 throu...

  17. Comparative Molecular Mechanics and Quantum Mechanics Study of Microhydration of Nucleic Acid Bases

    CERN Document Server

    Lino, J; Deriabina, A; Velasco, M; Poltev, V

    2013-01-01

    DNA is the most important biological molecule, and its hydration contributes essentially to the structure and functions of the double helix. We analyze the microhydration of the individual bases of nucleic acids and their methyl derivatives using methods of molecular mechanics (MM) with the Poltev-Malenkov (PM), AMBER and OPLS force fields, as well as ab initio Quantum Mechanics (QM) calculations at MP2/6-31G(d,p) level of theory. A comparison is made between the calculated interaction energies and the experimental enthalpies of microhydration of bases, obtained from mass spectrometry at low temperatures. Each local water-base interaction energy minimum obtained with MM corresponds to the minimum obtained with QM. General qualitative agreement was observed in the geometrical characteristics of the local minima obtained via the two groups of methods. MM minima correspond to slightly more coplanar structures than those obtained via QM methods, and the absolute MM energy values overestimate corresponding values ...

  18. Adriamycin increases podocyte permeability: evidence and molecular mechanism

    Institute of Scientific and Technical Information of China (English)

    李晓忠; 袁海涛; 张学光

    2003-01-01

    Objective To investigate the increased podocyte permeability by evidence of adriamycin (AD) and its molecular mechanism.Methods In this study, we explored the direct effects of AD on cultured mouse podocytes and the potential protection effects of Dexamethasome (Dex).Results After 24-hour AD (5×10-7 mol/L) treatment, albumin passage through podocyte monolayers was increased by 2.27-fold (P<0.01). AD caused a 62% decrease in Zonula Occluden -1 (ZO-1) protein (P<0.05), suggesting that AD might increase podocyte permeability by disrupting tight junctions. Dex (1×10-6 mol/L), co-administered with AD, protected podocytes from AD-induced increased albumin passage. This may be linked with an increased P-cadherin protein level to 1.93 fold of control (P<0.01).Conclusions AD has a direct, detrimental effect on podocyte permeability, probably through disrupting tight junctions; Dex could protect against AD-induced high podocyte permeability by upregulating adherent protein P-cadherin.

  19. [Molecular mechanisms of regulaion of transcription by PARP1].

    Science.gov (United States)

    Maliuchenko, N V; Kulaeva, O I; Kotova, E; Chupyrkina, A A; Nikitin, D V; Kirpichnikov, M P; Studitskiĭ, V M

    2015-01-01

    Poly-ADP-ribosylation is a covalent post-translational modification of nuclear proteins that plays a key role in the immediate response of cells to genotoxic stress. Poly(ADP-ribose) polymerase (PARP) synthesizes long and branched polymers of ADP-ribose onto acceptor regulator proteins, and thereby change their activity. Metabolism of poly-ADP regulates DNA repair, cell cycle, replication, aging and death of cells, as well as remodeling of chromatin structure and gene transcription. PARP1 is one of the most common nuclear proteins; it is responsible for production of -90% of the polymers of ADP-ribose in the cell. PARP1 inhibitors are promising antitumor agents. At the same time, the current inhibitors target the catalytic domain of PARP1 that leads to.a number of side effects. Therefore, considering the potential benefits of PARP1 inhibitors for the treatment of multiple diseases, it is necessary to develop new strategies of PARP1 inhibition. PARP1 has a modular structure and has catalytic, transcription and DNA-binding activities. The review focuses primarily on the role of PARP1 in transcriptional regulation; the structure and functional organization of PARP1, as well as multiple ways of regulation of chromatin remodeling, DNA methylation and transcription are covered in detail. Studies of the molecular mechanisms of regulation of transcription factor PARP1 can serve as a basis for search and design of new inhibitors.

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

    Science.gov (United States)

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

    2016-03-18

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

  1. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-12-15

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

  3. [Phenotype analysis and the molecular mechanism of enamel hypoplasia].

    Science.gov (United States)

    Lv, Ping; Gao, Xue-jun

    2009-02-18

    Enamel hypoplasia is a surface defect of the tooth crown caused by a disturbance of enamel matrix secretion. Enamel hypoplasia may be inherited, or result from illness, malnutrition, trauma, or high concentrations of fluorides or strontium in the drinking water or food. Different types of enamel hypoplasia have been distinguished, such as pit-type, plane-type, and linear enamel hypoplasia. Hypoplasia has been related to the intensity and duration of stress events, the number of affected ameloblasts, and their position along the forming tooth crown. Amelogenesis imperfecta (AI) is a heterogeneous group of inherited defects in dental enamel formation, most teeth are affected in both the primary and permanent dentition. The malformed enamel can be unusually thin, soft, rough and stained. The strict definition of AI includes only those cases where enamel defects occur in the absence of other symptoms. Currently, there are seven candidate genes for AI: amelogenin, enamelin, ameloblastin, tuftelin, distal-less homeobox 3, enamelysin, and kallikrein 4. Since the enamel is formed according to a strict chronological sequence, and once formed, undergoes no repair or regeneration. Then the analysis the phenotype of enamel hypoplasia can provide insights of the severity of inherited or environmental stress and the molecular mechanism during the period of enamel formation.

  4. Molecular mechanisms of pancreatic stone formation in chronic pancreatitis.

    Directory of Open Access Journals (Sweden)

    Shigeru B.H. Ko

    2012-11-01

    Full Text Available Chronic pancreatitis (CP is a progressive inflammatory disease in which the pancreatic secretory parenchyma is destroyed and replaced by fibrosis. The presence of intraductal pancreatic stone(s is important for the diagnosis of CP; however, the precise molecular mechanisms of pancreatic stone formation in CP were left largely unknown. CFTR is a chloride channel expressed in the apical plasma membrane of pancreatic duct cells and plays a central role in HCO3- secretion. In previous studies, we have found that CFTR is largely mislocalized to the cytoplasm of pancreatic duct cells in all forms of CP and corticosteroids normalizes the localization of CFTR to the proper apical membrane at least in autoimmune pancreatitis. From these observations, we could conclude that the mislocalization of CFTR is a cause of protein plug formation in CP, subsequently resulting in pancreatic stone formation.Considering our observation that the mislocalization of CFTR also occurs in alcoholic or idiopathic CP, it is very likely that these pathological conditions can also be treated by corticosteroids, thereby preventing pancreatic stone formation in these patients. Further studies are definitely required to clarify these fundamental issues.

  5. Molecular mechanisms of metabolic resistance to synthetic and natural xenobiotics.

    Science.gov (United States)

    Li, Xianchun; Schuler, Mary A; Berenbaum, May R

    2007-01-01

    Xenobiotic resistance in insects has evolved predominantly by increasing the metabolic capability of detoxificative systems and/or reducing xenobiotic target site sensitivity. In contrast to the limited range of nucleotide changes that lead to target site insensitivity, many molecular mechanisms lead to enhancements in xenobiotic metabolism. The genomic changes that lead to amplification, overexpression, and coding sequence variation in the three major groups of genes encoding metabolic enzymes, i.e., cytochrome P450 monooxygenases (P450s), esterases, and glutathione-S-transferases (GSTs), are the focus of this review. A substantial number of the adaptive genomic changes associated with insecticide resistance that have been characterized to date are transposon mediated. Several lines of evidence suggest that P450 genes involved in insecticide resistance, and perhaps insecticide detoxification genes in general, may share an evolutionary association with genes involved in allelochemical metabolism. Differences in the selective regime imposed by allelochemicals and insecticides may account for the relative importance of regulatory or structural mutations in conferring resistance.

  6. Cellular and molecular mechanisms of tooth root development.

    Science.gov (United States)

    Li, Jingyuan; Parada, Carolina; Chai, Yang

    2017-02-01

    The tooth root is an integral, functionally important part of our dentition. The formation of a functional root depends on epithelial-mesenchymal interactions and integration of the root with the jaw bone, blood supply and nerve innervations. The root development process therefore offers an attractive model for investigating organogenesis. Understanding how roots develop and how they can be bioengineered is also of great interest in the field of regenerative medicine. Here, we discuss recent advances in understanding the cellular and molecular mechanisms underlying tooth root formation. We review the function of cellular structure and components such as Hertwig's epithelial root sheath, cranial neural crest cells and stem cells residing in developing and adult teeth. We also highlight how complex signaling networks together with multiple transcription factors mediate tissue-tissue interactions that guide root development. Finally, we discuss the possible role of stem cells in establishing the crown-to-root transition, and provide an overview of root malformations and diseases in humans. © 2017. Published by The Company of Biologists Ltd.

  7. Molecular mechanism of resistance of Fusarium fujikuroi to benzimidazole fungicides.

    Science.gov (United States)

    Chen, Zihao; Gao, Tao; Liang, Shuping; Liu, Kexue; Zhou, Mingguo; Chen, Changjun

    2014-08-01

    Although carbendazim (MBC) and other benzimidazole fungicides have effectively controlled bakanae disease of rice (which is caused by Fusarium fujikuroi, F. proliferatum, and F. verticillioides) in the past, MBC resistance has become common. Previous research has shown that MBC resistance results from a mutation in the β1 -tubulin (β1 tub) gene in F. verticillioides. However, MBC resistance in F. fujikuroi, a predominant species in China, does not result from a mutation in the β1 tub. The molecular mechanism of F. fujikuroi resistance against benzimidazole fungicides is poorly understood. In this study, we determined that although β1 tub and β2 -tubulin (β2 tub) in F. fujikuroi have high homology with β1 tub and β2 tub in F. verticillioides, MBC resistance in F. fujikuroi results from mutations in β2 tub [GAG(Glu)→GTG(Val) at codon 198, TTC(Phe)→TAC(Tyr) at codon 200, and GGC(Gly)→GGT(Gly) at codon 235] but not in β1 tub. Δβ2 tub (β2 tub deletion) mutants were highly sensitive to MBC, produced fewer conidia and were less virulent than parental strains. Complementation of the Δβ2 tub mutants with a copy of the whole β2 tub locus from their parental strains restored the level of MBC resistance (or sensitivity) to that of the parental strain.

  8. Molecular mechanics study on conformation of perylene-quinonoid photosensitizers

    Institute of Scientific and Technical Information of China (English)

    张红雨; 张志义

    1997-01-01

    Using molecular mechanics method,values of the heat of formation (HF) of different conformations,of perylenequinonoid photosensitizes hypocrellin A (HA) and hypocrellin B (HB) were calculated and the variance of HF after phenolic protons’ dissociation were calculated as well The following was found:(i) The HF values of lour conformational isomers of HA and HB are similar to each other,so the four isomcrs can transform to each other room temperature,(ii) There exists the difference between the ability of dissociation of phenolic protons of HA and that of HB,the former is higher than the latter (iii) There exist two intramolecular hydrogen bonds in HA and HB The bond energy is approximately 8 kJ/mol and the energy of conformation Ⅰ is lower than that of conformationⅡ The bond energy of HA is lower than that of HB.(iv) There exists a low energy snot when phenolic hydroxyl bond twists 180° from the position where hydrogen bond is formed,which suggests that this kind of conformation probably exists,(v) Th

  9. 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.

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

    Directory of Open Access Journals (Sweden)

    Florian eMüller-Dahlhaus

    2013-12-01

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

  11. Chemopreventive functions and molecular mechanisms of garlic organosulfur compounds.

    Science.gov (United States)

    Trio, Phoebe Zapanta; You, Sixiang; He, Xi; He, Jianhua; Sakao, Kozue; Hou, De-Xing

    2014-05-01

    Garlic (Allium sativum L.) has long been used both for culinary and medicinal purposes by many cultures. Population and preclinical investigations have suggested that dietary garlic intake has health benefits, such as lowering the risk of esophageal, stomach and prostate cancers. Extensive studies from laboratory and animal models have revealed that garlic has a wide range of biological activities, and garlic organosulfur compounds (OSCs) are responsible for the biological activities. However, the presence and potency of garlic OSCs vary with respect to the mode of garlic preparation and extraction. Cooked or processed garlic products showed different kinds of garlic OSCs, some of which are highly unstable and instantly decomposed. These facts, possibly gave paradoxical results on the garlic effects. In this review, we first summarized the biotransformation processes of garlic alliin into different garlic OSCs as well as the garlic OSCs compositions from different garlic preparations. Next, we reviewed the chemopreventive functions and molecular mechanisms focusing on the anti-inflammation, antioxidation, anti-diabetes and anticancer activity behind different garlic OSCs.

  12. Identification of the Kelch family protein Nd1-L as a novel molecular interactor of KRIT1.

    Directory of Open Access Journals (Sweden)

    Paolo Guazzi

    Full Text Available Loss-of-function mutations of the KRIT1 gene (CCM1 have been associated with the Cerebral Cavernous Malformation (CCM disease, which is characterized by serious alterations of brain capillary architecture. The KRIT1 protein contains multiple interaction domains and motifs, suggesting that it might act as a scaffold for the assembly of functional protein complexes involved in signaling networks. In previous work, we defined structure-function relationships underlying KRIT1 intramolecular and intermolecular interactions and nucleocytoplasmic shuttling, and found that KRIT1 plays an important role in molecular mechanisms involved in the maintenance of the intracellular Reactive Oxygen Species (ROS homeostasis to prevent oxidative cellular damage. Here we report the identification of the Kelch family protein Nd1-L as a novel molecular interactor of KRIT1. This interaction was discovered through yeast two-hybrid screening of a mouse embryo cDNA library, and confirmed by pull-down and co-immunoprecipitation assays of recombinant proteins, as well as by co-immunoprecipitation of endogenous proteins in human endothelial cells. Furthermore, using distinct KRIT1 isoforms and mutants, we defined the role of KRIT1 domains in the Nd1-L/KRIT1 interaction. Finally, functional assays showed that Nd1-L may contribute to the regulation of KRIT1 nucleocytoplasmic shuttling and cooperate with KRIT1 in modulating the expression levels of the antioxidant protein SOD2, opening a novel avenue for future mechanistic studies. The identification of Nd1-L as a novel KRIT1 interacting protein provides a novel piece of the molecular puzzle involving KRIT1 and suggests a potential functional cooperation in cellular responses to oxidative stress, thus expanding the framework of molecular complexes and mechanisms that may underlie the pathogenesis of CCM disease.

  13. First quantum mechanics/molecular mechanics studies of the inhibition mechanism of cruzain by peptidyl halomethyl ketones.

    Science.gov (United States)

    Arafet, Kemel; Ferrer, Silvia; Moliner, Vicent

    2015-06-02

    Cruzain is a primary cysteine protease expressed by the protozoan parasite Trypanosoma cruzi during Chagas disease infection, and thus, the development of inhibitors of this protein is a promising target for designing an effective therapy against the disease. In this paper, the mechanism of inhibition of cruzain by two different irreversible peptidyl halomethyl ketones (PHK) inhibitors has been studied by means of hybrid quantum mechanics/molecular mechanics-molecular dynamics (MD) simulations to obtain a complete representation of the possible free energy reaction paths. These have been traced on free energy surfaces in terms of the potential of mean force computed at AM1d/MM and DFT/MM levels of theory. An analysis of the possible reaction mechanisms of the inhibition process has been performed showing that the nucleophilic attack of an active site cysteine, Cys25, on a carbon atom of the inhibitor and the cleavage of the halogen-carbon bond take place in a single step. PClK appears to be much more favorable than PFK from a kinetic point of view. This result would be in agreement with experimental studies in other papain-like enzymes. A deeper analysis of the results suggests that the origin of the differences between PClK and PFK can be the different stabilizing interactions established between the inhibitors and the residues of the active site of the protein. Any attempt to explore the viability of the inhibition process through a stepwise mechanism involving the formation of a thiohemiketal intermediate and a three-membered sulfonium intermediate has been unsuccessful. Nevertheless, a mechanism through a protonated thiohemiketal, with participation of His159 as a proton donor, appears to be feasible despite showing higher free energy barriers. Our results suggest that PClK can be used as a starting point to develop a proper inhibitor of cruzain.

  14. Update on Pyrin Functions and Mechanisms of Familial Mediterranean Fever

    Science.gov (United States)

    Manukyan, Gayane; Aminov, Rustam

    2016-01-01

    Mutations in the MEFV gene, which encodes the protein named pyrin (also called marenostrin or TRIM20), are associated with the autoinflammatory disease familial Mediterranean fever (FMF). Recent genetic and immunologic studies uncovered novel functions of pyrin and raised several new questions in relation to FMF pathogenesis. The disease is clinically heterogeneous reflecting the complexity and multiplicity of pyrin functions. The main functions uncovered so far include its involvement in innate immune response such as the inflammasome assemblage and, as a part of the inflammasome, sensing intracellular danger signals, activation of mediators of inflammation, and resolution of inflammation by the autophagy of regulators of innate immunity. Based on these functions, the FMF-associated versions of pyrin confer a heightened sensitivity to a variety of intracellular danger signals and postpone the resolution of innate immune responses. It remains to be demonstrated, however, what kind of selective advantage the heterozygous carriage conferred in the past to be positively selected and maintained in populations from the Mediterranean basin. PMID:27066000

  15. A computational study of the protein-ligand interactions in CDK2 inhibitors: using quantum mechanics/molecular mechanics interaction energy as a predictor of the biological activity.

    Science.gov (United States)

    Alzate-Morales, Jans H; Contreras, Renato; Soriano, Alejandro; Tuñon, Iñaki; Silla, Estanislao

    2007-01-15

    We report a combined quantum mechanics/molecular mechanics (QM/MM) study to determine the protein-ligand interaction energy between CDK2 (cyclin-dependent kinase 2) and five inhibitors with the N(2)-substituted 6-cyclohexyl-methoxy-purine scaffold. The computational results in this work show that the QM/MM interaction energy is strongly correlated to the biological activity and can be used as a predictor, at least within a family of substrates. A detailed analysis of the protein-ligand structures obtained from molecular dynamics simulations shows specific interactions within the active site that, in some cases, have not been reported before to our knowledge. The computed interaction energy gauges the strength of protein-ligand interactions. Finally, energy decomposition and multiple regression analyses were performed to check the contribution of the electrostatic and van der Waals energies to the total interaction energy and to show the capabilities of the computational model to identify new potent inhibitors.

  16. Molecular classification of familial non-BRCA1/BRCA2 breast cancer.

    Science.gov (United States)

    Hedenfalk, Ingrid; Ringner, Markus; Ben-Dor, Amir; Yakhini, Zohar; Chen, Yidong; Chebil, Gunilla; Ach, Robert; Loman, Niklas; Olsson, Håkan; Meltzer, Paul; Borg, Ake; Trent, Jeffrey

    2003-03-01

    In the decade since their discovery, the two major breast cancer susceptibility genes BRCA1 and BRCA2, have been shown conclusively to be involved in a significant fraction of families segregating breast and ovarian cancer. However, it has become equally clear that a large proportion of families segregating breast cancer alone are not caused by mutations in BRCA1 or BRCA2. Unfortunately, despite intensive effort, the identification of additional breast cancer predisposition genes has so far been unsuccessful, presumably because of genetic heterogeneity, low penetrance, or recessive/polygenic mechanisms. These non-BRCA1/2 breast cancer families (termed BRCAx families) comprise a histopathologically heterogeneous group, further supporting their origin from multiple genetic events. Accordingly, the identification of a method to successfully subdivide BRCAx families into recognizable groups could be of considerable value to further genetic analysis. We have previously shown that global gene expression analysis can identify unique and distinct expression profiles in breast tumors from BRCA1 and BRCA2 mutation carriers. Here we show that gene expression profiling can discover novel classes among BRCAx tumors, and differentiate them from BRCA1 and BRCA2 tumors. Moreover, microarray-based comparative genomic hybridization (CGH) to cDNA arrays revealed specific somatic genetic alterations within the BRCAx subgroups. These findings illustrate that, when gene expression-based classifications are used, BRCAx families can be grouped into homogeneous subsets, thereby potentially increasing the power of conventional genetic analysis.

  17. The vanilloid receptor family of calcium-permeable channels: molecular integrators of microenvironmental stimuli.

    Science.gov (United States)

    O'Neil, Roger G; Brown, Rachel C

    2003-12-01

    The TRPV subfamily of calcium-permeable channels is widely distributed in sensory and nonsensory cells from nematodes to mammals. These channels can be variably activated by a diverse range of stimuli (osmotic/mechanical stress, noxious chemicals and heat, endogenous mediators) that often converge on the same channel. Evidence is presented that TRPV channels function as novel "molecular integrators" of diverse microenvironmental stimuli.

  18. Nuclear functions and subcellular trafficking mechanisms of the epidermal growth factor receptor family

    Science.gov (United States)

    2012-01-01

    Accumulating evidence suggests that various diseases, including many types of cancer, result from alteration of subcellular protein localization and compartmentalization. Therefore, it is worthwhile to expand our knowledge in subcellular trafficking of proteins, such as epidermal growth factor receptor (EGFR) and ErbB-2 of the receptor tyrosine kinases, which are highly expressed and activated in human malignancies and frequently correlated with poor prognosis. The well-characterized trafficking of cell surface EGFR is routed, via endocytosis and endosomal sorting, to either the lysosomes for degradation or back to the plasma membrane for recycling. A novel nuclear mode of EGFR signaling pathway has been gradually deciphered in which EGFR is shuttled from the cell surface to the nucleus after endocytosis, and there, it acts as a transcriptional regulator, transmits signals, and is involved in multiple biological functions, including cell proliferation, tumor progression, DNA repair and replication, and chemo- and radio-resistance. Internalized EGFR can also be transported from the cell surface to several intracellular compartments, such as the Golgi apparatus, the endoplasmic reticulum, and the mitochondria, in addition to the nucleus. In this review, we will summarize the functions of nuclear EGFR family and the potential pathways by which EGFR is trafficked from the cell surface to a variety of cellular organelles. A better understanding of the molecular mechanism of EGFR trafficking will shed light on both the receptor biology and potential therapeutic targets of anti-EGFR therapies for clinical application. PMID:22520625

  19. Antiviral Mechanism and biochemical basis of the human APOBEC3 family

    Directory of Open Access Journals (Sweden)

    Mayumi eImahashi

    2012-07-01

    Full Text Available The human APOBEC3 (A3 family (A, B, C, DE, F, G, and H comprises host defense factors that potently inhibit the replication of diverse retroviruses, retrotransposons, and the other viral pathogens. HIV-1 has a counterstrategy that includes expressing the Vif protein to abrogate A3 antiviral function. Without Vif, A3 proteins, particularly APOBEC3G (A3G and APOBEC3F (A3F, inhibit HIV-1 replication by blocking reverse transcription and/or integration and hypermutating nascent viral cDNA. The molecular mechanisms of this antiviral activity have been primarily attributed to two biochemical characteristics common to A3 proteins: catalyzing cytidine deamination in single-stranded DNA (ssDNA and a nucleic acid-binding capability that is specific to ssDNA or ssRNA. Recent advances suggest that unique property of A3G dimer/oligomer formations, is also important for the modification of antiviral activity. In this review article we summarize how A3 proteins, particularly A3G, inhibit viral replication based on the biochemical and structural characteristics of the A3G protein.

  20. Nuclear functions and subcellular trafficking mechanisms of the epidermal growth factor receptor family

    Directory of Open Access Journals (Sweden)

    Wang Ying-Nai

    2012-04-01

    Full Text Available Abstract Accumulating evidence suggests that various diseases, including many types of cancer, result from alteration of subcellular protein localization and compartmentalization. Therefore, it is worthwhile to expand our knowledge in subcellular trafficking of proteins, such as epidermal growth factor receptor (EGFR and ErbB-2 of the receptor tyrosine kinases, which are highly expressed and activated in human malignancies and frequently correlated with poor prognosis. The well-characterized trafficking of cell surface EGFR is routed, via endocytosis and endosomal sorting, to either the lysosomes for degradation or back to the plasma membrane for recycling. A novel nuclear mode of EGFR signaling pathway has been gradually deciphered in which EGFR is shuttled from the cell surface to the nucleus after endocytosis, and there, it acts as a transcriptional regulator, transmits signals, and is involved in multiple biological functions, including cell proliferation, tumor progression, DNA repair and replication, and chemo- and radio-resistance. Internalized EGFR can also be transported from the cell surface to several intracellular compartments, such as the Golgi apparatus, the endoplasmic reticulum, and the mitochondria, in addition to the nucleus. In this review, we will summarize the functions of nuclear EGFR family and the potential pathways by which EGFR is trafficked from the cell surface to a variety of cellular organelles. A better understanding of the molecular mechanism of EGFR trafficking will shed light on both the receptor biology and potential therapeutic targets of anti-EGFR therapies for clinical application.

  1. Mechanisms of antibiotic resistance of Enterobacteriaceae family representatives

    Directory of Open Access Journals (Sweden)

    K. R. Kotsyuba

    2014-04-01

    Full Text Available The paper deals with the basic medical scheme of antibiotics use for treatment of lesions caused by enterobacteria and mechanisms of resistance of Enterobacteriaceae to different classes of antibiotics. It is known that the main mechanisms of resistance to antibiotics are enzymatic inactivation, modification of the target, efflux, violation of conduct through the membrane and formation of metabolic shunt. The most common cases of resistance to beta-lactams among Enterobacteriaceae relate to production of plasmid and chromosomal beta-lactamases, violation of the permeability of the outer membrane, and modification of target penicillin binding proteins. Active release of antibiotics from the cell, or efflux, in Enterobacteriaceae is used for maintaining resistance to tetracyclines, macrolides, carbapenems. Genes of efflux system are localized on plasmids and contribute to rapid spreading among Enterobacteriaceae. Mutations are the basis of resistance to novobiocinum and rifampicinum. Enzymatic inactivation by modifying is typical for resistance to aminoglycosides. Three groups of enzymes are engaged in the process, by adding the molecule of acetic acid, phosphate or adenine. Joining of these groups is irreversible and leads to complete loss of biological activity of the antibiotic. Resistance to aminoglycosides appears also due to inhibition of drug penetration, that is associated with genetically determined mechanisms of electron transport through the membrane. Resistance to quinolones and fluoroquinolones is associated with the modification of topoisomerase II and IV which are targets of these groups of antibiotics. Resistance is possible as a result of changes in the structure of the target, breaching of penetration into the cell, and active release from the cell. The highest level of resistance is develope in the case of two- or three-stage mutations in one or the other, or both, subunits in different genes. At the same time, for breaching of

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

    Science.gov (United States)

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

    2008-03-28

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

  3. Correction: Molecular evolution of the keratin associated protein gene family in mammals, role in the evolution of mammalian hair

    Directory of Open Access Journals (Sweden)

    Irwin David M

    2009-08-01

    Full Text Available Abstract Correction to Wu DD, Irwin DM, Zhang YP: Molecular evolution of the keratin associated protein gene family in mammals, role in the evolution of mammalian hair. BMC Evol Biol 2008, 8:241.

  4. Molecular analysis of the (CAGN repeat causing Huntington′s disease in 34 Iranian families

    Directory of Open Access Journals (Sweden)

    Hormozian F

    2004-01-01

    Full Text Available Huntington′s disease (HD is an inherited neurodegenerative disorder characterized by chorea and progressive dementia. The mutation causing the disease has been identified as an unstable expansion of a trinucleotide (CAG n at the 5′ end of the IT 15 gene on chromosome 4. We have analyzed the distribution of CAG repeats in 71 Iranian individuals (34 patients and 37 unaffected family members belonging to 31 unrelated families thought to segregate HD. We found one expanded CAG allele in 22 individuals (65% belonging to 21 unrelated families. In these HD patients, expanded alleles varied from 40 to 83 CAG units and normal alleles varied from 13 to 36 CAGs. A significant negative correlation between age at onset of symptoms and size of the expanded CAG allele was found (r= - 0.51; P=0. 1. In addition, we genotyped 25 unrelated control individuals (total of 50 alleles and found normal CAG repeats varying from 10 to 34 units. In conclusion, our results showed that molecular confirmation of the clinical diagnosis in HD should be sought in all suspected patients, making it possible for adequate genetic counseling. This Study is the first report of molecular diagnosis of Huntington disease among Iranian population and ever in Middle East and with regard to high frequency of consanguinity marriage in this region.

  5. Hyperphosphatemic familial tumoral calcinosis: response to acetazolamide and postulated mechanisms.

    Science.gov (United States)

    Finer, Gal; Price, Heather E; Shore, Richard M; White, Kenneth E; Langman, Craig B

    2014-06-01

    Hyperphosphatemic familial tumoral calcinosis (HFTC) is characterized by enhanced renal phosphate absorption, hyperphosphatemia, and tumor-like extraosseous calcifications due to inactivating mutations in FGF23 or associated proteins. Surgical excision is needed when low phosphate diet and phosphate binders are ineffective. Sporadic reports have supported acetazolamide use. We report on a 7-year-old African American boy who presented with severe HFTC requiring numerous surgical excisions. Tumors continued to appear and others reoccurred despite phosphate restriction and sevelamer carbonate. At the age of 9.5 years, acetazolamide (40 mg/kg/day) was added and resulted in mild metabolic acidosis (bicarbonate 25.3 mEq/L vs. 21.4 mEq/L, P < 0.001; serum pH 7.38 vs. 7.31, P = 0.013, pre- and post-acetazolamide, respectively) but no change in tubular reabsorption of phosphate (TRP) (96.9% vs. 95.9%, P = 0.34) or serum phosphate (6.6 mg/dl vs. 6.9 mg/dl, P = 0.52 pre- and post-acetazolamide, respectively). Following the initiation of acetazolamide therapy, the patient experienced significant improvement in disease course as indicated by resolution of localized bone pain, cessation of tumor formation, and no tumor recurrence. Despite mild metabolic acidosis, our patient had improved linear growth and did not develop any other side effects related to therapy. Intact FGF23 remained abnormally low throughout disease course, while C-terminal FGF23 increased with acetazolamide. We conclude that acetazolamide can control severe HFTC by inducing mild metabolic acidosis despite no change in serum phosphate or TRP. This effect may be exerted though improved calcium-phosphate complex solubility and increased FGF23 locally.

  6. Understanding mechanical properties of polymer nanocomposites with molecular dynamics simulations

    Science.gov (United States)

    Sen, Suchira

    Equilibrium Molecular Dynamics (MD) simulations are used extensively to study various aspects of polymer nanocomposite (PNC) behavior in the melt state---the key focus is on understanding mechanisms of mechanical reinforcement. Mechanical reinforcement of the nanocomposite is believed to be caused by the formation of a network-like structure---a result of polymer chains bridging particles to introduce network elasticity. In contrast, in traditional composites, where the particle size range is hundreds of microns and high loadings of particle are used, the dominant mechanism is the formation of a percolated filler structure. The difference in mechanism with varying particle sizes, at similar particle loading, arises from the polymer-particle interfacial area available, which increases dramatically as the particle size decreases. Our interest in this work is to find (a) the kind of polymer-particle interactions necessary to facilitate the formation of a polymer network in a nanocomposite, and (b) the reinforcing characteristics of such a polymer network. We find that very strong polymer-particle binding is necessary to create a reinforcing network. The strength of the binding has to be enough to immobilize polymer on the particle surface for timescales comparable and larger than the terminal relaxation time of the stress of the neat melt. The second finding, which is a direct outcome of very strong binding, is that the method of preparation plays a critical role in determining the reinforcement of the final product. The starting conformations of the polymer chains determine the quality of the network. The strong binding traps the polymer on the particle surface which gets rearranged to a limited extent, within stress relaxation times. Significant aging effects are seen in system relaxation; the inherent non-equilibrium consequences of such strong binding. The effect of the polymer immobilization slows down other relaxation processes. The diffusivity of all chains is

  7. Molecular Evolution and Expression Divergence of Aconitase (ACO Gene Family in Land Plants

    Directory of Open Access Journals (Sweden)

    Yi-ming Wang

    2016-12-01

    Full Text Available Aconitase (ACO is a key enzyme that catalyzes the isomerization of citrate to isocitrate in the tricarboxylic acid (TCA and glyoxylate cycles. The function of ACOs has been well studied in model plants, such as Arabidopsis. In contrast, the evolutionary patterns of the ACO family in land plants are poorly understood. In this study, we systematically examined the molecular evolution and expression divergence of the ACO gene family in 12 land plant species. Thirty-six ACO genes were identified from the 12 land plant species representing the four major land plant lineages: bryophytes, lycophytes, gymnosperms, and angiosperms. All of these ACOs belong to the cytosolic isoform. Three gene duplication events contributed to the expansion of the ACO family in angiosperms. The ancestor of angiosperms may have contained only one ACO gene. One gene duplication event split angiosperm ACOs into two distinct clades. Two clades showed a divergence in selective pressure and gene expression patterns. The cis-acting elements that function in light responsiveness were most abundant in the promoter region of the ACO genes, indicating that plant ACO genes might participate in light regulatory pathways. Our findings provide comprehensive insights into the ACO gene family in land plants.

  8. Molecular cytogenetic analysis of clustered sporadic and familial renal cell carcinoma-associated 3q13 approximately q22 breakpoints.

    NARCIS (Netherlands)

    Bodmer, D.; Janssen, I.M.; Jonkers, Y.M.H.; Berg, E. van den; Dijkhuizen, T.; Debiec-Rychter, M.; Schoenmakers, E.F.P.M.; Geurts van Kessel, A.H.M.

    2002-01-01

    We describe several relatives within one renal cell cancer (RCC) family sharing a constitutional t(2;3) (q35;q21). Based on molecular studies on several independent primary tumors in this family, a causative role for this translocation in tumor development was suggested. Subsequent positional clonin

  9. Molecular mechanisms of cholangiocarcinoma cell inhibition by medicinal plants

    Science.gov (United States)

    Leelawat, Surang; Leelawat, Kawin

    2017-01-01

    Cholangiocarcinoma (CCA) is one of the most common causes of cancer-associated mortality in Thailand. Certain phytochemicals have been demonstrated to modulate apoptotic signaling pathways, which may be targeted for the prevention and treatment of cancer. Therefore, the aim of the present study was to investigate the effect of specific medicinal plants on the inhibition of CCA cell proliferation, and to identify the molecular mechanisms underlying this. A WST-1 cell proliferation assay was performed using an RMCCA1 cell line, and apoptotic signaling pathways were also investigated using a PathScan Stress and Apoptosis Signaling Antibody Array Kit. The cell proliferation assay indicated that extracts from the Phyllanthus emblica fruit pulp (PEf), Phyllanthus emblica seed (PEs), Terminalia chebula fruit pulp (TCf), Terminalia chebula seed (TCs), Areca catechu seed (ACs), Curcuma longa (CL) and Moringa oleifera seed (MOs) exerted anti-proliferative activity in RMCCA1 cells. In addition, the PathScan assay revealed that certain pro-apoptotic molecules, including caspase-3, poly (ADP-ribose) polymerase, checkpoint kinase 2 and tumor protein 53, exhibited increased activity in RMCCA1 cells treated with the aforementioned selected plant extracts, with the exception of PEf. The mitogen-activated protein kinase (MAPK) pathways (including ERK1/2 and p38 MAPK) expression level was significantly increased in RMCCA1 cells pre-treated with extracts of PEs, TCf, CL and MOs. The activation of protein kinase B (Akt) was significantly demonstrated in RMCCA1 cells pre-treated with extracts of TCf, ACs and MOs. In summary, the present study demonstrated that extracts of PEs, TCf, TCs, ACs, CL and MOs exhibited anti-proliferative effects in CCA cells by inducing pro-apoptotic signals and modulating signal transduction molecules. Further studies in vivo are required to demonstrate the potential applications of specific plant extracts for the treatment of human cancer.

  10. Unraveling the Molecular Mechanisms Underlying the Nasopharyngeal Bacterial Community Structure

    Directory of Open Access Journals (Sweden)

    Wouter A. A. de Steenhuijsen Piters

    2016-03-01

    Full Text Available The upper respiratory tract is colonized by a diverse array of commensal bacteria that harbor potential pathogens, such as Streptococcus pneumoniae. As long as the local microbial ecosystem—also called “microbiome”—is in balance, these potentially pathogenic bacterial residents cause no harm to the host. However, similar to macrobiological ecosystems, when the bacterial community structure gets perturbed, potential pathogens can overtake the niche and cause mild to severe infections. Recent studies using next-generation sequencing show that S. pneumoniae, as well as other potential pathogens, might be kept at bay by certain commensal bacteria, including Corynebacterium and Dolosigranulum spp. Bomar and colleagues are the first to explore a specific biological mechanism contributing to the antagonistic interaction between Corynebacterium accolens and S. pneumoniae in vitro [L. Bomar, S. D. Brugger, B. H. Yost, S. S. Davies, K. P. Lemon, mBio 7(1:e01725-15, 2016, doi:10.1128/mBio.01725-15]. The authors comprehensively show that C. accolens is capable of hydrolyzing host triacylglycerols into free fatty acids, which display antipneumococcal properties, suggesting that these bacteria might contribute to the containment of pneumococcus. This work exemplifies how molecular epidemiological findings can lay the foundation for mechanistic studies to elucidate the host-microbe and microbial interspecies interactions underlying the bacterial community structure. Next, translation of these results to an in vivo setting seems necessary to unveil the magnitude and importance of the observed effect in its natural, polymicrobial setting.

  11. Molecular mechanism of parallel fiber-Purkinje cell synapse formation.

    Science.gov (United States)

    Mishina, Masayoshi; Uemura, Takeshi; Yasumura, Misato; Yoshida, Tomoyuki

    2012-01-01

    The cerebellum receives two excitatory afferents, the climbing fiber (CF) and the mossy fiber-parallel fiber (PF) pathway, both converging onto Purkinje cells (PCs) that are the sole neurons sending outputs from the cerebellar cortex. Glutamate receptor δ2 (GluRδ2) is expressed selectively in cerebellar PCs and localized exclusively at the PF-PC synapses. We found that a significant number of PC spines lack synaptic contacts with PF terminals and some of residual PF-PC synapses show mismatching between pre- and postsynaptic specializations in conventional and conditional GluRδ2 knockout mice. Studies with mutant mice revealed that in addition to PF-PC synapse formation, GluRδ2 is essential for synaptic plasticity, motor learning, and the restriction of CF territory. GluRδ2 regulates synapse formation through the amino-terminal domain, while the control of synaptic plasticity, motor learning, and CF territory is mediated through the carboxyl-terminal domain. Thus, GluRδ2 is the molecule that bridges synapse formation and motor learning. We found that the trans-synaptic interaction of postsynaptic GluRδ2 and presynaptic neurexins (NRXNs) through cerebellin 1 (Cbln1) mediates PF-PC synapse formation. The synaptogenic triad is composed of one molecule of tetrameric GluRδ2, two molecules of hexameric Cbln1 and four molecules of monomeric NRXN. Thus, GluRδ2 triggers synapse formation by clustering four NRXNs. These findings provide a molecular insight into the mechanism of synapse formation in the brain.

  12. Molecular mechanism of parallel fiber-Purkinje cell synapse formation

    Directory of Open Access Journals (Sweden)

    Masayoshi eMishina

    2012-11-01

    Full Text Available The cerebellum receives two excitatory afferents, the climbing fiber (CF and the mossy fiber-parallel fiber (PF pathway, both converging onto Purkinje cells (PCs that are the sole neurons sending outputs from the cerebellar cortex. Glutamate receptor δ2 (GluRδ2 is expressed selectively in cerebellar PCs and localized exclusively at the PF-PC synapses. We found that a significant number of PC spines lack synaptic contacts with PF terminals and some of residual PF-PC synapses show mismatching between pre- and postsynaptic specializations in conventional and conditional GluRδ2 knockout mice. Studies with mutant mice revealed that in addition to PF-PC synapse formation, GluRδ2 is essential for synaptic plasticity, motor learning and the restriction of CF territory. GluRδ2 regulates synapse formation through the amino-terminal domain, while the control of synaptic plasticity, motor learning and CF territory is mediated through the carboxyl-terminal domain. Thus, GluRδ2 is the molecule that bridges synapse formation and motor learning. We found that the trans-synaptic interaction of postsynaptic GluRδ2 and presynaptic neurexins (NRXNs through Cbln1 mediates PF-PC synapse formation. The synaptogenic triad is composed of one molecule of tetrameric GluRδ2, two molecules of hexameric Cbln1 and four molecules of monomeric NRXN. Thus, GluRδ2 triggers synapse formation by clustering four NRXNs. These findings provide a molecular insight into the mechanism of synapse formation in the brain.

  13. Molecular mechanisms of extensive mitochondrial gene rearrangementin plethodontid salamanders

    Energy Technology Data Exchange (ETDEWEB)

    Mueller, Rachel Lockridge; Boore, Jeffrey L.

    2005-06-01

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

  14. MOLECULAR DISSECTION OF THE CELLULAR MECHANISMS INVOLVED IN NICKEL HYPERACCUMULATION

    Energy Technology Data Exchange (ETDEWEB)

    Salt, David E.

    2001-06-01

    Hyperaccumulator plant species are able to accumulate between 1-5% of their biomass as metal. However, these plants are often small, slow growing, and do not produce a high biomass. Phytoextraction, a cost-effective, in situ, plant based approach to soil remediation takes advantage of the remarkable ability of hyperaccumulating plants to concentrate metals from the soil and accumulate them in their harvestable, above-ground tissues (Salt et al., 1998). However, to make use of the valuable genetic resources identified in metal hyperaccumulating species, it will be necessary to transfer this material to high biomass rapidly growing crop plants (Persans and Salt (2000)). These plants would then be ideally suited to the phytoremediation process, having the ability to produce large amount of metal-rich plant biomass for rapid harvest and soil cleanup. Although progress is being made in understanding the genetic basis of metal hyperaccumulation (Salt and Krdmer, 1999) a more complete understanding will be necessary before we can take full advantage of the genetic potential of these plants. Research funds provided by the DOE EMSP (DE-FG07-98ER20295) have been used to start to uncover the genetic processes involved in the hyperaccumulation of Ni in Thlaspi goesingense. Our strategy has focused on isolating and characterizing the key genetic information needed for expression of the metal-hyperaccumulation phenotype. In the last reporting period we determined that nickel tolerance was the key difference between the hyperaccumulator T. goesingense and the non-accumulator Thlaspi arvense. We also established that this nickel tolerance was primarily due to an enhanced ability to compartmentalize Ni in the leaf cell vacuoles of the hyperaccumulator. During the 2000-2001 reporting period we have been investigating the molecular genetic mechanism of this enhanced vacuolar accumulation of Ni in the hyperaccumulator.

  15. Molecular mechanisms of acid-base sensing by the kidney.

    Science.gov (United States)

    Brown, Dennis; Wagner, Carsten A

    2012-05-01

    A major function of the kidney is to collaborate with the respiratory system to maintain systemic acid-base status within limits compatible with normal cell and organ function. It achieves this by regulating the excretion and recovery of bicarbonate (mainly in the proximal tubule) and the secretion of buffered protons (mainly in the distal tubule and collecting duct). How proximal tubular cells and distal professional proton transporting (intercalated) cells sense and respond to changes in pH, bicarbonate, and CO(2) status is a question that has intrigued many generations of renal physiologists. Over the past few years, however, some candidate molecular pH sensors have been identified, including acid/alkali-sensing receptors (GPR4, InsR-RR), kinases (Pyk2, ErbB1/2), pH-sensitive ion channels (ASICs, TASK, ROMK), and the bicarbonate-stimulated adenylyl cyclase (sAC). Some acid-sensing mechanisms in other tissues, such as CAII-PDK2L1 in taste buds, might also have similar roles to play in the kidney. Finally, the function of a variety of additional membrane channels and transporters is altered by pH variations both within and outside the cell, and the expression of several metabolic enzymes are altered by acid-base status in parts of the nephron. Thus, it is possible that a master pH sensor will never be identified. Rather, the kidney seems equipped with a battery of molecules that scan the epithelial cell environment to mount a coordinated physiologic response that maintains acid-base homeostasis. This review collates current knowledge on renal acid-base sensing in the context of a whole organ sensing and response process.

  16. The molecular mechanism of embryonic stem cell pluripotency maintenance

    Institute of Scientific and Technical Information of China (English)

    WANG Qingzhong; LIU Yixun; HAN Chunsheng

    2005-01-01

    In vitro cultured embryonic stem (ES) cells are derived from the inner cell mass (ICM) of pre-implantation embryos, and are capable of giving rise to all cell and tissue types of the three germ layers upon being injected back into blastocysts. These cells are therefore said to possess pluripotency that can be maintained infinitely in culture under optimal conditions. Such pluripotency maintenance is believed to be due to the symmetrical cleavage of the cells in an undifferentiated state. The pluripotency of ES cells is the basis for their various practical and potential applications. ES cells can be used as donor cells to generate knockout or transgenic animals, as in vitro models of mammalian development, and as cell resources for cell therapy in regenerative medicine. The further success in these applications, particularly in the last two, is dependent on the establishment of a culture system with components in the medium clearly defined and the subsequent procedures for controlled differentiation of the cells into specific lineages. In turn, elucidating the molecular mechanism for pluripotency maintenance of ES cells is the prerequisite. This paper summarizes the recent progresses in this area, focusing mainly on the LIF/STAT3, BMPs/Smads, canonical Wnt, TGFβ/activin/nodal, PI3K and FGF signaling pathways and the genes such as oct4, nanog that are crucial in ES cell pluripotency maintenance. The regulatory systems of pluripotency maintenance in both mouse and human ES cells are also discussed. We believe that the cross-talkings between these signaling pathways, as well as the regulatory system underlying pluripotency maintenance will be the main focus in the area of ES cell researches in the future.

  17. Molecular mechanism of glucocorticoid resistance in inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    Sara De Iudicibus; Raffaella Franca; Stefano Martelossi; Alessandro Ventura; Giuliana Decorti

    2011-01-01

    Natural and synthetic glucocorticoids (GCs) are widely employed in a number of inflammatory, autoimmune and neoplastic diseases, and, despite the introduction of novel therapies, remain the first-line treatment for inducing remission in moderate to severe active Crohn’s disease and ulcerative colitis. Despite their extensive therapeutic use and the proven effectiveness, consider-able clinical evidence of wide inter-individual differences in GC efficacy among patients has been reported, in particular when these agents are used in inflammatory diseases. In recent years, a detailed knowledge of the GC mechanism of action and of the genetic variants affecting GC activity at the molecular level has arisen from several studies. GCs interact with their cytoplasmic receptor, and are able to repress inflammatory gene expression through several distinct mechanisms. The glucocorticoid receptor (GR) is therefore crucial for the effects of these agents: mutations in the GR gene (NR3C1, nuclear re-ceptor subfamily 3, group C, member 1) are the primary cause of a rare, inherited form of GC resistance; in ad-dition, several polymorphisms of this gene have been described and associated with GC response and toxicity. However, the GR is not self-standing in the cell and the receptor-mediated functions are the result of a complex interplay of GR and many other cellular partners. The latter comprise several chaperonins of the large coopera-tive hetero-oligomeric complex that binds the hormone-free GR in the cytosol, and several factors involved in the transcriptional machinery and chromatin remodeling, that are critical for the hormonal control of target genes transcription in the nucleus. Furthermore, variants in the principal effectors of GCs (e.g. cytokines and their regulators) have also to be taken into account for a com-prehensive evaluation of the variability in GC response. Polymorphisms in genes involved in the transport and/or metabolism of these hormones have also been

  18. Family Administration Mechanism and Family Business Growth in China%家族制与家族企业成长

    Institute of Scientific and Technical Information of China (English)

    郑月龙

    2012-01-01

    家族企业是我国民营企业的主流模式,受中国传统家文化、企业成长环境及企业家能力等因素的影响,家族制管理在推动家族企业成长进程中产生企业资源的挤出效应,从而揭示了中国家族企业偏好于采取网络化成长模式的必然性。%The mainstream patterns of private-owned firms are family business in China. Under the influence of traditional family culture, business growth conditions and entrepreneurs" capacities, family administration mechanism often produces a Crowding out Effect on business resource in the growth of enterprises. Furthermore, it reveals the Chi- nese family enterprises" inevitable choices about the network-based growth mode.

  19. New hybrid method for reactive systems from integrating molecular orbital or molecular mechanics methods with analytical potential energy surfaces.

    Science.gov (United States)

    Espinosa-Garciá, Joaquín; Rangel, Cipriano; Navarrete, Marta; Corchado, José C

    2004-09-15

    A computational approach to calculating potential energy surfaces for reactive systems is presented and tested. This hybrid approach is based on integrated methods where calculations for a small model system are performed by using analytical potential energy surfaces, and for the real system by using molecular orbital or molecular mechanics methods. The method is tested on a hydrogen abstraction reaction by using the variational transition-state theory with multidimensional tunneling corrections. The agreement between the calculated and experimental information depends on the quality of the method chosen for the real system. When the real system is treated by accurate quantum mechanics methods, the rate constants are in excellent agreement with the experimental measurements over a wide temperature range. When the real system is treated by molecular mechanics methods, the results are still good, which is very encouraging since molecular mechanics itself is not at all capable of describing this reactive system. Since no experimental information or additional fits are required to apply this method, it can be used to improve the accuracy of molecular orbital methods or to extend the molecular mechanics method to treat any reactive system with the single constraint of the availability of an analytical potential energy surface that describes the model system.

  20. Molecular analysis of the CTNS gene in Jordanian families with nephropathic cystinosis.

    Science.gov (United States)

    Jaradat, Saied; Al-Rababah, Bothina; Hazza, Issa; Akl, Kamal; Saca, Edward; Al-Younis, Doaa

    2015-01-01

    Nephropathic cystinosis is an autosomal recessive lysosomal storage disorder that is characterised by the accumulation of the amino acid cystine in several body tissues due to a mutation in the CTNS gene, which encodes the cystinosin protein. The aim of this study was to sequence the coding exons of the CTNS gene in five different Jordanian families and one family from Sudan with nephropathic cystinosis. Probands initially presented with Fanconi syndrome symptoms. An eye examination showed the accumulation of cystine crystals in the cornea by the age of 2 years, suggesting cystinosis. All of the coding exons and flanking intronic sequences and the promoter region of the CTNS gene were amplified using polymerase chain reaction and subjected to sequencing. None of the probands in this study carried the European 57-kb deletion in the CTNS gene. Seven variants in the coding and promoter sequence of the CTNS gene were identified in the probands of this study. Two of these variants were a CTNS mutation that was previously identified in a heterozygous genotype in two different patients of European descendant. The two mutations were c.829dupA in exon 10 and c.890G>A in exon 11. The proband of family 2 was compound-heterozygous for the two mutations. This study is the first molecular study of infantile nephropathic cystinosis in Jordan. We successfully identified the causative CTNS mutations in Jordanian families. The results provide a basis for the early detection of the disease using molecular tools in a highly consanguineous Jordanian population. Copyright © 2015 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

  1. 14-3-3 proteins: a family of versatile molecular regulators.

    Science.gov (United States)

    Obsilová, V; Silhan, J; Boura, E; Teisinger, J; Obsil, T

    2008-01-01

    The 14-3-3 proteins are a family of acidic regulatory molecules found in all eukaryotes. 14-3-3 proteins function as molecular scaffolds by modulating the conformation of their binding partners. Through the functional modulation of a wide range of binding partners, 14-3-3 proteins are involved in many processes, including cell cycle regulation, metabolism control, apoptosis, and control of gene transcription. This minireview includes a short overview of 14-3-3 proteins and then focuses on their role in the regulation of two important binding partners: FOXO forkhead transcription factors and an enzyme tyrosine hydroxylase.

  2. [Molecular genetics of familial tumour syndromes of the central nervous system].

    Science.gov (United States)

    Murnyák, Balázs; Szepesi, Rita; Hortobágyi, Tibor

    2015-02-01

    Although most of the central nervous system tumours are sporadic, rarely they are associated with familial tumour syndromes. These disorders usually present with an autosomal dominant inheritance and neoplasia develops at younger age than in sporadic cases. Most of these tumours are bilateral, multiplex or multifocal. The causative mutations occur in genes involved in cell cycle regulation, cell growth, differentiation and DNA repair. Studying these hereditary cancer predisposition syndromes associated with nervous system tumours can facilitate the deeper understanding of the molecular background of sporadic tumours and the development of novel therapeutic agents. This review is an update on hereditary tumour syndromes with nervous system involvement with emphasis on molecular genetic characteristics and their clinical implications.

  3. Heat shock protein 90 in plants: molecular mechanisms and roles in stress responses.

    Science.gov (United States)

    Xu, Zhao-Shi; Li, Zhi-Yong; Chen, Yang; Chen, Ming; Li, Lian-Cheng; Ma, You-Zhi

    2012-11-23

    The heat shock protein 90 (Hsp90) family mediates stress signal transduction, and plays important roles in the control of normal growth of human cells and in promoting development of tumor cells. Hsp90s have become a currently important subject in cellular immunity, signal transduction, and anti-cancer research. Studies on the physiological functions of Hsp90s began much later in plants than in animals and fungi. Significant progress has been made in understanding complex mechanisms of HSP90s in plants, including ATPase-coupled conformational changes and interactions with cochaperone proteins. A wide range of signaling proteins interact with HSP90s. Recent studies revealed that plant Hsp90s are important in plant development, environmental stress response, and disease and pest resistance. In this study, the plant HSP90 family was classified into three clusters on the basis of phylogenetic relationships, gene structure, and biological functions. We discuss the molecular functions of Hsp90s, and systematically review recent progress of Hsp90 research in plants.

  4. Heat Shock Protein 90 in Plants: Molecular Mechanisms and Roles in Stress Responses

    Directory of Open Access Journals (Sweden)

    You-Zhi Ma

    2012-11-01

    Full Text Available The heat shock protein 90 (Hsp90 family mediates stress signal transduction, and plays important roles in the control of normal growth of human cells and in promoting development of tumor cells. Hsp90s have become a currently important subject in cellular immunity, signal transduction, and anti-cancer research. Studies on the physiological functions of Hsp90s began much later in plants than in animals and fungi. Significant progress has been made in understanding complex mechanisms of HSP90s in plants, including ATPase-coupled conformational changes and interactions with cochaperone proteins. A wide range of signaling proteins interact with HSP90s. Recent studies revealed that plant Hsp90s are important in plant development, environmental stress response, and disease and pest resistance. In this study, the plant HSP90 family was classified into three clusters on the basis of phylogenetic relationships, gene structure, and biological functions. We discuss the molecular functions of Hsp90s, and systematically review recent progress of Hsp90 research in plants.

  5. 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.

  6. Quantum mechanics/molecular mechanics study of oxygen binding in hemocyanin.

    Science.gov (United States)

    Saito, Toru; Thiel, Walter

    2014-05-15

    We report a combined quantum mechanics/molecular mechanics (QM/MM) study on the mechanism of reversible dioxygen binding in the active site of hemocyanin (Hc). The QM region is treated by broken-symmetry density functional theory (DFT) with spin projection corrections. The X-ray structures of deoxygenated (deoxyHc) and oxygenated (oxyHc) hemocyanin are well reproduced by QM/MM geometry optimizations. The computed relative energies strongly depend on the chosen density functional. They are consistent with the available thermodynamic data for oxygen binding in hemocyanin and in synthetic model complexes when the BH&HLYP hybrid functional with 50% Hartree-Fock exchange is used. According to the QM(BH&HLYP)/MM results, the reaction proceeds stepwise with two sequential electron transfer (ET) processes in the triplet state followed by an intersystem crossing to the singlet product. The first ET step leads to a nonbridged superoxo CuB(II)-O2(•-) intermediate via a low-barrier transition state. The second ET step is even more facile and yields a side-on oxyHc complex with the characteristic Cu2O2 butterfly core, accompanied by triplet-singlet intersystem crossing. The computed barriers are very small so that the two ET processes are expected to very rapid and nearly simultaneous.

  7. 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.

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

    Science.gov (United States)

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

    2007-07-01

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

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

    Directory of Open Access Journals (Sweden)

    Kubicki JD

    2000-09-01

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

  10. 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

    A quantitative evaluation of 20 second-generation carbohydrate force fields was carried out using ab initio and density functional methods. Geometry-optimized structures (B3LYP/6-31G(d)) and relative energies using augmented correlation consistent basis sets were calculated in gas phase...... 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......-generation carbohydrate force fields. No single force field is consistently better than the others for all the test cases. A statistical assessment of the performance of the force fields indicates that CHEAT(95), CFF, certain versions of Amber and of MM3 have the best overall performance, for these gas phase...

  11. Nuclear magnetic shielding constants of liquid water: Insights from hybrid quantum mechanics/molecular mechanics models

    Science.gov (United States)

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

    2007-01-01

    We present a gauge-origin independent method for the calculation of nuclear magnetic shielding tensors of molecules in a structured and polarizable environment. The method is based on a combination of density functional theory (DFT) or Hartree-Fock wave functions with molecular mechanics. The method is unique in the sense that it includes three important properties that need to be fulfilled in accurate calculations of nuclear magnetic shielding constants: (i) the model includes electron correlation effects, (ii) the model uses gauge-including atomic orbitals to give gauge-origin independent results, and (iii) the effect of the environment is treated self-consistently using a discrete reaction-field methodology. The authors present sample calculations of the isotropic nuclear magnetic shielding constants of liquid water based on a large number of solute-solvent configurations derived from molecular dynamics simulations employing potentials which treat solvent polarization either explicitly or implicitly. For both the O17 and H1 isotropic shielding constants the best predicted results compare fairly well with the experimental data, i.e., they reproduce the experimental solvent shifts to within 4ppm for the O17 shielding and 1ppm for the H1 shielding.

  12. Nuclear magnetic shielding constants of liquid water: insights from hybrid quantum mechanics/molecular mechanics models.

    Science.gov (United States)

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

    2007-01-21

    We present a gauge-origin independent method for the calculation of nuclear magnetic shielding tensors of molecules in a structured and polarizable environment. The method is based on a combination of density functional theory (DFT) or Hartree-Fock wave functions with molecular mechanics. The method is unique in the sense that it includes three important properties that need to be fulfilled in accurate calculations of nuclear magnetic shielding constants: (i) the model includes electron correlation effects, (ii) the model uses gauge-including atomic orbitals to give gauge-origin independent results, and (iii) the effect of the environment is treated self-consistently using a discrete reaction-field methodology. The authors present sample calculations of the isotropic nuclear magnetic shielding constants of liquid water based on a large number of solute-solvent configurations derived from molecular dynamics simulations employing potentials which treat solvent polarization either explicitly or implicitly. For both the (17)O and (1)H isotropic shielding constants the best predicted results compare fairly well with the experimental data, i.e., they reproduce the experimental solvent shifts to within 4 ppm for the (17)O shielding and 1 ppm for the (1)H shielding.

  13. 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.

  14. 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.

  15. 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…

  16. 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…

  17. Molecular insights into the mechanism of sensing and signal transduction of the thermosensor DesK

    NARCIS (Netherlands)

    Ballering, J.|info:eu-repo/dai/nl/325784876

    2016-01-01

    The ability to sense and respond to environmental signals is essential for cell survival. Unraveling the molecular mechanisms underlying signaling processes remains a challenge, however. This thesis provides molecular insights into the mechanism of sensing and signal transduction of the thermosensor

  18. Epigenetics: Behavioral Influences on Gene Function, Part II--Molecular Mechanisms

    Science.gov (United States)

    Ogren, Marilee P.; Lombroso, Paul J.

    2008-01-01

    A study presented on the effect of parenting on stress response and other behaviors show that animals exposed to a high degree of nurturing show a blunted response to stress. Molecular mechanisms responsible for these differences in the adult offspring as well as the molecular mechanisms by which epigenetic effects are propagated from one…

  19. Epigenetics: Behavioral Influences on Gene Function, Part II--Molecular Mechanisms

    Science.gov (United States)

    Ogren, Marilee P.; Lombroso, Paul J.

    2008-01-01

    A study presented on the effect of parenting on stress response and other behaviors show that animals exposed to a high degree of nurturing show a blunted response to stress. Molecular mechanisms responsible for these differences in the adult offspring as well as the molecular mechanisms by which epigenetic effects are propagated from one…

  20. Molecular level detection and localization of mechanical damage in collagen enabled by collagen hybridizing peptides

    Science.gov (United States)

    Zitnay, Jared L.; Li, Yang; Qin, Zhao; San, Boi Hoa; Depalle, Baptiste; Reese, Shawn P.; Buehler, Markus J.; Yu, S. Michael; Weiss, Jeffrey A.

    2017-03-01

    Mechanical injury to connective tissue causes changes in collagen structure and material behaviour, but the role and mechanisms of molecular damage have not been established. In the case of mechanical subfailure damage, no apparent macroscale damage can be detected, yet this damage initiates and potentiates in pathological processes. Here, we utilize collagen hybridizing peptide (CHP), which binds unfolded collagen by triple helix formation, to detect molecular level subfailure damage to collagen in mechanically stretched rat tail tendon fascicle. Our results directly reveal that collagen triple helix unfolding occurs during tensile loading of collagenous tissues and thus is an important damage mechanism. Steered molecular dynamics simulations suggest that a likely mechanism for triple helix unfolding is intermolecular shearing of collagen α-chains. Our results elucidate a probable molecular failure mechanism associated with subfailure injuries, and demonstrate the potential of CHP targeting for diagnosis, treatment and monitoring of tissue disease and injury.

  1. MOLECULAR MECHANISMS REGULATING LPS-INDUCED INFLAMMATION IN THE BRAIN

    Directory of Open Access Journals (Sweden)

    Olena eLykhmus

    2016-03-01

    Full Text Available Neuro-inflammation, one of the pathogenic causes of neurodegenerative diseases, is regulated through the cholinergic anti-inflammatory pathway via the 7 nicotinic acetylcholine receptor (7 nAChR. We previously showed that either bacterial lipopolysaccharide (LPS or immunization with the 7(1-208 nAChR fragment decrease 7 nAChRs density in the mouse brain, exacerbating chronic inflammation, beta-amyloid accumulation and episodic memory decline, which mimic the early stages of Alzheimer’s disease. To study the molecular mechanisms underlying the LPS and antibody effects in the brain, we employed an in vivo model of acute LPS-induced inflammation and an in vitro model of cultured glioblastoma U373 cells. Here, we report that LPS challenge decreased the levels of 7 nAChR RNA and protein and of acetylcholinesterase (AChE RNA and activity in distinct mouse brain regions, sensitized brain mitochondria to the apoptogenic effect of Ca2+ and modified brain microRNA profiles, including the cholinergic-regulatory CholinomiRs-132/212, in favor of anti-inflammatory and pro-apoptotic ones. Adding 7(1-208-specific antibodies to the LPS challenge prevented elevation of both the anti-inflammatory and pro-apoptotic miRNAs while supporting the resistance of brain mitochondria to Ca2+ and maintaining 7 nAChR/AChE decreases. In U373 cells, 7-specific antibodies and LPS both stimulated interleukin-6 production through the p38/Src-dependent pathway. Our findings demonstrate that acute LPS-induced inflammation induces the cholinergic anti-inflammatory pathway in the brain, that 7 nAChR down-regulation limits this pathway, and that 7-specific antibodies aggravate neuroinflammation by inducing the pro-inflammatory interleukin-6 and dampening anti-inflammatory miRNAs; however, these antibodies may protect brain mitochondria and decrease the levels of pro-apoptotic miRNAs, preventing LPS-induced neurodegeneration.

  2. Molecular Mechanisms Regulating LPS-Induced Inflammation in the Brain

    Science.gov (United States)

    Lykhmus, Olena; Mishra, Nibha; Koval, Lyudmyla; Kalashnyk, Olena; Gergalova, Galyna; Uspenska, Kateryna; Komisarenko, Serghiy; Soreq, Hermona; Skok, Maryna

    2016-01-01

    Neuro-inflammation, one of the pathogenic causes of neurodegenerative diseases, is regulated through the cholinergic anti-inflammatory pathway via the α7 nicotinic acetylcholine receptor (α7 nAChR). We previously showed that either bacterial lipopolysaccharide (LPS) or immunization with the α7(1–208) nAChR fragment decrease α7 nAChRs density in the mouse brain, exacerbating chronic inflammation, beta-amyloid accumulation and episodic memory decline, which mimic the early stages of Alzheimer’s disease (AD). To study the molecular mechanisms underlying the LPS and antibody effects in the brain, we employed an in vivo model of acute LPS-induced inflammation and an in vitro model of cultured glioblastoma U373 cells. Here, we report that LPS challenge decreased the levels of α7 nAChR RNA and protein and of acetylcholinesterase (AChE) RNA and activity in distinct mouse brain regions, sensitized brain mitochondria to the apoptogenic effect of Ca2+ and modified brain microRNA profiles, including the cholinergic-regulatory CholinomiRs-132/212, in favor of anti-inflammatory and pro-apoptotic ones. Adding α7(1–208)-specific antibodies to the LPS challenge prevented elevation of both the anti-inflammatory and pro-apoptotic miRNAs while supporting the resistance of brain mitochondria to Ca2+ and maintaining α7 nAChR/AChE decreases. In U373 cells, α7-specific antibodies and LPS both stimulated interleukin-6 production through the p38/Src-dependent pathway. Our findings demonstrate that acute LPS-induced inflammation induces the cholinergic anti-inflammatory pathway in the brain, that α7 nAChR down-regulation limits this pathway, and that α7-specific antibodies aggravate neuroinflammation by inducing the pro-inflammatory interleukin-6 and dampening anti-inflammatory miRNAs; however, these antibodies may protect brain mitochondria and decrease the levels of pro-apoptotic miRNAs, preventing LPS-induced neurodegeneration. PMID:27013966

  3. Molecular mechanism for preQ1-II riboswitch function revealed by molecular dynamics

    Science.gov (United States)

    Aytenfisu, Asaminew H.; Liberman, Joseph A.; Wedekind, Joseph E.; Mathews, David H.

    2015-01-01

    Riboswitches are RNA molecules that regulate gene expression using conformational change, affected by binding of small molecule ligands. A crystal structure of a ligand-bound class II preQ1 riboswitch has been determined in a previous structural study. To gain insight into the dynamics of this riboswitch in solution, eight total molecular dynamic simulations, four with and four without ligand, were performed using the Amber force field. In the presence of ligand, all four of the simulations demonstrated rearranged base pairs at the 3′ end, consistent with expected base-pairing from comparative sequence analysis in a prior bioinformatic analysis; this suggests the pairing in this region was altered by crystallization. Additionally, in the absence of ligand, three of the simulations demonstrated similar changes in base-pairing at the ligand binding site. Significantly, although most of the riboswitch architecture remained intact in the respective trajectories, the P3 stem was destabilized in the ligand-free simulations in a way that exposed the Shine–Dalgarno sequence. This work illustrates how destabilization of two major groove base triples can influence a nearby H-type pseudoknot and provides a mechanism for control of gene expression by a fold that is frequently found in bacterial riboswitches. PMID:26370581

  4. Ochratoxin A: Molecular Interactions, Mechanisms of Toxicity and Prevention at the Molecular Level.

    Science.gov (United States)

    Kőszegi, Tamás; Poór, Miklós

    2016-04-15

    Ochratoxin A (OTA) is a widely-spread mycotoxin all over the world causing major health risks. The focus of the present review is on the molecular and cellular interactions of OTA. In order to get better insight into the mechanism of its toxicity and on the several attempts made for prevention or attenuation of its toxic action, a detailed description is given on chemistry and toxicokinetics of this mycotoxin. The mode of action of OTA is not clearly understood yet, and seems to be very complex. Inhibition of protein synthesis and energy production, induction of oxidative stress, DNA adduct formation, as well as apoptosis/necrosis and cell cycle arrest are possibly involved in its toxic action. Since OTA binds very strongly to human and animal albumin, a major emphasis is done regarding OTA-albumin interaction. Displacement of OTA from albumin by drugs and by natural flavonoids are discussed in detail, hypothesizing their potentially beneficial effect in order to prevent or attenuate the OTA-induced toxic consequences.

  5. Molecular mechanism for preQ1-II riboswitch function revealed by molecular dynamics.

    Science.gov (United States)

    Aytenfisu, Asaminew H; Liberman, Joseph A; Wedekind, Joseph E; Mathews, David H

    2015-11-01

    Riboswitches are RNA molecules that regulate gene expression using conformational change, affected by binding of small molecule ligands. A crystal structure of a ligand-bound class II preQ1 riboswitch has been determined in a previous structural study. To gain insight into the dynamics of this riboswitch in solution, eight total molecular dynamic simulations, four with and four without ligand, were performed using the Amber force field. In the presence of ligand, all four of the simulations demonstrated rearranged base pairs at the 3' end, consistent with expected base-pairing from comparative sequence analysis in a prior bioinformatic analysis; this suggests the pairing in this region was altered by crystallization. Additionally, in the absence of ligand, three of the simulations demonstrated similar changes in base-pairing at the ligand binding site. Significantly, although most of the riboswitch architecture remained intact in the respective trajectories, the P3 stem was destabilized in the ligand-free simulations in a way that exposed the Shine-Dalgarno sequence. This work illustrates how destabilization of two major groove base triples can influence a nearby H-type pseudoknot and provides a mechanism for control of gene expression by a fold that is frequently found in bacterial riboswitches.

  6. Hidden Mediterranean diversity: assessing species taxa by molecular phylogeny within the opilionid family Trogulidae (Arachnida, Opiliones).

    Science.gov (United States)

    Schönhofer, Axel L; Martens, Jochen

    2010-01-01

    This is the first comprehensive study to evaluate the relationships between the western palearctic harvestman families Dicranolasmatidae, Trogulidae and Nemastomatidae with focus on the phylogeny and systematics of Trogulidae, using combined sequence data of the nuclear 28S rRNA and the mitochondrial cytochrome b gene. Bayesian analysis and Maximum parsimony do not reliably resolve Dicranolasma as distinct family but place it on a similar phylogenetic level as several lineages of Trogulidae. Nemastomatidae and Trogulidae turned out to be monophyletic, as did genera Anelasmocephalus and Trogulus within the Trogulidae. The genera Calathocratus, Platybessobius and Trogulocratus each appeared para or polyphyletic, respectively and are synonymized with Calathocratus. The monotypic genus Kofiniotis is well supported. We show molecular data to be in general concordance with taxa characterized by morphology. Molecular data are especially useful to calibrate morphological characters for systematic purposes within homogeneous taxa. In the majority of closely related valid species we show the lowest level of genetic distance to be not lower than 5%. By this threshold in terms of traditionally accepted species the estimated number of species turns out to be 1.5-2.4 times higher than previously believed. With respect to European fauna cryptic diversity in Trogulidae is obviously extraordinarily high and hitherto largely underestimated.

  7. Characterization and molecular profiling of PSEN1 familial Alzheimer's disease iPSC-derived neural progenitors.

    Directory of Open Access Journals (Sweden)

    Andrew A Sproul

    Full Text Available Presenilin 1 (PSEN1 encodes the catalytic subunit of γ-secretase, and PSEN1 mutations are the most common cause of early onset familial Alzheimer's disease (FAD. In order to elucidate pathways downstream of PSEN1, we characterized neural progenitor cells (NPCs derived from FAD mutant PSEN1 subjects. Thus, we generated induced pluripotent stem cells (iPSCs from affected and unaffected individuals from two families carrying PSEN1 mutations. PSEN1 mutant fibroblasts, and NPCs produced greater ratios of Aβ42 to Aβ40 relative to their control counterparts, with the elevated ratio even more apparent in PSEN1 NPCs than in fibroblasts. Molecular profiling identified 14 genes differentially-regulated in PSEN1 NPCs relative to control NPCs. Five of these targets showed differential expression in late onset AD/Intermediate AD pathology brains. Therefore, in our PSEN1 iPSC model, we have reconstituted an essential feature in the molecular pathogenesis of FAD, increased generation of Aβ42/40, and have characterized novel expression changes.

  8. The mechanisms of Mg2+ and Co2+ transport by the CorA family of divalent cation transporters.

    Science.gov (United States)

    Guskov, Albert; Eshaghi, Said

    2012-01-01

    The metal ions Mg(2+) and Co(2+) are essential for life, although to different degree. They have similar chemical and physical properties, but their slight differences result in Mg(2+) to be the most abundant metal ion in living cells and the trace element Co(2+) being toxic at relatively low concentrations. Specialized transporters have evolved in living cells to supply and balance the Mg(2+) and Co(2+) need of the cells. The current knowledge of the molecular mechanisms of Mg(2+) and Co(2+) -specific transporters is very limited at this point. Recently, there has been remarkable advances to understand the CorA family, a family of transporters that are able to transport both ions. These new data have increased our insights in how Mg(2+) and Co(2+) are translocated across membranes. Presently, CorA is probably the best system to study the mechanisms of Mg(2+) and Co(2+) transport. This chapter discusses the mechanisms through which CorA selects, transports, and regulates the translocation of its substrate. In addition, we highlight the physical and chemical properties of the substrates, which are important parameters required for better understanding of the transporter action. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family

    Directory of Open Access Journals (Sweden)

    Hideaki Hasegawa

    2016-11-01

    , promiscuity within the IL-6/IL-12 family cytokines complicates structural and functional clarification and assignment of individual cytokines. A better understanding of the recent advances and expanding diversity in molecular structures and functions of the IL-6/IL-12 family cytokines could allow the creation of novel therapeutic strategies by using them as tools and targeted molecules.

  10. Requirement of Family Enterprises of Feed and Veterinary Drugs for Improving Professional Manager Mechanism and Recommendations

    Institute of Scientific and Technical Information of China (English)

    Zhongming; SHEN

    2014-01-01

    In the development of family enterprises of feed and veterinary drugs in China,there are many problems,such as lack of organic integration of human capital and social human capital.This paper introduced development thread of family enterprises of feed and veterinary drugs in China,analyzed theories and practical development requirement for improving professional manager mechanism,and came up with recommendations including establishing proper employing system,incentive and restraint mechanism,corporate culture,and professional manager market.

  11. Microscopic and macroscopic polarization within a combined quantum mechanics and molecular mechanics model.

    Science.gov (United States)

    Jensen, L; Swart, Marcel; van Duijnen, Piet Th

    2005-01-15

    A polarizable quantum mechanics and molecular mechanics model has been extended to account for the difference between the macroscopic electric field and the actual electric field felt by the solute molecule. This enables the calculation of effective microscopic properties which can be related to macroscopic susceptibilities directly comparable with experimental results. By separating the discrete local field into two distinct contribution we define two different microscopic properties, the so-called solute and effective properties. The solute properties account for the pure solvent effects, i.e., effects even when the macroscopic electric field is zero, and the effective properties account for both the pure solvent effects and the effect from the induced dipoles in the solvent due to the macroscopic electric field. We present results for the linear and nonlinear polarizabilities of water and acetonitrile both in the gas phase and in the liquid phase. For all the properties we find that the pure solvent effect increases the properties whereas the induced electric field decreases the properties. Furthermore, we present results for the refractive index, third-harmonic generation (THG), and electric field induced second-harmonic generation (EFISH) for liquid water and acetonitrile. We find in general good agreement between the calculated and experimental results for the refractive index and the THG susceptibility. For the EFISH susceptibility, however, the difference between experiment and theory is larger since the orientational effect arising from the static electric field is not accurately described.

  12. Quantum mechanics/molecular mechanics electrostatic embedding with continuous and discrete functions.

    Science.gov (United States)

    Cisneros, G Andrés; Piquemal, Jean-Philip; Darden, Thomas A

    2006-07-20

    A quantum mechanics/molecular mechanics (QM/MM) implementation that uses the Gaussian electrostatic model (GEM) as the MM force field is presented. GEM relies on the reproduction of electronic density by using auxiliary basis sets to calculate each component of the intermolecular interaction. This hybrid method has been used, along with a conventional QM/MM (point charges) method, to determine the polarization on the QM subsystem by the MM environment in QM/MM calculations on 10 individual H(2)O dimers and a Mg(2+)-H(2)O dimer. We observe that GEM gives the correct polarization response in cases when the MM fragment has a small charge, while the point charges produce significant over-polarization of the QM subsystem and in several cases present an opposite sign for the polarization contribution. In the case when a large charge is located in the MM subsystem, for example, the Mg(2+) ion, the opposite is observed at small distances. However, this is overcome by the use of a damped Hermite charge, which provides the correct polarization response.

  13. Calculations of Solvation Free Energy through Energy Reweighting from Molecular Mechanics to Quantum Mechanics.

    Science.gov (United States)

    Jia, Xiangyu; Wang, Meiting; Shao, Yihan; König, Gerhard; Brooks, Bernard R; Zhang, John Z H; Mei, Ye

    2016-02-09

    In this work, the solvation free energies of 20 organic molecules from the 4th Statistical Assessment of the Modeling of Proteins and Ligands (SAMPL4) have been calculated. The sampling of phase space is carried out at a molecular mechanical level, and the associated free energy changes are estimated using the Bennett Acceptance Ratio (BAR). Then the quantum mechanical (QM) corrections are computed through the indirect Non-Boltzmann Bennett's acceptance ratio (NBB) or the thermodynamics perturbation (TP) method. We show that BAR+TP gives a minimum analytic variance for the calculated solvation free energy at the Gaussian limit and performs slightly better than NBB in practice. Furthermore, the expense of the QM calculations in TP is only half of that in NBB. We also show that defining the biasing potential as the difference of the solute-solvent interaction energy, instead of the total energy, can converge the calculated solvation free energies much faster but possibly to different values. Based on the experimental solvation free energies which have been published before, it is discovered in this study that BLYP yields better results than MP2 and some other later functionals such as B3LYP, M06-2X, and ωB97X-D.

  14. 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.

  15. A multilocus molecular phylogeny of the endemic North American camel spider family Eremobatidae (Arachnida: Solifugae).

    Science.gov (United States)

    Cushing, Paula E; Graham, Matthew R; Prendini, Lorenzo; Brookhart, Jack O

    2015-11-01

    Camel spiders (Solifugae) are a diverse but poorly studied order of arachnids. No robust phylogenetic analysis has ever been carried out for the order or for any family within the Solifugae. We present a molecular phylogenetic analysis of the endemic North American family Eremobatidae Kraepelin, 1899, the first such analysis of a family of Solifugae. We use a multi-locus exemplar approach using DNA sequences from partial nuclear (28S rDNA and Histone H3) and mitochondrial (16S rRNA and Cytochrome c Oxidase I) gene loci for 81 ingroup exemplars representing all genera of Eremobatidae and most species groups within the genera Eremobates Banks, 1900, Eremochelis Roewer, 1934, and Hemerotrecha Banks, 1903. Maximum Likelihood and two Bayesian analyses consistently recovered the monophyly of Eremobatidae, Eremorhax Roewer, 1934 and Eremothera Muma, 1951 along with a group comprising all subfamily Eremobatinae Kraepelin, 1901 exemplars except Horribates bantai Muma, 1989 and a group comprising all Eremocosta Roewer, 1934 exemplars except Eremocosta acuitalpanensis (Vasquez and Gavin, 2000). The subfamily Therobatinae Muma, 1951 and the genera Chanbria Muma, 1951, Hemerotrecha, Eremochelis, and Eremobates were polyphyletic or paraphyletic. Only the banksi group of Hemerotrecha was monophyletic; the other species groups recognized within Eremobates, Eremochelis, and Hemerotrecha were paraphyletic or polyphyletic. We found no support for the monophyly of the subfamily Therobatinae. A time-calibrated phylogeny dated the most recent common ancestor of extant eremobatids to the late Eocene to early Miocene, with a mean estimate in the late Oligocene (32.2 Ma).

  16. What makes y family pols potential candidates for molecular targeted therapies and novel biotechnological applications.

    Science.gov (United States)

    Tomasso, A; Casari, G; Maga, G

    2014-01-01

    Nature has evolved DNA polymerases (Pols) with different replication fidelity with the purpose of maintaining and faithfully propagating the genetic information. Besides the four classical Pols (Pol α, δ, ε, γ), mammalian cells contain at least twelve specialized Pols whose functions have been discovered recently and are still not completely elucidated. Among them, Pols belonging to the Y family contribute to cell survival by promoting DNA damage tolerance. They are primarily involved in the translesion synthesis (TLS) pathway, incorporating dNTPs in an error-free or error-prone manner, depending on the nature of the DNA lesion. From an evolutionary point of view, their high mutagenic potential seems to guarantee the proper flexibility of vital importance for both adaptation to a changeable environment and evolution of the species. These Pols are subjected to a complex network of regulation, since their uncontrolled access to DNA might promote mutagenesis and neoplastic transformation. Altered expression of Y family is a hallmark of several tumor types. In recent years, the unique structure and properties of Y family Pols have been exploited to design molecules that selectively interfere with the Pol of interest with minimal effect on normal cells. In addition, their distinctive properties have been applied to innovative techniques, such as compartmentalized self-replication (CSR), short-patch CSR, phage display and molecular breeding. These approaches are based on mutant Pols provided with novel and ameliorated features and find applications in various fields, from biotechnology to diagnostics, paleontology and forensic analysis.

  17. Molecular analysis of 53 fragile X families with the probe StB12.3

    Energy Technology Data Exchange (ETDEWEB)

    Puissant, H.; Malinge, M.C.; Larget-Piet, A.; Larget-Piet, L. [Unite de Genetique CHU d`Angers (France); Martin, D. [Genetique Medicale CHR Le Mans (France); Chauveau, P. [Genetique Medicale CHR Le Havre (France); Odent, S.; Lemarec, B. [Genetique Medicale CHU Rennes (France); Plessis, G. [Genetique Medicale CHU de Caen (France); Parent, Ph. [Genetique Medicale CHU de Brest (France)

    1994-12-01

    Fifty-three pedigrees with the fragile X syndrome have been studied for amplification of the CGG repeat sequence adjacent to the CpG island in the FMR1 gene. Probe StB12.3 allowed direct detection of affected males, carrier females, normal transmitting males, as well as prenatal diagnosis. Comparison of our molecular data with our previous linkage data from 38 families indicates the effectiveness of direct DNA analysis. A total of 325 individuals were studied and no new mutation was found. All daughters of males with a premutation had a premutation. When the mother had a full mutation no children had a premutation. In premutated mothers, the size of the premutation seems to be a determining factor for the transition to the full mutation. All affected males had a full mutation or mosaicism and only 42% of the females with a full mutation were mentally impaired. Analysis of large families over 3 generations illustrated clearly the Sherman paradox. Furthermore, the analysis of these families is in reasonable agreement with the multiallelic model of Morton and Macpherson. Mosaic cases in the offspring of the mothers with a full mutation suggest a maternal germinal mosaicism. Then an abnormal methylation and a somatic heterogeneity established in very early steps of embryogenesis could explain these cases. 17 refs.

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

    Science.gov (United States)

    Popov, Dmitri; Maliev, Vecheslav

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

  19. On the molecular mechanism of flippase- and scramblase-mediated phospholipid transport.

    Science.gov (United States)

    Montigny, Cédric; Lyons, Joseph; Champeil, Philippe; Nissen, Poul; Lenoir, Guillaume

    2016-08-01

    Phospholipid flippases are key regulators of transbilayer lipid asymmetry in eukaryotic cell membranes, critical to many trafficking and signaling pathways. P4-ATPases, in particular, are responsible for the uphill transport of phospholipids from the exoplasmic to the cytosolic leaflet of the plasma membrane, as well as membranes of the late secretory/endocytic pathways, thereby establishing transbilayer asymmetry. Recent studies combining cell biology and biochemical approaches have improved our understanding of the path taken by lipids through P4-ATPases. Additionally, identification of several protein families catalyzing phospholipid 'scrambling', i.e. disruption of phospholipid asymmetry through energy-independent bi-directional phospholipid transport, as well as the recent report of the structure of such a scramblase, opens the way to a deeper characterization of their mechanism of action. Here, we discuss the molecular nature of the mechanism by which lipids may 'flip' across membranes, with an emphasis on active lipid transport catalyzed by P4-ATPases. This article is part of a Special Issue entitled: The cellular lipid landscape edited by Tim P. Levine and Anant K. Menon.

  20. Staphylococcal SplB serine protease utilizes a novel molecular mechanism of activation.

    Science.gov (United States)

    Pustelny, Katarzyna; Zdzalik, Michal; Stach, Natalia; Stec-Niemczyk, Justyna; Cichon, Przemyslaw; Czarna, Anna; Popowicz, Grzegorz; Mak, Pawel; Drag, Marcin; Salvesen, Guy S; Wladyka, Benedykt; Potempa, Jan; Dubin, Adam; Dubin, Grzegorz

    2014-05-30

    Staphylococcal SplB protease belongs to the chymotrypsin family. Chymotrypsin zymogen is activated by proteolytic processing at the N terminus, resulting in significant structural rearrangement at the active site. Here, we demonstrate that the molecular mechanism of SplB protease activation differs significantly and we characterize the novel mechanism in detail. Using peptide and protein substrates we show that the native signal peptide, or any N-terminal extension, has an inhibitory effect on SplB. Only precise N-terminal processing releases the full proteolytic activity of the wild type analogously to chymotrypsin. However, comparison of the crystal structures of mature SplB and a zymogen mimic show no rearrangement at the active site whatsoever. Instead, only the formation of a unique hydrogen bond network, distant form the active site, by the new N-terminal glutamic acid of mature SplB is observed. The importance of this network and influence of particular hydrogen bond interactions at the N terminus on the catalytic process is demonstrated by evaluating the kinetics of a series of mutants. The results allow us to propose a consistent model where changes in the overall protein dynamics rather than structural rearrangement of the active site are involved in the activation process.

  1. Molecular mechanism of dehydrin in response to environmental stress in plant

    Institute of Scientific and Technical Information of China (English)

    ZHANG Yuxiu; WANG Zi; XU Jin

    2007-01-01

    Dehydrins, known as the D-11 subgroup of late embryogenesis abundant (LEA) protein, are an immunologically distinct family of proteins, which typically accumulate in desiccation-tolerant seed embryo or in vegetative tissues in response to various environmental stresses such as drought, salinity and freezing. The existence of conservative sequences designated as K, S, and Y segments is a structural feature of dehydrins, and the K segment found in all dehydrins represents a highly conserved 15 amino acid motif (EKKGIMDKIKEKLPG) and forms an amphiphilic a-helix. According to the arrangement of these domains and clustering analysis, dehydrins are subdivided into 5 subtypes: YnSK, Kn, KnS, SKn and YnK. Different types of dehydrins are induced by different environmental stress in plants. Study results showed that dehydrins might play important protective roles under abiotic stress via a number of different mechanisms, including improving or protecting enzyme activities by the cryoprotective activity in responding to freeze/thaw or dehydration; stabilizing vesicles or other endomembrane structures by function as the membrane stabilizer during freeze induced dehydration,and preventing the membrane system from the oxidative damage induced by reactive oxygen radicals as the radical scavenger. Here, the gene expression and molecular mechanisms of dehydrin in response to stress in plants are discussed.

  2. Molecular Mechanisms in Amyotrophic Lateral Sclerosis: The Role of Angiogenin, a Secreted RNase

    Directory of Open Access Journals (Sweden)

    Isabela M. Aparicio-Erriu

    2012-11-01

    Full Text Available Amyotrophic lateral sclerosis is a fatal neurodegenerative disease caused by the loss of motoneurons. The precise molecular and cellular basis for neuronal death is not yet well established, but the contemporary view is that it is a culmination of multiple aberrant biological processes. Among the proposed mechanisms of motoneuron degeneration, alterations in the homeostasis of RNA binding proteins (RBP and the consequent changes in RNA metabolism have received attention recently.The ribonuclease, angiogenin was one of the first RBPs associated with familial and sporadic ALS. It is enriched in motoneurons under physiological conditions, and is required for motoneuron survival under stress conditions. Furthermore, delivery of angiogenin protects cultured motoneurons against stress-induced injury, and significantly increases the survival of motoneurons in SODG93A mice. In this overview on the role of angiogenin in RNA metabolism and in the control of motoneuron survival, we discuss potential pathogenic mechanisms of angiogenin dysfunction relevant to ALS and other neurodegenerative disorders. We also discuss recent evidence demonstrating that angiogenin secreted from stressed motoneurons may alter RNA metabolism in astrocytes.

  3. Molecular Properties and Functional Divergence of the Dehydroascorbate Reductase Gene Family in Lower and Higher Plants.

    Directory of Open Access Journals (Sweden)

    Yuan-Jie Zhang

    Full Text Available Dehydroascorbate reductase (DHAR, which reduces oxidized ascorbate, is important for maintaining an appropriate ascorbate redox state in plant cells. To date, genome-wide molecular characterization of DHARs has only been conducted in bryophytes (Physcomitrella patens and eudicots (e.g. Arabidopsis thaliana. In this study, to gain a general understanding of the molecular properties and functional divergence of the DHARs in land plants, we further conducted a comprehensive analysis of DHARs from the lycophyte Selaginella moellendorffii, gymnosperm Picea abies and monocot Zea mays. DHARs were present as a small gene family in all of the land plants we examined, with gene numbers ranging from two to four. All the plants contained cytosolic and chloroplastic DHARs, indicating dehydroascorbate (DHA can be directly reduced in the cytoplasm and chloroplast by DHARs in all the plants. A novel vacuolar DHAR was found in Z. mays, indicating DHA may also be reduced in the vacuole by DHARs in Z. mays. The DHARs within each species showed extensive functional divergence in their gene structures, subcellular localizations, and enzymatic characteristics. This study provides new insights into the molecular characteristics and functional divergence of DHARs in land plants.

  4. 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...

  5. The first hyperpolarizability of p-nitroaniline in 1,4-dioxane : A quantum mechanical/molecular mechanics study

    NARCIS (Netherlands)

    Jensen, L; van Duijnen, PT

    2005-01-01

    In this work we have investigated the first hyperpolarizability of pNA in 1,4-dioxane solution using a quantum mechanics/molecular mechanics (QM/MM) model. The particular model adopted is the recently developed discrete solvent reaction field (DRF) model. The DRF model is a polarizable QM/MM model i

  6. The molecular features of uncoupling protein 1 support a conventional mitochondrial carrier-like mechanism.

    Science.gov (United States)

    Crichton, Paul G; Lee, Yang; Kunji, Edmund R S

    2017-03-01

    Uncoupling protein 1 (UCP1) is an integral membrane protein found in the mitochondrial inner membrane of brown adipose tissue, and facilitates the process of non-shivering thermogenesis in mammals. Its activation by fatty acids, which overcomes its inhibition by purine nucleotides, leads to an increase in the proton conductance of the inner mitochondrial membrane, short-circuiting the mitochondrion to produce heat rather than ATP. Despite 40 years of intense research, the underlying molecular mechanism of UCP1 is still under debate. The protein belongs to the mitochondrial carrier family of transporters, which have recently been shown to utilise a domain-based alternating-access mechanism, cycling between a cytoplasmic and matrix state to transport metabolites across the inner membrane. Here, we review the protein properties of UCP1 and compare them to those of mitochondrial carriers. UCP1 has the same structural fold as other mitochondrial carriers and, in contrast to past claims, is a monomer, binding one purine nucleotide and three cardiolipin molecules tightly. The protein has a single substrate binding site, which is similar to those of the dicarboxylate and oxoglutarate carriers, but also contains a proton binding site and several hydrophobic residues. As found in other mitochondrial carriers, UCP1 has two conserved salt bridge networks on either side of the central cavity, which regulate access to the substrate binding site in an alternating way. The conserved domain structures and mobile inter-domain interfaces are consistent with an alternating access mechanism too. In conclusion, UCP1 has retained all of the key features of mitochondrial carriers, indicating that it operates by a conventional carrier-like mechanism. Copyright © 2017 Medical research Council. Published by Elsevier B.V. All rights reserved.

  7. [Clinical and molecular genetic analysis of a family with normokalemic periodic paralysis].

    Science.gov (United States)

    Wei, Cui-jie; Wang, Dong; Wang, Shuo; Jiao, Hui; Hong, Dao-jun; Pu, Li-hua; Xiong, Hui

    2013-01-01

    Periodic paralysis (PP) is one type of skeletal muscle channelopathies characterized by episodic attacks of weakness. It is usually classified into hyperkalemic periodic paralysis (HyperPP), hypokalemic periodic paralysis (HypoPP) and normokalemic periodic paralysis (NormoPP) based on the blood potassium levels. HypoPP is the most common type of these three and NormoPP is the rarest one. The aim of this study was to explore the clinical and genetic features of a Chinese family with normokalemic periodic paralysis (NormoKPP). Clinical features of all patients in the family with NormoKPP were analyzed. Genomic DNA was extracted from peripheral blood leukocytes and amplified with PCR. We screened all 24 exons of SCN4A gene and then sequence analysis was performed in those who showed heteroduplex as compared with unaffected controls. (1) Fifteen members of the family were clinically diagnosed NormoKPP, and their common features are: onset within infacy, episodic attacks of weakness, the blood potassium levels were within normal ranges, high sodium diet or large dosage of normal saline could attenuate the symptom. One muscle biopsy was performed and examination of light and electronic microscopy showed occasionally degenerating myofibers. (2) Gene of 12 patients were screened and confirmed mutations of SCN4A genes--c. 2111 T > C/p. Thr704Met. The study further defined the clinical features of patients with NormoKPP, and molecular genetic analysis found SCN4A gene c. 2111 T > C/p. Thr704Met point mutation contributed to the disease. In line with the autosomal dominant inheritance laws, this family can be diagnosed with periodic paralysis, and be provided with genetic counseling. And the study may also help the clinical diagnosis, guide treatment and genetic counseling of this rare disease in China.

  8. Systematics and molecular phylogeny of the family oscarellidae (homoscleromorpha with description of two new oscarella species.

    Directory of Open Access Journals (Sweden)

    Eve Gazave

    Full Text Available The family Oscarellidae is one of the two families in the class Homoscleromorpha (phylum Porifera and is characterized by the absence of a skeleton and the presence of a specific mitochondrial gene, tatC. This family currently encompasses sponges in two genera: Oscarella with 17 described species and Pseudocorticium with one described species. Although sponges in this group are relatively well-studied, phylogenetic relationships among members of Oscarellidae and the validity of genus Pseudocorticium remain open questions. Here we present a phylogenetic analysis of Oscarellidae using four markers (18S rDNA, 28S rDNA, atp6, tatC, and argue that it should become a mono-generic family, with Pseudocorticium being synonymized with Oscarella, and with the transfer of Pseudocorticium jarrei to Oscarella jarrei. We show that the genus Oscarella can be subdivided into four clades, each of which is supported by either a small number of morphological characters or by molecular synapomorphies. In addition, we describe two new species of Oscarella from Norwegian fjords: O. bergenensis sp. nov. and O. nicolae sp. nov., and we compare their morphology, anatomy, and cytology with other species in this genus. Internal anatomical characters are similar in both species, but details of external morphology and particularly of cytological characters provide diagnostic features. Our study also confirms that O. lobularis and O. tuberculata are two distinct polychromic sibling species. This study highlights the difficulties of species identification in skeleton-less sponges and, more generally, in groups where morphological characters are scarce. Adopting a multi-marker approach is thus highly suitable for these groups.

  9. Molecular structure and diversity of PBAN/Pyrokinin family peptides in ants

    Directory of Open Access Journals (Sweden)

    Man-Yeon eChoi

    2012-02-01

    Full Text Available Neuropeptides are the largest group of insect hormones. They are produced in the central and peripheral nervous systems and affect insect development, reproduction, feeding and behavior. A variety of neuropeptide families have been identified in insects. One of these families is the PBAN/pyrokinin family defined by a common FXPRLamide or similar amino acid fragment at the C-terminal end. These peptides, found in all insects studied thus far, have been conserved throughout evolution. The most well studied physiological function is regulation of moth sex pheromone biosynthesis through the Pheromone Biosynthesis Activating Neurohormone (PBAN, although several developmental functions have also been reported. Over the past years we have extended knowledge of the PBAN/pyrokinin family of peptides to ants, focusing mainly on the fire ant, Solenopsis invicta. The fire ant is one of the most studied social insects and over the last 60 years a great deal has been learned about many aspects of this ant, including the behaviors and chemistry of pheromone communication. However, virtually nothing is known about the regulation of these pheromone systems. Recently, we demonstrated the presence of PBAN/pyrokinin immunoreactive neurons in the fire ant, and identified and characterized PBAN and additional neuropeptides. We have mapped the fire ant PBAN gene structure and determined the tissue expression level in the central nervous system of the ant. We review here our research to date on the molecular structure and diversity of ant PBAN/pyrokinin peptides in preparation for determining the function of the neuropeptides in ants and other social insects.

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

    Energy Technology Data Exchange (ETDEWEB)

    Ojeda-May, Pedro; Pu, Jingzhi, E-mail: jpu@iupui.edu [Department of Chemistry and Chemical Biology, Indiana University–Purdue University Indianapolis, 402 N. Blackford Street, Indianapolis, Indiana 46202 (United States)

    2015-11-07

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

  11. 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.

  12. [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.

  13. Molecular adaptations in human atrial fibrillation : mechanisms of protein remodeling

    NARCIS (Netherlands)

    Brundel, Bianca Johanna Josephina Maria

    2000-01-01

    The main goal was to study the molecular remodeling in human atrial fibrillation. We focussed on gene expression of proteins wich influence the calcium homeostasis and action potential duration in human AF. The impact of modulation sysems like the natriuretic peptide system and the endothelin system

  14. Molecular mechanisms and treatment strategies for Dupuytren’s disease

    Directory of Open Access Journals (Sweden)

    David B O’Gorman

    2010-08-01

    Full Text Available David B O’Gorman1,2,3,4, Linda Vi1,2,5, Bing Siang Gan1,2,3,5,61Cell and Molecular Biology Laboratory, 2The Hand and Upper Limb Centre, St. Joseph’s Health Care London, Schulich School of Medicine and Dentistry, 3Departments of Surgery, 4Biochemistry, 5Physiology and Pharmacology, 6Medical Biophysics, The University of Western Ontario, London, OT, CanadaAbstract: Dupuytren’s disease (DD is a common disease of the hand and is characterized by thickening of the palmar fascia and formation of tight collagenous disease cords. At present, the disease is incurable and the molecular pathophysiology of DD is unknown. Surgery remains the most commonly used treatment for DD, but this requires extensive postoperative therapy and is associated with high rates of recurrence. Over the past decades, more indepth exploration of the molecular basis of DD has raised the hopes of developing new treatment modalities. This paper reviews the clinical presentation and molecular pathophysiology of this disease, as well as current and emerging treatment. It also explores the implications of new findings in the laboratory for future treatment.Keywords: Dupuytren’s contracture, Dupuytren’s disease, fibrosis

  15. Comparison of the Folding Mechanism of Highly Homologous Proteins in the Lipid-binding Protein Family

    Science.gov (United States)

    The folding mechanism of two closely related proteins in the intracellular lipid binding protein family, human bile acid binding protein (hBABP) and rat bile acid binding protein (rBABP) were examined. These proteins are 77% identical (93% similar) in sequence Both of these singl...

  16. Comparison of the Folding Mechanism of Highly Homologous Proteins in the Lipid-binding Protein Family

    Science.gov (United States)

    The folding mechanism of two closely related proteins in the intracellular lipid binding protein family, human bile acid binding protein (hBABP) and rat bile acid binding protein (rBABP) were examined. These proteins are 77% identical (93% similar) in sequence Both of these singl...

  17. Conical intersections in solution: formulation, algorithm, and implementation with combined quantum mechanics/molecular mechanics method.

    Science.gov (United States)

    Cui, Ganglong; Yang, Weitao

    2011-05-28

    The significance of conical intersections in photophysics, photochemistry, and photodissociation of polyatomic molecules in gas phase has been demonstrated by numerous experimental and theoretical studies. Optimization of conical intersections of small- and medium-size molecules in gas phase has currently become a routine optimization process, as it has been implemented in many electronic structure packages. However, optimization of conical intersections of small- and medium-size molecules in solution or macromolecules remains inefficient, even poorly defined, due to large number of degrees of freedom and costly evaluations of gradient difference and nonadiabatic coupling vectors. In this work, based on the sequential quantum mechanics and molecular mechanics (QM/MM) and QM/MM-minimum free energy path methods, we have designed two conical intersection optimization methods for small- and medium-size molecules in solution or macromolecules. The first one is sequential QM conical intersection optimization and MM minimization for potential energy surfaces; the second one is sequential QM conical intersection optimization and MM sampling for potential of mean force surfaces, i.e., free energy surfaces. In such methods, the region where electronic structures change remarkably is placed into the QM subsystem, while the rest of the system is placed into the MM subsystem; thus, dimensionalities of gradient difference and nonadiabatic coupling vectors are decreased due to the relatively small QM subsystem. Furthermore, in comparison with the concurrent optimization scheme, sequential QM conical intersection optimization and MM minimization or sampling reduce the number of evaluations of gradient difference and nonadiabatic coupling vectors because these vectors need to be calculated only when the QM subsystem moves, independent of the MM minimization or sampling. Taken together, costly evaluations of gradient difference and nonadiabatic coupling vectors in solution or

  18. Biochemical and Molecular Mechanisms of Desiccation Tolerance in Bryophytes

    Science.gov (United States)

    Bryophytes, because they descend from the earliest branching events in the phylogeny of land plants, hold an important position in our investigations into the mechanisms by which plants respond to dehydration and by what paths such mechanisms have evolved. This is true regardless of what aspect of p...

  19. Transference of some microsatellite molecular markers from Fabaceae family to Andean Lupin (Lupinus mutabilis Sweet

    Directory of Open Access Journals (Sweden)

    Michelle C. Chirinos-Arias

    2015-03-01

    Full Text Available In order to analyze transferibility of 15 microsatellite primers from Fabaceae family to Lupinus mutabilis Sweet "andean lupine" chosen to present transferability between species and genera, by its high rate of polymorphic content (PIC and high degree of observed and expected heterozygosity. DNA was extracted of 300 andean lupines plants, PCR conditions were standardized by gradients of master mix components. Primers for screening were run on 3% agarose gel with some samples. Finally population was amplified and run on 6% polyacrylamide gel for its highest resolution. Only 6.67% of primers were amplified, but they were monomorphic, so they cannot be used for molecular characterization. We proposed eight microsatellite primers for andean lupin wich should be probed in laboratory conditions.

  20. Molecular basis of epithelial Ca2+ and Mg2+ transport: insights from the TRP channel family

    DEFF Research Database (Denmark)

    Dimke, Henrik Anthony; Hoenderop, Joost G J; Bindels, René J M

    2011-01-01

    potential (TRP) family identified several new ion channels acting as gatekeepers of Ca(2+) and Mg(2+) transport in these epithelia, greatly increasing our understanding of the molecular processes that facilitate the movement of these minerals. In the intestine, TRP channels contribute to the saturable...... active transcellular movement of divalent cations from the lumen into the enterocyte. Furthermore, in bone, TRPV channels play important roles by influencing the osteoclastic resorption process, thereby contributing importantly to overall bone mineral content. The divalent cation-permeable TRPV5 and TRPM......6 channels are located in the renal distal convolution, the main site of active transcellular Ca(2+) and Mg(2+) transport. The channels are regulated by a multitude of factors and hormones that contribute importantly to keeping the systemic concentrations of Ca(2+) and Mg(2+) within normal limits...

  1. Molecular Descriptors Family on Structure Activity Relationships 3. Antituberculotic Activity of some Polyhydroxyxanthones

    Directory of Open Access Journals (Sweden)

    Sorana BOLBOACĂ

    2005-06-01

    Full Text Available The antituberculotic activity of some polyhydroxyxanthones was estimated using the Molecular Descriptors Family on Structure Activity Relationships methodology. From a total number of 298110 real and distinct calculated descriptors, 94843 were significantly different and entered into multiple linear regression analysis. The best performing bi-varied model was obtained by use of all polyhydroxyxanthones. The MDF SAR model was validated splitting the molecules into training and test sets. A correlated correlations analysis was applied in other to compare the MDF SAR models with the previous SAR model. The prediction ability of antituberculotic activity of polyhydroxyxanthones with MDF SAR methodology is sustained by three arguments: leave-one-out procedure, training vs. test procedure, and the correlated correlations analysis. Looking at the bi-varied MDF SAR model, we can conclude that the antituberculotic activity of polyhydroxyxanthones is almost of geometrical nature (99% and is strongly dependent on partial atomic charge and group electronegativity.

  2. Molecular pathways: targeting the kinase effectors of RHO-family GTPases.

    Science.gov (United States)

    Prudnikova, Tatiana Y; Rawat, Sonali J; Chernoff, Jonathan

    2015-01-01

    RHO GTPases, members of the RAS superfamily of small GTPases, are adhesion and growth factor-activated molecular switches that play important roles in tumor development and progression. When activated, RHO-family GTPases such as RAC1, CDC42, and RHOA, transmit signals by recruiting a variety of effector proteins, including the protein kinases PAK, ACK, MLK, MRCK, and ROCK. Genetically induced loss of RHO function impedes transformation by a number of oncogenic stimuli, leading to an interest in developing small-molecule inhibitors that either target RHO GTPases directly, or that target their downstream protein kinase effectors. Although inhibitors of RHO GTPases and their downstream signaling kinases have not yet been widely adopted for clinical use, their potential value as cancer therapeutics continues to facilitate pharmaceutical research and development and is a promising therapeutic strategy.

  3. Molecular phylogeny of moth-specialized spider sub-family Cyrtarachninae, which includes bolas spiders.

    Science.gov (United States)

    Tanikawa, Akio; Shinkai, Akira; Miyashita, Tadashi

    2014-11-01

    The evolutionary process of the unique web architectures of spiders of the sub-family Cyrtarachninae, which includes the triangular web weaver, bolas spider, and webless spider, is thought to be derived from reduction of orbicular 'spanning-thread webs' resembling ordinal orb webs. A molecular phylogenetic analysis was conducted to explore this hypothesis using orbicular web spiders Cyrtarachne, Paraplectana, Poecilopachys, triangular web spider Pasilobus, bolas spiders Ordgarius and Mastophora, and webless spider Celaenia. The phylogeny inferred from partial sequences of mt-COI, nuclear 18S-rRNA and 28S-rRNA showed that the common ancestor of these spiders diverged into two clades: a spanning-thread web clade and a bolas or webless clade. This finding suggests that the triangular web evolved by reduction of an orbicular spanning web, but that bolas spiders evolved in the early stage, which does not support the gradual web reduction hypothesis.

  4. On the vibrational behavior of graphynes and its family: a molecular dynamics investigation

    Energy Technology Data Exchange (ETDEWEB)

    Rouhi, S.; Salmalian, K., E-mail: s_rouhi@iaul.ac.ir [Young Researchers Club, Langroud Branch, Islamic Azad University, Langroud, Guilan (Iran, Islamic Republic of); Ghasemi, A. [Young Researchers and Elite Club, Science and Research Branch, Islamic Azad University, Tehran (Iran, Islamic Republic of)

    2015-10-01

    Molecular dynamics (MD) simulation is used to investigate the vibrational behavior of γ-graphyne and its family. Five different nanosheet types including graphyne, graphdiyne, 3-graphyne, 4-graphyne, and 5-graphyne are considered for investigation. The fundamental natural frequencies of armchair and zigzag nanosheets with different geometrical sizes under different boundary conditions are computed. It is shown that increasing the size of γ-graphyne results in decreasing the natural frequency. Comparing the vibrational behavior of armchair and zigzag nanosheets, it is shown that for large nanosheets, the effect of atomic structure on the fundamental natural frequency can be neglected. Besides, it is represented that increasing the number of acetylene links connecting neighboring hexagons in the structure of nanosheets leads to decreasing the frequency. (author)

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

    Science.gov (United States)

    Zhu, Wenyou; Liu, Yongjun; Ling, Baoping

    2015-08-25

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

  6. Mechanisms of Helicobacter pylori antibiotic resistance and molecular testing

    OpenAIRE

    Toshihiro eNishizawa; Hidekazu eSuzuki

    2014-01-01

    Antibiotic resistance in Helicobacter pylori (H. pylori) is the main factor affecting the efficacy of current treatment methods against infection caused by this organism. The traditional culture methods for testing bacterial susceptibility to antibiotics are expensive and require 10 to 14 days. Since resistance to clarithromycin, fluoroquinolone, and tetracycline seems to be exclusively caused by specific mutations in a small region of the responsible gene, molecular methods offer an attracti...

  7. Molecular mechanisms of Strawberry Plant Defence against colletotrichum acutatum

    OpenAIRE

    Amil-Ruiz, Francisco

    2013-01-01

    This thesis is focused on strawberry molecular studies aimed by the strong economic impact and social staple that represents this crop. With an annual production of 500000 tons and an economic weigh of 650 million €, Spain is the third producing country in world (FAOSTAT Agriculture Data [http://faostat.fao.org/]). Important losses in strawberry yields occur due to diseases and pests. Although resistant cultivars are a priority of most strawberry breeding programs, completely r...

  8. Molecular mechanisms of Strawberry Plant Defence against colletotrichum acutatum

    OpenAIRE

    Amil-Ruiz, Francisco

    2013-01-01

    This thesis is focused on strawberry molecular studies aimed by the strong economicimpact and social staple that represents this crop. With an annual production of 500000tons and an economic weigh of 650 million €, Spain is the third producing country inworld (FAOSTAT Agriculture Data [http://faostat.fao.org/]). Important losses instrawberry yields occur due to diseases and pests. Although resistant cultivars are apriority of most strawberry breeding programs, completely resistant cultivars h...

  9. Molecular Mechanisms of Disease Pathogenesis Differ in Krabbe Disease Variants

    DEFF Research Database (Denmark)

    Spratley, Samantha J; Hill, Chris H; Viuff, Agnete H;

    2016-01-01

    Krabbe disease is a severe, fatal neurodegenerative disorder caused by defects in the lysosomal enzyme galactocerebrosidase (GALC). The correct targeting of GALC to the lysosome is essential for the degradation of glycosphingolipids including the primary lipid component of myelin. Over 100 differ...... to bind essential cofactors. The classification of disease pathogenesis presented here provides a molecular framework for appropriate targeting of future Krabbe disease therapies....

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

    Science.gov (United States)

    Mobberley, Jennifer

    2013-01-01

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

  11. Family matters: The first molecular phylogeny of the Onchidorididae Gray, 1827 (Mollusca, Gastropoda, Nudibranchia).

    Science.gov (United States)

    Hallas, Joshua M; Gosliner, Terrence M

    2015-07-01

    Recent investigations into the evolution of the Onchidorididae using morphological based methods have resulted in low support for relationships among genera. This study aims to determine if molecular data corroborates recent morphological interpretations of the evolution of Onchidorididae. Five genetic markers: 16S, 18S, 28S, cytochrome c oxidase 1 (COI) and histone 3 (H3), were sequenced from 32 species comprising Onchidorididae and five other families, three from Phanerobranchia and two from Cryptobranchia. Phylogenies were estimated using maximum likelihood, and Bayesian inference analyses; with both yielding similar topologies. Molecular analyses resulted in high support for the monophyly of the suctorian clade and the placement of the genera within Onchidorididae. However, the Onchidorididae forms a paraphyletic grouping due to the recovery of the Goniodorididae and the Akiodorididae nested within family. In addition, the placement of Corambe as the most derived member of Onchidorididae is contradicted by the present study. Rather it is sister to a large clade that includes Acanthodoris and the species traditionally placed in Onchidoris and Adalaria, now defined as Onchidorididae. We have chosen to maintain Corambidae as a distinct taxon (including Corambe and Loy), sister to Onchidorididae. We also maintain Goniodorididae, Akiodorididae and Calycidoridae (including Calycidoris and Diaphorodoris), which along with the Onchidorididae and Corambidae comprise the suctorian superfamily Onchidoridoidea. Ancestral character reconstruction also suggests that the formation of a gill pocket, a character that currently defines the Cryptobranchia, may have evolved multiple times from an ancestor that lacked the ability to retract its gills into a fully formed gill pocket. The diversity of gill morphology displayed by the Onchidoridoidea will help give new insight into the evolution of this complex character within the Nudibranchia.

  12. Molecular evolutionary analysis of the high-affinity K+ transporter gene family in angiosperms.

    Science.gov (United States)

    Yang, P; Hua, C; Zhou, F; Zhang, B-J; Cai, X-N; Chen, Q-Z; Wang, R-L

    2016-07-15

    The high-affinity K(+) transporter (HKT) family comprises a group of multifunctional cation transporters widely distributed in organisms ranging from Bacteria to Eukarya. In angiosperms, the HKT family consists primarily of nine types, whose evolutionary relationships are not fully understood. The available sequences from 31 plant species were used to perform a comprehensive evolutionary analysis, including an examination of selection pressure and estimating phylogenetic tree and gene duplication events. Our results show that a gene duplication in the HKT1;5/HKT1;4 cluster might have led to the divergence of the HKT1;5 and HKT1;4 subfamilies. Additionally, maximum likelihood analysis revealed that the HKT family has undergone a strong purifying selection. An analysis of the amino acids provided strong statistical evidence for a functional divergence between subfamilies 1 and 2. Our study was the first to provide evidence of this functional divergence between these two subfamilies. Analysis of co-evolution in HKT identified 25 co-evolved groups. These findings expanded our understanding of the evolutionary mechanisms driving functional diversification of HKT proteins.

  13. Molecular mechanism of crystallization impacting calcium phosphate cements

    Energy Technology Data Exchange (ETDEWEB)

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

    2009-05-31

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

  14. Results from the Use of Molecular Descriptors Family on Structure Property/Activity Relationships

    Directory of Open Access Journals (Sweden)

    Sorana-Daniela Bolboacă

    2007-03-01

    Full Text Available The aim of the paper is to present the results obtained by utilization of an originalapproach called Molecular Descriptors Family on Structure-Property (MDF-SPR andStructure-Activity Relationships (MDF-SAR applied on classes of chemical compoundsand its usefulness as precursors of models elaboration of new compounds with betterproperties and/or activities and low production costs. The MDF-SPR/MDF-SARmethodology integrates the complex information obtained from compound’s structure inunitary efficient models in order to explain properties/activities. The methodology has beenapplied on a number of thirty sets of chemical compounds. The best subsets of moleculardescriptors family members able to estimate and predict property/activity of interest wereidentified and were statistically and visually analyzed. The MDF-SPR/MDF-SAR modelswere validated through internal and/or external validation methods. The estimation andprediction abilities of the MDF-SPR/MDF-SAR models were compared with previousreported models by applying of correlated correlation analysis, which revealed that theMDF-SPR/MDF-SAR methodology is reliable. The MDF-SPR/MDF-SAR methodologyopens a new pathway in understanding the relationships between compound’s structure andproperty/activity, in property/activity prediction, and in discovery, investigation andcharacterization of new chemical compounds, more competitive as costs andproperty/activity, being a method less expensive comparative with experimental methods.

  15. A recent shark radiation: molecular phylogeny, biogeography and speciation of wobbegong sharks (family: Orectolobidae).

    Science.gov (United States)

    Corrigan, Shannon; Beheregaray, Luciano B

    2009-07-01

    The elasmobranch fish are an ancient, evolutionarily successful, but under-researched vertebrate group, particularly in regard to their recent evolutionary history. Their lineage has survived four mass extinction events and most present day taxa are thought to be derived from Mesozoic forms. Here we present a molecular phylogenetic analysis of the family Orectolobidae that provides evidence for recent events of diversification in this shark group. Species interrelationships in Orectolobidae were reconstructed based on four mitochondrial and nuclear genes. In line with previous morphological work, our results do not support current taxonomic arrangements in Orectolobidae and indicate that a taxonomic revision of the family is warranted. We propose that the onset of diversification of orectolobid sharks is of Miocene age and occurred within the Indo-Australian region. Surprisingly, we also find evidence for a recent ( approximately last 2 million years) and rapid radiation of wobbegong sharks. Allopatric speciation followed by range expansion seems like the general most likely explanation to account for wobbegong relationships and distributions. We suggest that the evolution of this shark group was mostly influenced by two temporal scenarios of diversification. The oldest relates to major geological changes in the Indo-West Pacific associated with the Miocene collision of the Indo-Australian and Eurasian plates. The most recent scenario was influenced by changes in oceanography and the emergence of biogeographic barriers related to Pleistocene glacial cycles in Australian waters.

  16. Molecular characterization and evolution of an interspersed repetitive DNA family of oysters.

    Science.gov (United States)

    López-Flores, Inmaculada; Ruiz-Rejón, Carmelo; Cross, Ismael; Rebordinos, Laureana; Robles, Francisca; Navajas-Pérez, Rafael; de la Herrán, Roberto

    2010-12-01

    When genomic DNA from the European flat oyster Ostrea edulis L. was digested by BclI enzyme, a band of about 150 bp was observed in agarose gel. After cloning and sequencing this band and analysing their molecular characteristics and genomic organization by means of Southern blot, in situ hybridisation, and polymerase chain reaction (PCR) protocols, we concluded that this band is an interspersed highly repeated DNA element, which is related in sequence to the flanking regions of (CT)-microsatellite loci of the species O. edulis and Crassostrea gigas. Furthermore, we determined that this element forms part of a longer repetitive unit of 268 bp in length that, at least in some loci, is present in more than one copy. By Southern blot hybridisation and PCR amplifications-using primers designed for conserved regions of the 150-bp BclI clones of O. edulis-we determined that this repetitive DNA family is conserved in five other oyster species (O. stentina, C. angulata, C. gigas, C. ariakensis, and C. sikamea) while it is apparently absent in C. gasar. Finally, based on the analysis of the repetitive units in these oyster species, we discuss the slow degree of concerted evolution in this interspersed repetitive DNA family and its use for phylogenetic analysis.

  17. Molecular genetic analysis on the remains of the Dark Countess: Revisiting the French Royal family.

    Science.gov (United States)

    Parson, Walther; Berger, Cordula; Sänger, Timo; Lutz-Bonengel, Sabine

    2015-11-01

    The "Dark Counts" were a mysterious couple that appeared in the Thuringian village Eishausen in 1807. After living in self imposed solitude for 30 years the woman died and was buried under the name Sophia Botta. Her companion, who presented himself as Vavel de Versay, died in 1845 and was later identified as Leonardus Cornelius van der Valck, secretary of the Dutch embassy in Paris. Their lifestyle led to speculations that she was the true princess Marie Thérèse Charlotte of France, daughter of Louis XVI and Marie Antoinette. According to these speculations she was substituted by another young woman on a voyage from Paris to Vienna. Molecular genetic analyses were set out to test the remains attributed to the Dark Countess. Mitochondrial DNA testing brought concordant results determined in two forensic laboratories (Innsbruck, Austria and Freiburg, Germany) on parallel samples of the remains. The results were in exclusion to both, the mitochondrial lineage earlier reported for the French Royal family and the mitochondrial haplotype observed in a living descendant of the Royal family.

  18. Molecular mechanisms and potential functions of histone demethylases

    DEFF Research Database (Denmark)

    Kooistra, Susanne Marije; Helin, Kristian

    2012-01-01

    Histone modifications are thought to regulate chromatin structure, transcription and other nuclear processes. Histone methylation was originally believed to be an irreversible modification that could only be removed by histone eviction or by dilution during DNA replication. However, the isolation...... of two families of enzymes that can demethylate histones has changed this notion. The biochemical activities of these histone demethylases towards specific Lys residues on histones, and in some cases non-histone substrates, have highlighted their importance in developmental control, cell-fate decisions...

  19. Molecular evolution of a chordate specific family of G protein-coupled receptors

    Directory of Open Access Journals (Sweden)

    Leese Florian

    2011-08-01

    Full Text Available Abstract Background Chordate evolution is a history of innovations that is marked by physical and behavioral specializations, which led to the development of a variety of forms from a single ancestral group. Among other important characteristics, vertebrates obtained a well developed brain, anterior sensory structures, a closed circulatory system and gills or lungs as blood oxygenation systems. The duplication of pre-existing genes had profound evolutionary implications for the developmental complexity in vertebrates, since mutations modifying the function of a duplicated protein can lead to novel functions, improving the evolutionary success. Results We analyzed here the evolution of the GPRC5 family of G protein-coupled receptors by comprehensive similarity searches and found that the receptors are only present in chordates and that the size of the receptor family expanded, likely due to genome duplication events in the early history of vertebrate evolution. We propose that a single GPRC5 receptor coding gene originated in a stem chordate ancestor and gave rise by duplication events to a gene family comprising three receptor types (GPRC5A-C in vertebrates, and a fourth homologue present only in mammals (GPRC5D. Additional duplications of GPRC5B and GPRC5C sequences occurred in teleost fishes. The finding that the expression patterns of the receptors are evolutionarily conserved indicates an important biological function of these receptors. Moreover, we found that expression of GPRC5B is regulated by vitamin A in vivo, confirming previous findings that linked receptor expression to retinoic acid levels in tumor cell lines and strengthening the link between the receptor expression and the development of a complex nervous system in chordates, known to be dependent on retinoic acid signaling. Conclusions GPRC5 receptors, a class of G protein-coupled receptors with unique sequence characteristics, may represent a molecular novelty that helped non

  20. Identification and in silico analysis of the Citrus HSP70 molecular chaperone gene family

    Directory of Open Access Journals (Sweden)

    Luciano G. Fietto

    2007-01-01

    Full Text Available The completion of the genome sequencing of the Arabidopsis thaliana model system provided a powerful molecular tool for comparative analysis of gene families present in the genome of economically relevant plant species. In this investigation, we used the sequences of the Arabidopsis Hsp70 gene family to identify and annotate the Citrus Hsp70 genes represented in the CitEST database. Based on sequence comparison analysis, we identified 18 clusters that were further divided into 5 subgroups encoding four mitochondrial mtHsp70s, three plastid csHsp70s, one ER luminal Hsp70 BiP, two HSP110/SSE-related proteins and eight cytosolic Hsp/Hsc70s. We also analyzed the expression profile by digital Northern of each Hsp70 transcript in different organs and in response to stress conditions. The EST database revealed a distinct population distribution of Hsp70 ESTs among isoforms and across the organs surveyed. The Hsp70-5 isoform was highly expressed in seeds, whereas BiP, mitochondrial and plastid HSp70 mRNAs displayed a similar expression profile in the organs analyzed, and were predominantly represented in flowers. Distinct Hsp70 mRNAs were also differentially expressed during Xylella infection and Citrus tristeza viral infection as well as during water deficit. This in silico study sets the groundwork for future investigations to fully characterize functionally the Citrus Hsp70 family and underscores the relevance of Hsp70s in response to abiotic and biotic stresses in Citrus.