Science.gov

Sample records for alters molecular systems

  1. Controlled Contusion Injury Alters Molecular Systems Associated With Cognitive Performance

    PubMed Central

    Griesbach, Grace Sophia; Sutton, Richard L.; Hovda, David A.; Ying, Zhe; Gomez-Pinilla, Fernando

    2009-01-01

    We investigated whether a learning impairment after a controlled cortical impact (CCI) injury was associated with alterations in molecules involved in synaptic plasticity and learning and memory. Adult male rats with moderate CCI to the left parietal cortex, tested in a Morris water maze (MWM) beginning at postinjury day 10, showed impaired cognitive performance compared with sham-treated rats. Tissue was extracted for mRNA analysis on postinjury day 21. The expression of brain-derived neurotrophic factor (BDNF), synapsin I, cyclic-AMP response element binding protein (CREB), and calcium-calmodulin–dependent protein kinase II (α-CAMKII) were all significantly decreased compared with sham injury levels within the ipsilateral hippocampus after CCI. No significant molecular level changes were found in the contralateral hippocampus. Decreased expression of BDNF and synapsin I was also found within the ipsilateral parietal cortex of CCI-injured rats compared with shams. However, BDNF and synapsin I expressions were significantly increased in the contralateral parietal cortex of the CCI rats. CREB expression was significantly decreased within the contralateral cortex of the CCI group. These findings show enduring reductions in the expression of BDNF, synapsin I, CREB, and α-CAMKII ipsilateral to a CCI injury, which seem associated with the spatial learning deficits observed in this injury model. In addition, the delayed increase in the expression of BDNF and synapsin I within the cortex contralateral to CCI may reflect restorative processes in areas homotypical to the injury. PMID:18831070

  2. Molecular alteration of a muscarinic acetylcholine receptor system during synaptogenesis

    SciTech Connect

    Large, T.H.; Cho, N.J.; De Mello, F.G.; Klein, W.L.

    1985-07-25

    Biochemical properties of the muscarinic acetylcholine receptor system of the avian retina were found to change during the period when synapses form in ovo. Comparison of ligand binding to membranes obtained before and after synaptogenesis showed a significant increase in the affinity, but not proportion, of the high affinity agonist-binding state. There was no change in receptor sensitivity to antagonists during this period. Pirenzepine binding, which can discriminate muscarinic receptor subtypes, showed the presence of a single population of low affinity sites (M2) before and after synaptogenesis. The change in agonist binding was not due to the late development of receptor function. However, detergent-solubilization of membranes eliminated differences in agonist binding between receptors from embryos and hatched chicks, suggesting a developmental change in interactions of the receptor with functionally related membrane components. A possible basis for altered interactions was obtained from isoelectric point data showing that the muscarinic receptor population underwent a transition from a predominantly low pI form (4.25) in 13 day embryos to a predominantly high pI form (4.50) in newly hatched chicks. The possibility that biochemical changes in the muscarinic receptor play a role in differentiation of the system by controlling receptor position on the surface of nerve cells is discussed.

  3. Molecular alterations of canalicular transport systems in experimental models of cholestasis: possible functional correlations.

    PubMed Central

    Trauner, M.

    1997-01-01

    The discovery of unidirectional, ATP-dependent canalicular transport systems (also termed "export pumps") for bile salts, amphiphilic anionic conjugates, lipophilic cations, and phospholipids has opened new opportunities for understanding biliary physiology and the pathophysiology of cholestasis. In addition, ATP-independent canalicular transport systems for glutathione and bicarbonate contribute to (bile acid-independent) bile formation. Canalicular excretion of bile salts and several non-bile acid organic anions is impaired in various experimental models of cholestasis. Recent cloning of several canalicular transport systems now facilitates studies on their molecular regulation in cholestasis. Although the picture is far from complete, experimental evidence now exists that decreased or even absent expression of canalicular transport proteins may explain impaired transport function resulting in hyperbilirubinemia and cholestasis. With the increasing availability of molecular probes for these transport systems in humans, new information on the molecular regulation of canalicular transport proteins in human cholestatic liver diseases is beginning to emerge and should bring new insights into their pathophysiology and treatment. This article gives an overview on molecular alterations of canalicular transport systems in experimental models of cholestasis and discusses the potential implications of these changes for the pathophysiology of cholestasis. PMID:9626757

  4. Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics.

    PubMed

    Haenisch, Britta; Nöthen, Markus M; Molderings, Gerhard J

    2012-11-01

    Despite increasing understanding of its pathophysiology, the aetiology of systemic mast cell activation disease (MCAD) remains largely unknown. Research has shown that somatic mutations in kinases are necessary for the establishment of a clonal mast cell population, in particular mutations in the tyrosine kinase Kit and in enzymes and receptors with crucial involvement in the regulation of mast cell activity. However, other, as yet undetermined, abnormalities are necessary for the manifestation of clinical disease. The present article reviews molecular genetic research into the identification of disease-associated genes and their mutational alterations. The authors also present novel data on familial systemic MCAD and review the associated literature. Finally, the importance of understanding the molecular basis of inherited mutations in terms of diagnostics and therapy is emphasized.

  5. Altered sympathetic nervous system signaling in the diabetic heart: emerging targets for molecular imaging

    PubMed Central

    Thackeray, James T; Beanlands, Rob S; DaSilva, Jean N

    2012-01-01

    Diabetes is commonly associated with increased risk of cardiovascular morbidity and mortality. Perturbations in sympathetic nervous system (SNS) signaling have been linked to the progression of diabetic heart disease. Glucose, insulin, and free fatty acids contribute to elevated sympathetic nervous activity and norepinephrine release. Reduced left ventricular compliance and impaired cardiac function lead to further SNS activation. Chronic elevation of cardiac norepinephrine culminates in altered expression of pre- and post-synaptic sympathetic signaling elements, changes in calcium regulatory proteins, and abnormal contraction-excitation coupling. Clinically, these factors manifest as altered resting heart rate, depressed heart rate variability, and impaired cardiac autonomic reflex, which may contribute to elevated cardiovascular risk. Development of molecular imaging probes enable a comprehensive evaluation of cardiac SNS signaling at the neuron, postsynaptic receptor, and intracellular second messenger sites of signal transduction, providing mechanistic insights into cardiac pathology. This review will examine the evidence for abnormal SNS signaling in the diabetic heart and establish the physiological consequences of these changes, drawing from basic biological research in isolated heart and rodent models of diabetes, as well as from clinical reports. Particular attention will be paid to the use of molecular imaging approaches to non-invasively characterize and evaluate sympathetic signal transduction in diabetes, including pre-synaptic norepinephrine reuptake assessment using 11C-meta-hydroxyephedrine (11C-HED) with PET or 123I-metaiodobenzylguanidine (123I-MIBG) with SPECT, and postsynaptic β-adrenoceptor density measurements using CGP12177 derivatives. Finally, the review will attempt to define the future role of these non-invasive nuclear imaging techniques in diabetes research and clinical care. PMID:23133819

  6. Molecular and Genomic Alterations in Glioblastoma Multiforme.

    PubMed

    Crespo, Ines; Vital, Ana Louisa; Gonzalez-Tablas, María; Patino, María del Carmen; Otero, Alvaro; Lopes, María Celeste; de Oliveira, Catarina; Domingues, Patricia; Orfao, Alberto; Tabernero, Maria Dolores

    2015-07-01

    In recent years, important advances have been achieved in the understanding of the molecular biology of glioblastoma multiforme (GBM); thus, complex genetic alterations and genomic profiles, which recurrently involve multiple signaling pathways, have been defined, leading to the first molecular/genetic classification of the disease. In this regard, different genetic alterations and genetic pathways appear to distinguish primary (eg, EGFR amplification) versus secondary (eg, IDH1/2 or TP53 mutation) GBM. Such genetic alterations target distinct combinations of the growth factor receptor-ras signaling pathways, as well as the phosphatidylinositol 3-kinase/phosphatase and tensin homolog/AKT, retinoblastoma/cyclin-dependent kinase (CDK) N2A-p16(INK4A), and TP53/mouse double minute (MDM) 2/MDM4/CDKN2A-p14(ARF) pathways, in cells that present features associated with key stages of normal neurogenesis and (normal) central nervous system cell types. This translates into well-defined genomic profiles that have been recently classified by The Cancer Genome Atlas Consortium into four subtypes: classic, mesenchymal, proneural, and neural GBM. Herein, we review the most relevant genetic alterations of primary versus secondary GBM, the specific signaling pathways involved, and the overall genomic profile of this genetically heterogeneous group of malignant tumors. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  7. System modeling reveals the molecular mechanisms of HSC cell cycle alteration mediated by Maff and Egr3 under leukemia.

    PubMed

    Li, Rudong; Wang, Yin; Cheng, Hui; Liu, Gang; Cheng, Tao; Liu, Yunlong; Liu, Lei

    2017-10-03

    Molecular mechanisms of the functional alteration of hematopoietic stem cells (HSCs) in leukemic environment attract intensive research interests. As known in previous researches, Maff and Egr3 are two important genes having opposite functions on cell cycle; however, they are both highly expressed in HSCs under leukemia. Hence, exploring the molecular mechanisms of how the genes act on cell cycle will help revealing the functional alteration of HSCs. We herein utilize the bioinformatic resources to computationally model the acting mechanisms of Maff and Egr3 on cell cycle. Using the data of functional experiments as reference, molecular acting mechanisms are optimally enumerated through model selection. The results are consolidated by evidences from gene sequence analysis, thus having enhanced the confidence of our pilot findings, which suggest that HSCs possibly undergo a "adaptation - suppression" process in response to the malignant environment of leukemia. As a pilot research, our results may provide valuable insights for further experimental studies. Meanwhile, our research method combining computational modeling and data from functional experiments can be worthwhile for knowledge discovery; and it can be generalized and extended to other biological/biomedical studies.

  8. Molecular multiproxy analysis of ancient root systems suggests strong alteration of deep subsoil organic matter by rhizomicrobial activity

    NASA Astrophysics Data System (ADS)

    Gocke, Martina; Huguet, Arnaud; Derenne, Sylvie; Kolb, Steffen; Wiesenberg, Guido L. B.

    2013-04-01

    Roots have a high potential capacity to store large amounts of CO2 in the subsoil. However, associated with rooting, microorganisms enter the subsoil and might contribute to priming effects of carbon mineralisation in the microbial hotspot rhizosphere. Although these processes are well known for recent surface soils, it remains questionable, if and how microorganisms contribute to priming effects in the subsoil and if these effects can be traced after the roots' lifetime. The current study implies several state-of-the-art techniques like DNA and lipid molecular proxies to trace remains of microbial biomass in ancient root systems. These can provide valuable information if parts of the root and rhizomicrobial biomass are preserved, e.g. by encrustation with secondary carbonate during the root's lifespan or shortly thereafter. At the Late Pleistocene loess-paleosol sequence near Nussloch (SW Germany), rhizoliths (calcified roots) occur highly abundant in the deep subsoil from 1 to 9 m depth and below. They were formed by Holocene woody vegetation. Their size can account for up to several cm in diameter and up to > 1 m length. Rhizoliths and surrounding sediment with increasing distances of up to 10 cm, as well as reference loess without visible root remains were collected at several depth intervals. Samples were analysed for n-fatty acids (FAs) and glycerol dialkyl glycerol tetraethers (GDGTs; membrane lipids from Archaea and some Bacteria), as well as structural diversity based on the RNA gene of the prokaryotic ribosome subunit 16S (16S rRNA). GDGT represent organic remains from microbial biomass, whereas FA comprise both microbial remains and degradation products. 16S rRNA indicates the presence of both living cells and/or cell fragments. Despite the general low RNA contents in the sample set, results pointed to a much higher abundance of bacterial compared to archaeal RNA. The latter occured in notable amounts only in some rhizoliths. This was in part enforced by

  9. Molecular alterations and biomarkers in colorectal cancer

    PubMed Central

    Grady, William M.; Pritchard, Colin C.

    2013-01-01

    The promise of precision medicine is now a clinical reality. Advances in our understanding of the molecular genetics of colorectal cancer genetics is leading to the development of a variety of biomarkers that are being used as early detection markers, prognostic markers, and markers for predicting treatment responses. This is no more evident than in the recent advances in testing colorectal cancers for specific molecular alterations in order to guide treatment with the monoclonal antibody therapies cetuximab and panitumumab, which target the epidermal growth factor receptor (EGFR). In this review, we update a prior review published in 2010 and describe our current understanding of the molecular pathogenesis of colorectal cancer and how these alterations relate to emerging biomarkers for early detection and risk stratification (diagnostic markers), prognosis (prognostic markers), and the prediction of treatment responses (predictive markers). PMID:24178577

  10. System-based proteomic and metabonomic analysis of the Df(16)A+/− mouse identifies potential miR-185 targets and molecular pathway alterations

    PubMed Central

    Wesseling, H; Xu, B; Want, E J; Holmes, E; Guest, P C; Karayiorgou, M; Gogos, J A; Bahn, S

    2017-01-01

    Deletions on chromosome 22q11.2 are a strong genetic risk factor for development of schizophrenia and cognitive dysfunction. We employed shotgun liquid chromatography–mass spectrometry (LC-MS) proteomic and metabonomic profiling approaches on prefrontal cortex (PFC) and hippocampal (HPC) tissue from Df(16)A+/− mice, a model of the 22q11.2 deletion syndrome. Proteomic results were compared with previous transcriptomic profiling studies of the same brain regions. The aim was to investigate how the combined effect of the 22q11.2 deletion and the corresponding miRNA dysregulation affects the cell biology at the systems level. The proteomic brain profiling analysis revealed PFC and HPC changes in various molecular pathways associated with chromatin remodelling and RNA transcription, indicative of an epigenetic component of the 22q11.2DS. Further, alterations in glycolysis/gluconeogenesis, mitochondrial function and lipid biosynthesis were identified. Metabonomic profiling substantiated the proteomic findings by identifying changes in 22q11.2 deletion syndrome (22q11.2DS)-related pathways, such as changes in ceramide phosphoethanolamines, sphingomyelin, carnitines, tyrosine derivates and panthothenic acid. The proteomic findings were confirmed using selected reaction monitoring mass spectrometry, validating decreased levels of several proteins encoded on 22q11.2, increased levels of the computationally predicted putative miR-185 targets UDP-N-acetylglucosamine-peptide N-acetylglucosaminyltransferase 110 kDa subunit (OGT1) and kinesin heavy chain isoform 5A and alterations in the non-miR-185 targets serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform, neurofilament light chain and vesicular glutamate transporter 1. Furthermore, alterations in the proteins associated with mammalian target of rapamycin signalling were detected in the PFC and with glutamatergic signalling in the hippocampus. Based on the proteomic and metabonomic findings, we were

  11. Can Molecular Hippocampal Alterations Explain Behavioral ...

    EPA Pesticide Factsheets

    Studies in both humans and animals have shown that prenatal stress can alter cognitive function and other neurological behaviors in adult offspring. One possible underlying mechanism for this may lie with alterations in hippocampal gene expression. The present study examined genotypical outcomes in adult male and female offspring of rats exposed to variable stress during pregnancy. Dams (n=15/treatment) were subjected to several non-chemical stressors including intermittent noise, light, crowding, restraint, and altered circadian lighting, from gestational day (GD) 13 to 20. Tail blood was drawn on GD 12, 16 and 20 to verify a stress response. Corticosterone levels were not different between the stressed and non-stressed dams on GD12 but was significantly increased in stressed dams on GD 16 and 20 compared to controls. Dams gave birth on GD22 (postnatal day or PND 0). Several behavioral tests were used to assess the cognitive and behavioral phenotype of the offspring from PND 49 through 86, including the Morris water maze and novel object recognition. Male and female stressed offspring showed reduced reversal learning on the Morris water maze and stressed females did not show a significant preference for the novel object (57 ± 8%) while control females did (71 ± 3%). This indicates altered cognition in prenatally stressed offspring. On PND 91-92, offspring were necropsied and hippocampal tissue was collected. Genotypic outcomes of prenatal stress w

  12. [Histological and molecular alterations in inflammatory myopathies].

    PubMed

    Vázquez Del Mercado Espinosa, Mónica; Arana Argaez, Víctor; Petri, Marcelo Heron; Aguilar Arreola, Jorge

    2009-11-01

    The histological findings in muscle biopsies of inflammatory myopathies have been divided into 2 groups: A) Endomisial infiltrates mainly by T CD8+, CD4+ and macrophages and B) Perivascular infiltrates by CD4+, B cells and macrophages. The first kind of infiltrate suggests an immune reaction against muscle fibers very common in PM and inclusion body myositis, On the other hand the perivascular infiltrate is a hallmark of DM. It has ben shown that autoantigens related with myopathies such as Mi-2, Jo-1, OJ, PL12, Ku, PM/Scl are able to suffer proteolytic cleavage by granzyme B and other stimulus induced by cytotoxic T cells. In this chapter we will review the histological and molecular findings of inflammatory myopathies but we will also discuss a special group of myopathies related to the presence of antibodies against the SRP complex, in particular the SRP72 and SRP54 antibodies, which are associated with a poor prognosis and clinical outcome and present an inadequate response to conventional treatment. Copyright © 2009 Elsevier España, S.L. All rights reserved.

  13. Molecular gearing systems

    SciTech Connect

    Gakh, Andrei A.; Sachleben, Richard A.; Bryan, Jeff C.

    1997-11-01

    The race to create smaller devices is fueling much of the research in electronics. The competition has intensified with the advent of microelectromechanical systems (MEMS), in which miniaturization is already reaching the dimensional limits imposed by physics of current lithographic techniques. Also, in the realm of biochemistry, evidence is accumulating that certain enzyme complexes are capable of very sophisticated modes of motion. Complex synergistic biochemical complexes driven by sophisticated biomechanical processes are quite common. Their biochemical functions are based on the interplay of mechanical and chemical processes, including allosteric effects. In addition, the complexity of this interplay far exceeds that of typical chemical reactions. Understanding the behavior of artificial molecular devices as well as complex natural molecular biomechanical systems is difficult. Fortunately, the problem can be successfully resolved by direct molecular engineering of simple molecular systems that can mimic desired mechanical or electronic devices. These molecular systems are called technomimetics (the name is derived, by analogy, from biomimetics). Several classes of molecular systems that can mimic mechanical, electronic, or other features of macroscopic devices have been successfully synthesized by conventional chemical methods during the past two decades. In this article we discuss only one class of such model devices: molecular gearing systems.

  14. Molecular gearing systems

    DOE PAGES

    Gakh, Andrei A.; Sachleben, Richard A.; Bryan, Jeff C.

    1997-11-01

    The race to create smaller devices is fueling much of the research in electronics. The competition has intensified with the advent of microelectromechanical systems (MEMS), in which miniaturization is already reaching the dimensional limits imposed by physics of current lithographic techniques. Also, in the realm of biochemistry, evidence is accumulating that certain enzyme complexes are capable of very sophisticated modes of motion. Complex synergistic biochemical complexes driven by sophisticated biomechanical processes are quite common. Their biochemical functions are based on the interplay of mechanical and chemical processes, including allosteric effects. In addition, the complexity of this interplay far exceeds thatmore » of typical chemical reactions. Understanding the behavior of artificial molecular devices as well as complex natural molecular biomechanical systems is difficult. Fortunately, the problem can be successfully resolved by direct molecular engineering of simple molecular systems that can mimic desired mechanical or electronic devices. These molecular systems are called technomimetics (the name is derived, by analogy, from biomimetics). Several classes of molecular systems that can mimic mechanical, electronic, or other features of macroscopic devices have been successfully synthesized by conventional chemical methods during the past two decades. In this article we discuss only one class of such model devices: molecular gearing systems.« less

  15. MOLECULAR ALTERATIONS IN GLIOBLASTOMA: POTENTIAL TARGETS FOR IMMUNOTHERAPY

    PubMed Central

    Haque, Azizul; Banik, Naren L.; Ray, Swapan K.

    2015-01-01

    Glioblastoma is the most common and deadly brain tumor, possibly arising from genetic and epigenetic alterations in normal astroglial cells. Multiple cytogenetic, chromosomal, and genetic alterations have been identified in glioblastoma, with distinct expression of antigens (Ags) and biomarkers that may alter therapeutic potential of this aggressive cancer. Current therapy consists of surgical resection, followed by radiation therapy and chemotherapy. In spite of these treatments, the prognosis for glioblastoma patients is poor. Although recent studies have focused on the development of novel immunotherapeutics against glioblastoma, little is known about glioblastoma specific immune responses. A better understanding of the molecular interactions among glioblastoma tumors, host immune cells, and the tumor microenvironment may give rise to novel integrated approaches for the simultaneous control of tumor escape pathways and the activation of antitumor immune responses. This review provides a detailed overview concerning genetic alterations in glioblastoma, their effects on Ag and biomarker expression and the future design of chemoimmunotherapeutics against glioblastoma. PMID:21199773

  16. Sex speeds adaptation by altering the dynamics of molecular evolution.

    PubMed

    McDonald, Michael J; Rice, Daniel P; Desai, Michael M

    2016-03-10

    Sex and recombination are pervasive throughout nature despite their substantial costs. Understanding the evolutionary forces that maintain these phenomena is a central challenge in biology. One longstanding hypothesis argues that sex is beneficial because recombination speeds adaptation. Theory has proposed several distinct population genetic mechanisms that could underlie this advantage. For example, sex can promote the fixation of beneficial mutations either by alleviating interference competition (the Fisher-Muller effect) or by separating them from deleterious load (the ruby in the rubbish effect). Previous experiments confirm that sex can increase the rate of adaptation, but these studies did not observe the evolutionary dynamics that drive this effect at the genomic level. Here we present the first, to our knowledge, comparison between the sequence-level dynamics of adaptation in experimental sexual and asexual Saccharomyces cerevisiae populations, which allows us to identify the specific mechanisms by which sex speeds adaptation. We find that sex alters the molecular signatures of evolution by changing the spectrum of mutations that fix, and confirm theoretical predictions that it does so by alleviating clonal interference. We also show that substantially deleterious mutations hitchhike to fixation in adapting asexual populations. In contrast, recombination prevents such mutations from fixing. Our results demonstrate that sex both speeds adaptation and alters its molecular signature by allowing natural selection to more efficiently sort beneficial from deleterious mutations.

  17. Sex Speeds Adaptation by Altering the Dynamics of Molecular Evolution

    PubMed Central

    McDonald, Michael J.; Rice, Daniel P.; Desai, Michael M.

    2016-01-01

    Sex and recombination are pervasive throughout nature despite their substantial costs1. Understanding the evolutionary forces that maintain these phenomena is a central challenge in biology2,3. One longstanding hypothesis argues that sex is beneficial because recombination speeds adaptation4. Theory has proposed a number of distinct population genetic mechanisms that could underlie this advantage. For example, sex can promote the fixation of beneficial mutations either by alleviating interference competition (the Fisher-Muller effect)5,6 or by separating them from deleterious load (the ruby in the rubbish effect)7,8. Previous experiments confirm that sex can increase the rate of adaptation9–17, but these studies did not observe the evolutionary dynamics that drive this effect at the genomic level. Here, we present the first comparison between the sequence-level dynamics of adaptation in experimental sexual and asexual populations, which allows us to identify the specific mechanisms by which sex speeds adaptation. We find that sex alters the molecular signatures of evolution by changing the spectrum of mutations that fix, and confirm theoretical predictions that it does so by alleviating clonal interference. We also show that substantially deleterious mutations hitchhike to fixation in adapting asexual populations. In contrast, recombination prevents such mutations from fixing. Our results demonstrate that sex both speeds adaptation and alters its molecular signature by allowing natural selection to more efficiently sort beneficial from deleterious mutations. PMID:26909573

  18. Prognostic Significance of the European LeukemiaNet Standardized System for Reporting Cytogenetic and Molecular Alterations in Adults With Acute Myeloid Leukemia

    PubMed Central

    Mrózek, Krzysztof; Marcucci, Guido; Nicolet, Deedra; Maharry, Kati S.; Becker, Heiko; Whitman, Susan P.; Metzeler, Klaus H.; Schwind, Sebastian; Wu, Yue-Zhong; Kohlschmidt, Jessica; Pettenati, Mark J.; Heerema, Nyla A.; Block, AnneMarie W.; Patil, Shivanand R.; Baer, Maria R.; Kolitz, Jonathan E.; Moore, Joseph O.; Carroll, Andrew J.; Stone, Richard M.; Larson, Richard A.; Bloomfield, Clara D.

    2012-01-01

    Purpose To evaluate the prognostic significance of the international European LeukemiaNet (ELN) guidelines for reporting genetic alterations in acute myeloid leukemia (AML). Patients and Methods We analyzed 1,550 adults with primary AML, treated on Cancer and Leukemia Group B first-line trials, who had pretreatment cytogenetics and, for cytogenetically normal patients, mutational status of NPM1, CEBPA, and FLT3 available. We compared complete remission (CR) rates, disease-free survival (DFS), and overall survival (OS) among patients classified into the four ELN genetic groups (favorable, intermediate-I, intermediate-II, adverse) separately for 818 younger (age < 60 years) and 732 older (age ≥ 60 years) patients. Results The percentages of younger versus older patients in the favorable (41% v 20%; P < .001), intermediate-II (19% v 30%; P < .001), and adverse (22% v 31%; P < .001) genetic groups differed. The favorable group had the best and the adverse group the worst CR rates, DFS, and OS in both age groups. Both intermediate groups had significantly worse outcomes than the favorable but better than the adverse group. Intermediate-I and intermediate-II groups in older patients had similar outcomes, whereas the intermediate-II group in younger patients had better OS but not better CR rates or DFS than the intermediate-I group. The prognostic significance of ELN classification was confirmed by multivariable analyses. For each ELN group, older patients had worse outcomes than younger patients. Conclusion The ELN classification clearly separates the genetic groups by outcome, supporting its use for risk stratification in clinical trials. Because they have different proportions of genetic alterations and outcomes, younger and older patients should be reported separately when using the ELN classification. PMID:22987078

  19. Molecular alteration of marine dissolved organic matter under experimental hydrothermal conditions

    NASA Astrophysics Data System (ADS)

    Hawkes, Jeffrey A.; Hansen, Christian T.; Goldhammer, Tobias; Bach, Wolfgang; Dittmar, Thorsten

    2016-02-01

    Marine dissolved organic matter (DOM) is a large (660 Pg) pool of reduced carbon that is subject to thermal alteration in hydrothermal systems and sedimentary basins. In natural high-temperature hydrothermal systems, DOM is almost completely removed, but the mechanism and temperature dependence of this removal have not been studied to date. We investigated molecular-level changes to DOM that was solid-phase extracted (SPE-DOM) from the deep ocean of the North Pacific Ocean. This complex molecular mixture was experimentally exposed to temperatures between 100 and 380 °C over the course of two weeks in artificial seawater, and was then characterised on a molecular level via ultrahigh-resolution Fourier-transform ion cyclotron mass spectrometry (FT-ICR-MS). Almost 93% of SPE-DOM was removed by the treatment at 380 °C, and this removal was accompanied by a consistent pattern of SPE-DOM alteration across the temperatures studied. Higher molecular weight and more oxygen rich compounds were preferentially removed, suggesting that decarboxylation and dehydration of carboxylic acid and alcohol groups are the most rapid degradation mechanisms. Nitrogen containing compounds followed the same overall trends as those containing just C, H and O up to 300 °C. Above this temperature, the most highly altered samples contained very little of the original character of marine DOM, instead being mainly composed of very low intensity N- and S- containing molecules with a high H/C ratio (>1.5). Our results suggest that abiotic hydrothermal alteration of SPE-DOM may already occur at temperatures above 68 °C. Our experiments were conducted without a sedimentary or mineral phase, and demonstrate that profound molecular alteration and almost complete removal of marine SPE-DOM requires nothing more than heating in a seawater matrix.

  20. Genetic/molecular alterations of meningiomas and the signaling pathways targeted

    PubMed Central

    Domingues, Patrícia; González-Tablas, María; Otero, Álvaro; Pascual, Daniel; Ruiz, Laura; Miranda, David; Sousa, Pablo; Gonçalves, Jesús María; Lopes, María Celeste; Orfao, Alberto; Tabernero, María Dolores

    2015-01-01

    Meningiomas are usually considered to be benign central nervous system tumors; however, they show heterogenous clinical, histolopathological and cytogenetic features associated with a variable outcome. In recent years important advances have been achieved in the identification of the genetic/molecular alterations of meningiomas and the signaling pathways involved. Thus, monosomy 22, which is often associated with mutations of the NF2 gene, has emerged as the most frequent alteration of meningiomas; in addition, several other genes (e.g. AKT1, KLF4, TRAF7, SMO) and chromosomes have been found to be recurrently altered often in association with more complex karyotypes and involvement of multiple signaling pathways. Here we review the current knowledge about the most relevant genes involved and the signaling pathways targeted by such alterations. In addition, we summarize those proposals that have been made so far for classification and prognostic stratification of meningiomas based on their genetic/genomic features. PMID:25965831

  1. Molecular alterations in malignant blue nevi and related blue lesions.

    PubMed

    Yilmaz, Ismail; Gamsizkan, Mehmet; Sari, Sule Ozturk; Yaman, Banu; Demirkesen, Cuyan; Heper, Aylin; Calli, Aylin Orgen; Narli, Gizem; Kucukodaci, Zafer; Berber, Ufuk; Demirel, Dilaver; Akalin, Taner; Demiriz, Murat; Buyukbabani, Nesimi

    2015-12-01

    Malignant blue nevi (MBN) are extremely rare dermal melanocytic tumors that arise in association with atypical cellular blue nevi (ACBN), cellular blue nevi (CBN), common blue nevi (BN), or de novo. The frequency of BRAF, NRAS, and KIT mutations in malignant melanoma varies according to histological subtype and localization. These mutations are rarely observed in blue nevi, which have recently been shown to carry activating mutations in GNAQ/GNA11 genes. Only few small molecular studies of MBN have been published. The aim of the present study was to analyze in MBN and related blue lesions such as ACBN, CBN, and BN the prevalence of BRAF, NRAS, KIT, GNAQ, and GNA11 gene mutations and their association with clinicopathological features. We included in our study 12 MBN, 6 ACBN, 29 CBN, and 35 common BN diagnosed between 1996 and 2014. Sanger sequencing method was used for mutation analysis. Overall, GNAQ exon 5 mutation was the most frequent alteration (46 %), in 2 of 12 (17 %) MBN, 1 of 6 (17 %) ACBN, 22 of 29 (76 %) CBN, and 13 of 35 (37 %) common BN. BRAF V600E and GNA11 exon 5 mutations were respectively detected in 3 of 12 (25 %) and in 2 of 12 (17 %) MBN while none in ACBN, CBN, and common BN. None of the cases harbored NRAS exon 2/3, KIT exon 9/11/13/17/18, or GNAQ/GNA11 exon 4 mutations. GNAQ gene exon 5 mutations are rare in MBN and ACBN but frequent in CBN and common BN. Remarkably, BRAF V600E and GNA11 exon 5 mutations were only detected in MBN, whereas none were found in ACBN, CBN, or common BN. Our data contribute new elements to the limited data on molecular alterations in MBN.

  2. Buprenorphine Alters Inflammatory and Oxidative Stress Molecular Markers in Arthritis

    PubMed Central

    Hitchon, Carol

    2017-01-01

    Buprenorphine is recommended for use as an analgesic in animal models including in murine models of collagen-induced arthritis (CIA). However, the effect of buprenorphine on the expression of disease-associated biomarkers is not well defined. We examined the effect of buprenorphine administration on disease progression and the expression of inflammatory and oxidative stress markers, in a murine model of CIA. Buprenorphine administration altered the expression of cytokines, IFN-γ, IL-6, and MMP-3, and oxidative markers, for example, iNOS, superoxide dismutase (SOD1), and catalase (CAT), in the CIA mice. As buprenorphine is an analgesic, we further monitored the association of expression of these biomarkers with pain scores in a human cohort of early rheumatoid arthritis (RA). Serum MMP-3 levels and blood mRNA expression of antioxidants sod1 and cat correlated with pain scores in the RA cohort. We have demonstrated that administration of buprenorphine alters the expression of inflammatory and oxidative stress-related molecular markers in a murine model of CIA. This caveat needs to be considered in animal experiments using buprenorphine as an analgesic, as it can be a confounding factor in murine studies used for prediction of response to therapy. Furthermore, the antioxidant enzymes that showed an association with pain scores in the human cohort may be explored as biomarkers for pain in future studies. PMID:28572711

  3. Wall-selective chemical alteration of silicon nanotube molecular carriers.

    PubMed

    Ben-Ishai, Moshit; Patolsky, Fernando

    2011-02-09

    Recently, there has been significant interest in the synthesis and potential applications of semiconductor nanotubes (NTs). In this context, many efforts have been invested in developing new routes to control and engineer their surface chemistry. We report herein on a simple route to differentially and selectively functionalize the inner and outer surfaces of silicon nanotubes (SiNTs) with organic molecular layers containing different functional groups and hydrophobicity/hydrophilicity chemical nature, via covalent binding, to give nanotubular structures with dual chemical properties. Significantly, our unique synthetic approach can be further extended to directly form hollow crystalline nanotubular structures with their inner/outer surfaces independently and selectively altered chemically. Additionally, SiNTs inner and/or outer walls can be selectively decorated with metal nanoparticles. Both inner and outer walls can be individually and separately modified with the same metal nanoparticles, with different metal NPs in the inside and outside walls or with a combination of metal NPs decoration and molecular layers, if so required. Furthermore, the dually modified nanotubes were then exploited as phase extraction nanocarriers to demonstrate their potential in future chemical and biological separation, extraction, and filtering applications.

  4. Expression alterations define unique molecular characteristics of spinal ependymomas

    PubMed Central

    Lourdusamy, Anbarasu; Rahman, Ruman; Grundy, Richard G.

    2015-01-01

    Ependymomas are glial tumors that originate in either intracranial or spinal regions. Although tumors from different regions are histologically similar, they are biologically distinct. We therefore sought to identify molecular characteristics of spinal ependymomas (SEPN) in order to better understand the disease biology of these tumors. Using gene expression profiles of 256 tumor samples, we identified increased expression of 1,866 genes in SEPN when compared to intracranial ependymomas. These genes are mainly related to anterior/posterior pattern specification, response to oxidative stress, glial cell differentiation, DNA repair, and PPAR signalling, and also significantly enriched with cellular senescence genes (P = 5.5 × 10−03). In addition, a high number of significantly down-regulated genes in SEPN are localized to chromosome 22 (81 genes from chr22: 43,325,255 – 135,720,974; FDR = 1.77 × 10−23 and 22 genes from chr22: 324,739 – 32,822,302; FDR = 2.07 × 10−09) including BRD1, EP300, HDAC10, HIRA, HIC2, MKL1, and NF2. Evaluation of NF2 co-expressed genes further confirms the enrichment of chromosome 22 regions. Finally, systematic integration of chromosome 22 genes with interactome and NF2 co-expression data identifies key candidate genes. Our results reveal unique molecular characteristics of SEPN such as altered expression of cellular senescence and chromosome 22 genes. PMID:25909290

  5. Adenosquamous carcinoma of the pancreas: preoperative diagnosis and molecular alterations.

    PubMed

    Murakami, Yoshiaki; Yokoyama, Takashi; Yokoyama, Yujiro; Kanehiro, Tetsuya; Uemura, Kenichiro; Sasaki, Masaru; Morifuji, Masahiko; Sueda, Taijiro

    2003-01-01

    Adenosquamous carcinoma of the pancreas is a rare tumor which has a less favorable prognosis than common ductal cell carcinoma of the pancreas, and a definite preoperative diagnosis of this tumor is quite difficult. We herein report two cases of this rare variant. The patients were a 41-year-old man (patient 1) and a 67-year-old woman (patient 2). Patient 1 had a hypoechoic mass measuring 3 cm in the uncus of the pancreas, while patient 2 had a huge mass, measuring 8 cm, in the tail of the pancreas. Patient 2 was successfully diagnosed preoperatively as having an adenosquamous carcinoma, by cytological examination of the pure pancreatic juice obtained by endoscopic retrograde pancreatic juice aspiration. A pylorus-preserving pancreatoduodenectomy was performed for patient 1, and a distal pancreatectomy with resection of the spleen and the left kidney was performed for patient 2. Subsequent pathological findings of these two tumors revealed adenosquamous carcinoma of the pancreas. K- ras point mutation, p53 overexpression, and telomerase activity in both tumor specimens were detected by the mutant allele specific amplification method, immunohistochemical staining, and telomeric repeat amplification protocol assay, respectively. The two patients died of recurrent disease 5 and 4 months, respectively, after surgery. Cytological examination of pure pancreatic juice is a useful modality for the preoperative diagnosis of this tumor, and frequent molecular alterations may be associated with the poor prognosis of adenosquamous carcinoma of the pancreas.

  6. A highly specific coding system for structural chromosomal alterations.

    PubMed

    Martínez-Frías, M L; Martínez-Fernández, M L

    2013-04-01

    The Spanish Collaborative Study of Congenital Malformations (ECEMC, from the name in Spanish) has developed a very simple and highly specific coding system for structural chromosomal alterations. Such a coding system would be of value at present due to the dramatic increase in the diagnosis of submicroscopic chromosomal deletions and duplications through molecular techniques. In summary, our new coding system allows the characterization of: (a) the type of structural anomaly; (b) the chromosome affected; (c) if the alteration affects the short or/and the long arm, and (d) if it is a non-pure dicentric, a non-pure isochromosome, or if it affects several chromosomes. We show the distribution of 276 newborn patients with these types of chromosomal alterations using their corresponding codes according to our system. We consider that our approach may be useful not only for other registries, but also for laboratories performing these studies to store their results on case series. Therefore, the aim of this article is to describe this coding system and to offer the opportunity for this coding to be applied by others. Moreover, as this is a SYSTEM, rather than a fixed code, it can be implemented with the necessary modifications to include the specific objectives of each program. Copyright © 2013 Wiley Periodicals, Inc.

  7. Molecular Alterations in Primary Prostate Cancer After Androgen Ablation Therapy

    PubMed Central

    Best, Carolyn J. M.; Gillespie, John W.; Yi, Yajun; Chandramouli, G.V. R.; Perlmutter, Mark A.; Gathright, Yvonne; Erickson, Heidi S.; Georgevich, Lauren; Tangrea, Michael A.; Duray, Paul H.; González, Sergio; Velasco, Alfredo; Linehan, W. Marston; Matusik, Robert J.; Price, Douglas K.; Figg, William D.; Emmert-Buck, Michael R.; Chuaqui, Rodrigo F.

    2005-01-01

    PURPOSE After an initial response to androgen ablation, most prostate tumors recur, ultimately progressing to highly aggressive androgen independent (AI) cancer. The molecular mechanisms underlying progression are not well known, in part due to the rarity of AI samples from primary and metastatic sites. EXPERIMENTAL DESIGN We compared the gene expression profiles of ten AI primary prostate tumor biopsies with ten primary, untreated androgen-dependent (AD) tumors. Samples were laser capture microdissected, the RNA was amplified, and gene expression was assessed using Affymetrix Human Genome U133A Gene Chips. Differential expression was examined with principle component analysis (PCA) and Student t testing. Analysis of gene ontology was performed with Expression Analysis Systematic Explorer (EASE) and gene expression data were integrated with genomic alterations with DIfferential Gene locus MAPping (DIGMAP). RESULTS Unsupervised PCA showed that the AD and AI tumors segregated from one another. After filtering the data, 239 differentially expressed genes were identified. Two main gene ontologies were found discordant between AI and AD tumors: macromolecule biosynthesis was down-regulated and cell adhesion up-regulated in AI tumors. Other differentially expressed genes were related to IL-6 signaling, as well as angiogenesis, cell adhesion, apoptosis, oxidative stress, and hormone response. The DIGMAP analysis identified nine regions of potential chromosomal deletion in the AI tumors including 1p36, 3p21, 6p21, 8p21, 11p15, 11q12, 12q23, 16q12, and 16q21. CONCLUSIONS Taken together, these data identify several unique characteristics of AI prostate cancer that may hold potential for the development of targeted therapeutic intervention. PMID:16203770

  8. Sulfide solubilities in Alteration-controlled Systems

    USGS Publications Warehouse

    Hemley, J.J.; Meyer, C.; Hodgson, C.J.; Thatcher, A.B.

    1967-01-01

    Solubilities of sphalerite (ZnS) and galena (PbS) were determined at 300?? to 500??C and 1000 bars total pressure in a chemical environment buffered by silicate mineral equilibria. Chloride solutions and muscovite-bearing assemblages characteristic of hydrothermal wall-rock alteration were used; weak acidities at temperature were therefore involved. The metal concentrations encountered tended to be higher than those observed in high bisulfide-H2S systems at neutral to weakly basic pH used in most previous experimentation; the chemical conditions of the work, although not completely satisfactory, are geologically more realistic than previous experimentation done in the basic-pH region.

  9. Immune system alterations in amyotrophic lateral sclerosis.

    PubMed

    Hovden, H; Frederiksen, J L; Pedersen, S W

    2013-11-01

    Amyotrophic lateral sclerosis is a disease of which the underlying cause and pathogenesis are unknown. Cumulatative data clearly indicates an active participation by the immune system in the disease. An increasingly recognized theory suggests a non-cell autonomous mechanism, meaning that multiple cells working together are necessary for the pathogenesis of the disease. Observed immune system alterations could indicate an active participation in this mechanism. Damaged motor neurons are able to activate microglia, astrocytes and the complement system, which further can influence each other and contribute to neurodegeneration. Infiltrating peripheral immune cells appears to correlate with disease progression, but their significance and composition is unclear. The deleterious effects of this collaborating system of cells appear to outweigh the protective aspects, and revealing this interplay might give more insight into the disease. Markers from the classical complement pathway are elevated where its initiator C1q appears to derive primarily from motor neurons. Activated microglia and astrocytes are found in close proximity to dying motor neurons. Their activation status and proliferation seemingly increases with disease progression. Infiltrating monocytes, macrophages and T cells are associated with these areas, although with mixed reports regarding T cell composition. This literature review will provide evidence supporting the immune system as an important part of ALS disease mechanism and present a hypothesis to direct the way for further studies.

  10. Chopped molecular beam multiplexing system

    NASA Technical Reports Server (NTRS)

    Adams, Billy R. (Inventor)

    1986-01-01

    The integration of a chopped molecular beam mass spectrometer with a time multiplexing system is described. The chopping of the molecular beam is synchronized with the time intervals by a phase detector and a synchronous motor. Arithmetic means are generated for phase shifting the chopper with respect to the multiplexer. A four channel amplifier provides the capacity to independently vary the baseline and amplitude in each channel of the multiplexing system.

  11. Sulfide solubilities in alteration-controlled systems.

    PubMed

    Hemley, J J; Meyer, C; Hodgson, C J; Thatcher, A B

    1967-12-22

    Solubilities of sphalerite (ZnS) and galena (PbS) were determined at 300 degrees to 500 degrees C and 1000 bars total pressure in a chemical environment buffered by silicate mineral equilibria. Chloride solutions and muscovite-bearing assemblages characteristic of hydrothermal wall-rock alteration were used; weak acidities at temperature were therefore involved. The metal concentrations encountered tended to be higher than those observed in high bisulfide-H(2)S systems at neutral to weakly basic pH used in most previous experimentation; the chemical conditions of the work, although not completely satisfactory, are geologically more realistic than previous experimentation done in the basic-pH region.

  12. Molecular Sieve Regeneration System (MSRS)

    SciTech Connect

    Nasise, J.E.; Anderson, J.L. ); Naruse, Y. )

    1992-01-01

    A Molecular Sieve Regeneration System (MSRS) was added to the existing Tritium Waste Treatment system (TWT) within the Tritium Systems Test Assembly (TSTA) at Los Alamos National Laboratory. The Department of Energy (DOE) no longer allows inventory by difference'' for radioactive wastes that are to be buried. The MSRS was designed and built to comply with this requirement. Within the TWT, water is generated by the catalytic conversion of hydrogen isotopes and removed by molecular sieve trapping prior to release to the environment. Molecular sieve regeneration is required to remove the trapped water and to rejuvenate the beds. The MSRS permits the collection and direct tritium assay of regenerated tritiated water from molecular sieve beds. This paper describes the MSRS in detail and how it is interfaced with the TWT.

  13. Molecular Sieve Regeneration System (MSRS)

    SciTech Connect

    Nasise, J.E.; Anderson, J.L.; Naruse, Y.

    1992-03-01

    A Molecular Sieve Regeneration System (MSRS) was added to the existing Tritium Waste Treatment system (TWT) within the Tritium Systems Test Assembly (TSTA) at Los Alamos National Laboratory. The Department of Energy (DOE) no longer allows ``inventory by difference`` for radioactive wastes that are to be buried. The MSRS was designed and built to comply with this requirement. Within the TWT, water is generated by the catalytic conversion of hydrogen isotopes and removed by molecular sieve trapping prior to release to the environment. Molecular sieve regeneration is required to remove the trapped water and to rejuvenate the beds. The MSRS permits the collection and direct tritium assay of regenerated tritiated water from molecular sieve beds. This paper describes the MSRS in detail and how it is interfaced with the TWT.

  14. Conformational Transitions in Molecular Systems

    NASA Astrophysics Data System (ADS)

    Bachmann, M.; Janke, W.

    2008-11-01

    Proteins are the "work horses" in biological systems. In almost all functions specific proteins are involved. They control molecular transport processes, stabilize the cell structure, enzymatically catalyze chemical reactions; others act as molecular motors in the complex machinery of molecular synthetization processes. Due to their significance, misfolds and malfunctions of proteins typically entail disastrous diseases, such as Alzheimer's disease and bovine spongiform encephalopathy (BSE). Therefore, the understanding of the trinity of amino acid composition, geometric structure, and biological function is one of the most essential challenges for the natural sciences. Here, we glance at conformational transitions accompanying the structure formation in protein folding processes.

  15. 32 CFR 310.33 - New and altered record systems.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... alterations. (ii) Increases in numbers of individuals due to normal growth are not considered alterations... significantly the scope of population covered (for example, expansion of a system of records covering a...

  16. 32 CFR 310.33 - New and altered record systems.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... alterations. (ii) Increases in numbers of individuals due to normal growth are not considered alterations... significantly the scope of population covered (for example, expansion of a system of records covering a single...

  17. 32 CFR 310.33 - New and altered record systems.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... alterations. (ii) Increases in numbers of individuals due to normal growth are not considered alterations... significantly the scope of population covered (for example, expansion of a system of records covering a single...

  18. Molecular Integrity of Mitochondria Alters by Potassium Chloride.

    PubMed

    Mishra, Suman; Mishra, Rajnikant

    2015-01-01

    Potassium chloride (KCl) has been commonly used in homogenization buffer and procedures of protein extraction. It is known to facilitate release of membrane-associated molecules but the higher concentration of KCl may affect the integrity of mitochondria by breaching the electrostatic force between the lipids and proteins. Therefore, it has been intended to explore the effect of KCl on mitochondrial proteome. The mitochondria were isolated from the mice liver and sub-fractionated into mitochondrial matrix and outer mitochondrial membrane fraction. The fractions were analysed by denaturing polyacrylamide gel electrophoresis (PAGE) and 2D-PAGE. The analysis of ultrastructure and protein profiles by MALDI-MS and data-mining reveals KCl-associated alterations in the integrity of mitochondria and its proteome. The mitochondrial membrane, cristae, and the matrix proteins appear altered under the influence of KCl.

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

    USDA-ARS?s Scientific Manuscript database

    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...

  20. Overview of major molecular alterations during progression from Barrett's esophagus to esophageal adenocarcinoma.

    PubMed

    Kalatskaya, Irina

    2016-10-01

    Esophageal adenocarcinoma (EAC) develops in the sequential transformation of normal epithelium into metaplastic epithelium, called Barrett's esophagus (BE), then to dysplasia, and finally cancer. BE is a common condition in which normal stratified squamous epithelium of the esophagus is replaced with an intestine-like columnar epithelium, and it is the most prominent risk factor for EAC. This review aims to impartially systemize the knowledge from a large number of publications that describe the molecular and biochemical alterations occurring over this progression sequence. In order to provide an unbiased extraction of the knowledge from the literature, a text-mining methodology was used to select genes that are involved in the BE progression, with the top candidate genes found to be TP53, CDKN2A, CTNNB1, CDH1, GPX3, and NOX5. In addition, sample frequencies across analyzed patient cohorts at each stage of disease progression are summarized. All six genes are altered in the majority of EAC patients, and accumulation of alterations correlates well with the sequential progression of BE to cancer, indicating that the text-mining method is a valid approach for gene prioritization. This review discusses how, besides being cancer drivers, these genes are functionally interconnected and might collectively be considered a central hub of BE progression. © 2016 New York Academy of Sciences.

  1. Molecular Mechanism of Altered Ezetimibe Disposition in Nonalcoholic Steatohepatitis

    PubMed Central

    Hardwick, Rhiannon N.; Fisher, Craig D.; Street, Stephanie M.; Canet, Mark J.

    2012-01-01

    Ezetimibe (EZE) lowers serum lipid levels by blocking cholesterol uptake in the intestine. Disposition of EZE and its pharmacologically active glucuronide metabolite (EZE-GLUC) to the intestine is dependent on hepatobiliary efflux. Previous studies suggested that hepatic transporter expression and function may be altered during nonalcoholic steatohepatitis (NASH). The purpose of the current study was to determine whether NASH-induced changes in the expression and function of hepatic transporters result in altered disposition of EZE and EZE-GLUC. Rats fed a methionine- and choline-deficient (MCD) diet for 8 weeks were administered 10 mg/kg EZE either by intravenous bolus or oral gavage. Plasma and bile samples were collected over 2 h followed by terminal urine and tissue collection. EZE and EZE-GLUC concentrations were determined by liquid chromatography-tandem mass spectrometry. The sinusoidal transporter Abcc3 was induced in MCD rats, which correlated with increased plasma concentrations of EZE-GLUC, regardless of dosing method. Hepatic expression of the biliary transporters Abcc2 and Abcb1 was also increased in MCD animals, but the biliary efflux of EZE-GLUC was slightly diminished, whereas biliary bile acid concentrations were unaltered. The cellular localization of Abcc2 and Abcb1 appeared to be internalized away from the canalicular membrane in MCD livers, providing a mechanism for the shift to plasma drug efflux. The combination of induced expression and altered localization of efflux transporters in NASH shifts the disposition profile of EZE-GLUC toward plasma retention away from the site of action. This increased plasma retention of drugs in NASH may have implications for the pharmacological effect and safety of numerous drugs. PMID:22112382

  2. Molecular and cellular alterations in Down syndrome: toward the identification of targets for therapeutics.

    PubMed

    Créau, Nicole

    2012-01-01

    Down syndrome is a complex disease that has challenged molecular and cellular research for more than 50 years. Understanding the molecular bases of morphological, cellular, and functional alterations resulting from the presence of an additional complete chromosome 21 would aid in targeting specific genes and pathways for rescuing some phenotypes. Recently, progress has been made by characterization of brain alterations in mouse models of Down syndrome. This review will highlight the main molecular and cellular findings recently described for these models, particularly with respect to their relationship to Down syndrome phenotypes.

  3. Molecular reconstruction of a fungal genetic code alteration.

    PubMed

    Mateus, Denisa D; Paredes, João A; Español, Yaiza; Ribas de Pouplana, Lluís; Moura, Gabriela R; Santos, Manuel A S

    2013-06-01

    Fungi of the CTG clade translate the Leu CUG codon as Ser. This genetic code alteration is the only eukaryotic sense-to-sense codon reassignment known to date, is mediated by an ambiguous serine tRNA (tRNACAG(Ser)), exposes unanticipated flexibility of the genetic code and raises major questions about its selection and fixation in this fungal lineage. In particular, the origin of the tRNACAG(Ser) and the evolutionary mechanism of CUG reassignment from Leu to Ser remain poorly understood. In this study, we have traced the origin of the tDNACAG(Ser) gene and studied critical mutations in the tRNACAG(Ser) anticodon-loop that modulated CUG reassignment. Our data show that the tRNACAG(Ser) emerged from insertion of an adenosine in the middle position of the 5'-CGA-3'anticodon of a tRNACGA(Ser) ancestor, producing the 5'-CAG-3' anticodon of the tRNACAG(Ser), without altering its aminoacylation properties. This mutation initiated CUG reassignment while two additional mutations in the anticodon-loop resolved a structural conflict produced by incorporation of the Leu 5'-CAG-3'anticodon in the anticodon-arm of a tRNA(Ser). Expression of the mutant tRNACAG(Ser) in yeast showed that it cannot be expressed at physiological levels and we postulate that such downregulation was essential to maintain Ser misincorporation at sub-lethal levels during the initial stages of CUG reassignment. We demonstrate here that such low level CUG ambiguity is advantageous in specific ecological niches and we propose that misreading tRNAs are targeted for degradation by an unidentified tRNA quality control pathway.

  4. Molecular reconstruction of a fungal genetic code alteration

    PubMed Central

    Mateus, Denisa D.; Paredes, João A.; Español, Yaiza; Ribas de Pouplana, Lluís; Moura, Gabriela R.; Santos, Manuel A.S.

    2013-01-01

    Fungi of the CTG clade translate the Leu CUG codon as Ser. This genetic code alteration is the only eukaryotic sense-to-sense codon reassignment known to date, is mediated by an ambiguous serine tRNA (tRNACAGSer), exposes unanticipated flexibility of the genetic code and raises major questions about its selection and fixation in this fungal lineage. In particular, the origin of the tRNACAGSer and the evolutionary mechanism of CUG reassignment from Leu to Ser remain poorly understood. In this study, we have traced the origin of the tDNACAGSer gene and studied critical mutations in the tRNACAGSer anticodon-loop that modulated CUG reassignment. Our data show that the tRNACAGSer emerged from insertion of an adenosine in the middle position of the 5′-CGA-3′anticodon of a tRNACGASer ancestor, producing the 5′-CAG-3′ anticodon of the tRNACAGSer, without altering its aminoacylation properties. This mutation initiated CUG reassignment while two additional mutations in the anticodon-loop resolved a structural conflict produced by incorporation of the Leu 5′-CAG-3′anticodon in the anticodon-arm of a tRNASer. Expression of the mutant tRNACAGSer in yeast showed that it cannot be expressed at physiological levels and we postulate that such downregulation was essential to maintain Ser misincorporation at sub-lethal levels during the initial stages of CUG reassignment. We demonstrate here that such low level CUG ambiguity is advantageous in specific ecological niches and we propose that misreading tRNAs are targeted for degradation by an unidentified tRNA quality control pathway. PMID:23619021

  5. Common Somatic Alterations Identified in Maffucci Syndrome by Molecular Karyotyping

    PubMed Central

    Amyere, Mustapha; Dompmartin, Anne; Wouters, Vinciane; Enjolras, Odile; Kaitila, Ilkka; Docquier, Pierre-Louis; Godfraind, Catherine; Mulliken, John Butler; Boon, Laurence Myriam; Vikkula, Miikka

    2014-01-01

    Maffucci syndrome (MS) is a rare congenital disorder characterized by multiple central cartilaginous tumors (enchondromas) in association with cutaneous spindle cell hemangiomas. These patients have a high incidence of malignant transformation. No familial case is known and the etiopathogenic cause remains unknown. In enchondromatosis (Ollier disease, OD), which is comprised of enchondromas only, 4 mutations in the PTHR1 gene have been identified in 4 patients; 3 were somatic and 1 was germline. No PTHR1 mutations have been detected in MS, whereas somatic IDH1 and, more rarely, IDH2 mutations have been observed in 77% of patients with MS and 81% of patients with OD. These genetic alterations are shared with other tumors, including glioma, leukemia and carcinoma. To search for underlying somatic genomic causes, we screened MS tissues using Affymetrix SNP-chips. We looked for CNVs, LOH and uniparental isodisomy (UPID) by performing pairwise analyses between allelic intensities in tumoral DNA versus the corresponding blood-extracted DNA. While common chromosomal anomalies were absent in constitutional DNA, several shared CNVs were identified in MS-associated tumors. The most frequently encountered somatic alterations were localized in 2p22.3, 2q24.3 and 14q11.2, implicating these chromosomal rearrangements in the formation of enchondromas and spindle cell hemangiomas in MS. In one chondrosarcoma specimen, large amplifications and/or deletions were observed in chromosomes 3, 6, 9, 10, 12, 13, and 19. Some of these genetic changes have been reported in other chondrosarcomas suggesting an etiopathogenic role. No LOH/UPID was observed in any Maffucci tissue. Our findings identify frequent somatic chromosomal rearrangements on 2p22.3, 2q24.3 and 14q11.2, which may unmask mutations leading to the lesions pathognomonic of MS. PMID:25565925

  6. A Molecular Genetic Basis Explaining Altered Bacterial Behavior in Space

    PubMed Central

    Prasad, Nripesh; Levy, Shawn E.; Stodieck, Louis; Jones, Angela; Shrestha, Shristi; Klaus, David

    2016-01-01

    Bacteria behave differently in space, as indicated by reports of reduced lag phase, higher final cell counts, enhanced biofilm formation, increased virulence, and reduced susceptibility to antibiotics. These phenomena are theorized, at least in part, to result from reduced mass transport in the local extracellular environment, where movement of molecules consumed and excreted by the cell is limited to diffusion in the absence of gravity-dependent convection. However, to date neither empirical nor computational approaches have been able to provide sufficient evidence to confirm this explanation. Molecular genetic analysis findings, conducted as part of a recent spaceflight investigation, support the proposed model. This investigation indicated an overexpression of genes associated with starvation, the search for alternative energy sources, increased metabolism, enhanced acetate production, and other systematic responses to acidity—all of which can be associated with reduced extracellular mass transport. PMID:27806055

  7. Genetic Alterations in the Molecular Subtypes of Bladder Cancer: Illustration in the Cancer Genome Atlas Dataset.

    PubMed

    Choi, Woonyoung; Ochoa, Andrea; McConkey, David J; Aine, Mattias; Höglund, Mattias; Kim, William Y; Real, Francisco X; Kiltie, Anne E; Milsom, Ian; Dyrskjøt, Lars; Lerner, Seth P

    2017-09-01

    Recent whole genome mRNA expression profiling studies revealed that bladder cancers can be grouped into molecular subtypes, some of which share clinical properties and gene expression patterns with the intrinsic subtypes of breast cancer and the molecular subtypes found in other solid tumors. The molecular subtypes in other solid tumors are enriched with specific mutations and copy number aberrations that are thought to underlie their distinct progression patterns, and biological and clinical properties. The availability of comprehensive genomic data from The Cancer Genome Atlas (TCGA) and other large projects made it possible to correlate the presence of DNA alterations with tumor molecular subtype membership. Our overall goal was to determine whether specific DNA mutations and/or copy number variations are enriched in specific molecular subtypes. We used the complete TCGA RNA-seq dataset and three different published classifiers developed by our groups to assign TCGA's bladder cancers to molecular subtypes, and examined the prevalence of the most common DNA alterations within them. We interpreted the results against the background of what was known from the published literature about the prevalence of these alterations in nonmuscle-invasive and muscle-invasive bladder cancers. The results confirmed that alterations involving RB1 and NFE2L2 were enriched in basal cancers, whereas alterations involving FGFR3 and KDM6A were enriched in luminal tumors. The results further reinforce the conclusion that the molecular subtypes of bladder cancer are distinct disease entities with specific genetic alterations. Our observation showed that some of subtype-enriched mutations and copy number aberrations are clinically actionable, which has direct implications for the clinical management of patients with bladder cancer. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  8. An antilock molecular braking system.

    PubMed

    Sun, Wei-Ting; Huang, Shou-Ling; Yao, Hsuan-Hsiao; Chen, I-Chia; Lin, Ying-Chih; Yang, Jye-Shane

    2012-08-17

    A light-driven molecular brake displaying an antilock function is constructed by introducing a nonradiative photoinduced electron transfer (PET) decay channel to compete with the trans (brake-off) → cis (brake-on) photoisomerization. A fast release of the brake can be achieved by deactivating the PET process through addition of protons. The cycle of irradiation-protonation-irradiation-deprotonation conducts the brake function and mimics the antilock braking system (ABS) of vehicles.

  9. Nicotine alters the expression of molecular markers of endocrine disruption in zebrafish.

    PubMed

    Kanungo, Jyotshna; Cuevas, Elvis; Guo, Xiaoqing; Lopez, Aida G; Ramirez-Lee, Manuel A; Trickler, William; Paule, Merle G; Ali, Syed F

    2012-09-27

    Nicotine, a drug of abuse, has been reported to have many adverse effects on the developing nervous system. In rodents, chronic nicotine exposure inhibits estrogen-mediated neuroprotection against cerebral ischemia in females suggesting that nicotine could disrupt endocrine targets. Zebrafish have been used as a model system for examining mechanisms underlying nicotinic effects on neuronal development. Here, using zebrafish embryos, we demonstrate that nicotine alters the expression of the validated endocrine disruption (ED) biomarkers, vitellogenin (vtg 1 and vtg 2) and cytochrome p450 aromatase (cyp19a1a and cyp19a1b) at the transcriptional level. Increased expression of three of these molecular markers (vtg 1, vtg 2 and cyp19a1b) in response to 17β-estradiol (E2) was more pronounced in 48hpf (hours post-fertilization) embryos than in the 24hpf embryos. While 24hpf embryos were non-responsive in this regard to 25μM nicotine, a similar exposure of the 48hpf embryos for 24h significantly down-regulated the expression of all four ED biomarker genes indicating that nicotine's anti-estrogenic effects are detectable in the 48hpf zebrafish embryos. These results provide direct molecular evidence that nicotine is an endocrine disruptor in zebrafish.

  10. Genetically modified animal models recapitulating molecular events altered in human hepatocarcinogenesis.

    PubMed

    Sánchez, Aránzazu; Fabregat, Isabel

    2009-04-01

    New advancements have been made in recent years in the understanding of the molecular mechanisms that govern human liver tumorigenesis. Experimental animal models have been widely used, especially mouse models. In this review we highlight some of the genetically engineered mouse models that have proved to be excellent tools to study the intracellular signalling pathways altered in hepatocarcinogenesis and establish potential correlations with data from humans, with special focus on hepatocellular carcinoma (HCC), the most common type of primary liver cancer. Information obtained from these animal models will help to design future therapeutic approaches to HCC, particularly those that explore drugs that specifically target the altered molecular pathways.

  11. Chronic mild stress alters circadian expressions of molecular clock genes in the liver.

    PubMed

    Takahashi, Kei; Yamada, Tetsuya; Tsukita, Sohei; Kaneko, Keizo; Shirai, Yuta; Munakata, Yuichiro; Ishigaki, Yasushi; Imai, Junta; Uno, Kenji; Hasegawa, Yutaka; Sawada, Shojiro; Oka, Yoshitomo; Katagiri, Hideki

    2013-02-01

    Chronic stress is well known to affect metabolic regulation. However, molecular mechanisms interconnecting stress response systems and metabolic regulations have yet to be elucidated. Various physiological processes, including glucose/lipid metabolism, are regulated by the circadian clock, and core clock gene dysregulation reportedly leads to metabolic disorders. Glucocorticoids, acting as end-effectors of the hypothalamus-pituitary-adrenal (HPA) axis, entrain the circadian rhythms of peripheral organs, including the liver, by phase-shifting core clock gene expressions. Therefore, we examined whether chronic stress affects circadian expressions of core clock genes and metabolism-related genes in the liver using the chronic mild stress (CMS) procedure. In BALB/c mice, CMS elevated and phase-shifted serum corticosterone levels, indicating overactivation of the HPA axis. The rhythmic expressions of core clock genes, e.g., Clock, Npas2, Bmal1, Per1, and Cry1, were altered in the liver while being completely preserved in the hypothalamic suprachiasmatic nuculeus (SCN), suggesting that the SCN is not involved in alterations in hepatic core clock gene expressions. In addition, circadian patterns of glucose and lipid metabolism-related genes, e.g., peroxisome proliferator activated receptor (Ppar) α, Pparγ-1, Pparγ-coactivator-1α, and phosphoenolepyruvate carboxykinase, were also disturbed by CMS. In contrast, in C57BL/6 mice, the same CMS procedure altered neither serum corticosterone levels nor rhythmic expressions of hepatic core clock genes and metabolism-related genes. Thus, chronic stress can interfere with the circadian expressions of both core clock genes and metabolism-related genes in the liver possibly involving HPA axis overactivation. This mechanism might contribute to metabolic disorders in stressful modern societies.

  12. Molecular pathways associated with transcriptional alterations in hyperparathyroidism

    PubMed Central

    LEE, FANG; LEE, JIE-JEN; JAN, WOAN-CHING; WU, CHIH-JEN; CHEN, HAN-HSIANG; CHENG, SHIH-PING

    2016-01-01

    Hyperparathyroidism is characterized by the oversecretion of parathyroid hormone biochemically and increased cell proliferation histologically. Primary and secondary hyperparathyroidism exhibit distinct pathophysiology but share certain common microscopic features. The present study performed the first genome-wide expression analysis directly comparing the expression profile of primary and secondary hyperparathyroidism. Microarray gene expression analyses were performed in parathyroid tissues from 2 primary hyperparathyroidism patients and 3 secondary hyperparathyroidism patients. Unsupervised hierarchical clustering analysis identified two natural subgroups containing different types of hyperparathyroidism. Combined with additional data extracted from a publicly available database, a meta-signature was constructed to represent an intersection of two sets of differential expression profile. Multiple pathways were identified that are aberrantly regulated in hyperparathyroidism. In primary hyperparathyroidism, dysregulated pathways included cell adhesion molecules, peroxisome proliferator-activated receptor signaling pathway, and neuroactive ligand-receptor interaction. Pathways implicated in secondary hyperparathyroidism included tryptophan metabolism, tight junctions, renin-angiotensin system, steroid hormone biosynthesis, and O-glycan biosynthesis. The present study demonstrates that different pathophysiology is associated with differential gene profiling in hyperparathyroidism. Several pathways are involved in parathyroid dysregulation and may be future targets for therapeutic intervention. PMID:27347190

  13. Elucidation of Molecular Alterations in Precursor Lesions of Ovarian Serous Carcinoma

    DTIC Science & Technology

    2013-07-01

    Precursor Lesions of Ovarian Serous Carcinoma PRINCIPAL INVESTIGATOR: Robert Kurman, M.D...5a. CONTRACT NUMBER Elucidation of Molecular Alterations in Precursor Lesions of Ovarian Serous Carcinoma 5b. GRANT NUMBER W81XWH-09-1-0249...Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT 15. SUBJECT TERMS prevention, p53 mutations, high grade serous

  14. [Circadian alterations of the cardiovascular system].

    PubMed

    Hernandes Fernandes, E; Coelho, D; Missel Correa, J R; Kumpinski, D

    2000-01-01

    Circadian variations have been known for a long time for the influence they have on the physiological systems, including the cardiovascular system. The study of the mechanisms with circadian variation that change the function of the cardiovascular system and its diseases has increased greatly in recent years due to its clinical prominence. Through these studies, physiopathology, epidemiology and factors involved in cardiovascular diseases are more understandable. Thus, the incidence of cardiac events has been clearly associated with the morning hours, as well as the possible mechanisms involved in this variation during the daytime hours. The arterial blood pressure, plasma catecholamine levels and cortisol, platelet aggregation, and fibrinolytic system action are the most implicated mechanisms. From this knowledge, it is possible to design new therapeutic strategies that should consider the time of the day of higher risk for the onset of cardiovascular events.

  15. Chronic ethanol consumption alters the selective usage of phosphatidylethanolamine molecular species by methyltransferases

    SciTech Connect

    Ellingson, J.S.; Pukys, T.; Rubin, E. )

    1992-01-01

    The authors have examined the effects of chronic ethanol consumption on phospholipid methyltransferases, which may play a special role by synthesizing phosphatidylcholine (PC) molecules containing predominantly polyunsaturated fatty acids. Rat liver microsomes from adenosylmethionine to convert endogenous phoshatidylethanolamine (PE) to radiolabeled PC, which was separated into its individual molecular species by reversed-phase HPLC. To assess the selective usage of PE molecular species for methylation, the authors determined the mole % of the PE molecular species in microsomes from control and ethanol-fed rats. Chronic ethanol consumption increased the selective usage of phospholipid molecular species containing palmitic acid combined with arachidonic acid or docosahexaenoic acid, whereas it did not affect the use of the corresponding stearic acid species. These results suggest that the long term interference with cellular physiology by altering the metabolism of a specific metabolic pool of molecular species is a mechanism by which chronic ethanol consumption could exert adverse effects of the liver.

  16. General Anesthesia and Altered States of Arousal: A Systems Neuroscience Analysis

    PubMed Central

    Brown, Emery N.; Purdon, Patrick L.; Van Dort, Christa J.

    2011-01-01

    Placing a patient in a state of general anesthesia is crucial for safely and humanely performing most surgical and many nonsurgical procedures. How anesthetic drugs create the state of general anesthesia is considered a major mystery of modern medicine. Unconsciousness, induced by altered arousal and/or cognition, is perhaps the most fascinating behavioral state of general anesthesia. We perform a systems neuroscience analysis of the altered arousal states induced by five classes of intravenous anesthetics by relating their behavioral and physiological features to the molecular targets and neural circuits at which these drugs are purported to act. The altered states of arousal are sedation-unconsciousness, sedation-analgesia, dissociative anesthesia, pharmaco-logic non-REM sleep, and neuroleptic anesthesia. Each altered arousal state results from the anesthetic drugs acting at multiple targets in the central nervous system. Our analysis shows that general anesthesia is less mysterious than currently believed. PMID:21513454

  17. Low molecular weight heparin restores antithrombin III activity from hyperglycemia induced alterations.

    PubMed

    Ceriello, A; Marchi, E; Palazzni, E; Quatraro, A; Giugliano, D

    1990-01-01

    Alteration of antithrombin III (ATIII) activity, glycemia level dependent, exists in diabetes mellitus. In this study the ability of a low molecular weight heparin (LMWH) (Fluxum, Alfa-Wassermann S.p.A., Bologna, Italy), as well as unfractioned héparin, to preserve ATIII activity from glucose-induced alterations, both in vitro and in vivo, is reported. The subcutaneous and intravenous LMWH and heparin administration increases basal depressed ATIII activity in diabetic patients. Heparin shows an equivalent effect on both anti-IIa and anti-Xa activity of ATIII, while LMWH is more effective in preserving the anti-Xa activity. Similarity, heparin preserves ATIII activity from hyperglycemia-induced alterations, during hyperglycemic clamp, and LMWH infusion is able to preserve a significant amount of anti-Xa activity from glucose-induced alterations. Since diabetic patients show a high incidence of thrombotic accidents, LMWH appears to be a promising innovation for the prevention of diabetic thrombophylia.

  18. Molecular Spectroscopy of Living Systems

    NASA Astrophysics Data System (ADS)

    Cheng, Ji-Xin

    2016-06-01

    Molecular spectroscopy has been a powerful tool in the study of molecules in gas phase, condensed phase, and at interfaces. The transition from in vitro spectroscopy to spectroscopic imaging of living systems is opening new opportunities to reveal cellular machinery and to enable molecule-based diagnosis (Science 2015, 350: 1054). Such a transition involves more than a simple combination of spectrometry and microscopy. In this presentation, I will discuss the most recent efforts that have pushed the physical limits of spectroscopic imaging in terms of spectral acquisition speed, detection sensitivity, spatial resolution and imaging depth. I will further highlight significant applications in functional analysis of single cells and in label-free detection of diseases.

  19. Toluene alters brainstem enkephalinergic system in rats.

    PubMed

    de Gandarias, J M; Echevarria, E; Serrano, R; Silio, M; Casis, L

    1998-07-01

    Acute exposure to high doses of toluene can generate respiratory depression. However, neurotoxic mechanism of its action in the brainstem is not completely clear. In this work, acute, but not subchronic, exposure of rats to toluene increased leu-enkephalin immunostaining in several myelencephalic nuclei implicated in cardiorespiratory control. Due to the physiological role of enkephalins in the central regulation of breathing, it is suggested that the enkephalinergic system could play a role in neurotoxic respiratory depression induced by high dose acute toluene exposure.

  20. Reactions of small molecular systems

    SciTech Connect

    Wittig, C.

    1993-12-01

    This DOE program remains focused on small molecular systems relevant to combustion. Though a number of experimental approaches and machines are available for this research, the authors` activities are centered around the high-n Rydberg time-of-flight (HRTOF) apparatus in this laboratory. One student and one postdoc carry out experiments with this machine and also engage in small intra-group collaborations involving shared equipment. This past year was more productive than the previous two, due to the uninterrupted operation of the HRTOF apparatus. Results were obtained with CH{sub 3}OH, CH{sub 3}SH, Rg-HX complexes, HCOOH, and their deuterated analogs where appropriate. One paper is in print, three have been accepted for publication, and one is under review. Many preliminary results that augur well for the future were obtained with other systems such as HNO{sub 3}, HBr-HI complexes, toluene, etc. Highlights from the past year are presented below that display some of the features of this program.

  1. Therapeutic strategies in male breast cancer: clinical implications of chromosome 17 gene alterations and molecular subtypes.

    PubMed

    Schildhaus, Hans-Ulrich; Schroeder, Lars; Merkelbach-Bruse, Sabine; Binot, Elke; Büttner, Reinhard; Kuhn, Walther; Rudlowski, Christian

    2013-12-01

    Male breast cancer (MBC) is a rare disease. To date, therapy is mainly based on studies and clinical experiences with breast cancer in women. Only little is known about molecular typing of MBC, particularly with regard to potential biological predictors for adjuvant therapy. In female breast cancer tumors with chromosome 17 centromere (CEP17) duplication, HER2 and/or Topoisomerase II alpha (Topo II-α) gene alterations have been suggested to be associated with poor prognosis and increased sensitivity to anthracycline-containing regimens. In a well characterized cohort of 96 primary invasive MBC, we studied CEP17, HER2 and Topo II-α alterations by fluorescence in-situ hybridization (FISH), and expression of hormone receptors (HR), HER2 and Ki67 by immunohistochemistry to define molecular subtypes. Tumor characteristics and follow-up data were available and correlated with molecular findings. HER2 amplification and Topo II-α amplification/deletion were exceptionally rare in MBC (6.3% and 3.1%, respectively). CEP17 polysomy were found in 9.4% of tumors. HER2, Topo II-α and CEP17 gene alterations were not correlated to patients outcome. 96.9% of our cases were HR positive. Triple negative tumors were found in only 3.1% of the cases. In nodal negative tumors luminal A subtypes were significantly associated with better overall survival. Our results provide evidence for a predominant male breast cancer phenotype, characterized by HR expression and a lack of HER2/Topo II-α alterations and CEP17 duplicates. Therefore, the impact of anthracycline sensitivity linked to HER2/Topo II-α alterations as found in female breast cancer has low clinical significance for this specific male breast cancer phenotype. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Nicotine-induced molecular alterations are modulated by GABAB receptor activity.

    PubMed

    Varani, Andres P; Pedrón, Valeria T; Aon, Amira J; Höcht, Christian; Acosta, Gabriela B; Bettler, Bernhard; Balerio, Graciela N

    2017-04-17

    It has been demonstrated that GABAB receptors modulate nicotine (NIC) reward effect; nevertheless, the mechanism implicated is not well known. In this regard, we evaluated the involvement of GABAB receptors on the behavioral, neurochemical, biochemical and molecular alterations associated with the rewarding effects induced by NIC in mice, from a pharmacological and genetic approach. NIC-induced rewarding properties (0.5 mg/kg, subcutaneously, sc) were evaluated by conditioned place preference (CPP) paradigm. CPP has three phases: preconditioning, conditioning and postconditioning. GABAB receptor antagonist 2-hydroxysaclofen (0.25, 0.5 and 1 mg/kg; intraperitoneally, ip) or the GABAB receptor agonist baclofen (3 mg/kg; ip) was injected before NIC during the conditioning phase. GABAB1 knockout (GABAB1 KO) mice received NIC during the conditioning phase. Vehicle and wild-type controls were employed. Neurochemical (dopamine, serotonin and their metabolites), biochemical (nicotinic receptor α4β2, α4β2nAChRs) and molecular (c-Fos) alterations induced by NIC were analyzed after the postconditioning phase by high-performance liquid chromatography (HPLC), receptor-ligand binding assays and immunohistochemistry, respectively, in nucleus accumbens (Acb), prefrontal cortex (PFC) and ventral tegmental area (VTA). NIC induced rewarding effects in the CPP paradigm and increased dopamine levels in Acb and PFC, α4β2nAChRs density in VTA and c-Fos expression in Acb shell (AcbSh), VTA and PFC. We showed that behavioral, neurochemical, biochemical and molecular alterations induced by NIC were prevented by baclofen. However, in 2-hydroxysaclofen pretreated and GABAB1 KO mice, these alterations were potentiated, suggesting that GABAB receptor activity is necessary to control alterations induced by NIC-induced rewarding effects. Therefore, the present findings provided important contributions to the mechanisms implicated in NIC-induced rewarding effects. © 2017 Society for the

  3. Integrated molecular analysis reveals complex interactions between genomic and epigenomic alterations in esophageal adenocarcinomas

    PubMed Central

    Peng, DunFa; Guo, Yan; Chen, Heidi; Zhao, Shilin; Washington, Kay; Hu, TianLing; Shyr, Yu; El-Rifai, Wael

    2017-01-01

    The incidence of esophageal adenocarcinoma (EAC) is rapidly rising in the United States and Western countries. In this study, we carried out an integrative molecular analysis to identify interactions between genomic and epigenomic alterations in regulating gene expression networks in EAC. We detected significant alterations in DNA copy numbers (CN), gene expression levels, and DNA methylation profiles. The integrative analysis demonstrated that altered expression of 1,755 genes was associated with changes in CN or methylation. We found that expression alterations in 84 genes were associated with changes in both CN and methylation. These data suggest a strong interaction between genetic and epigenetic events to modulate gene expression in EAC. Of note, bioinformatics analysis detected a prominent K-RAS signature and predicted activation of several important transcription factor networks, including β-catenin, MYB, TWIST1, SOX7, GATA3 and GATA6. Notably, we detected hypomethylation and overexpression of several pro-inflammatory genes such as COX2, IL8 and IL23R, suggesting an important role of epigenetic regulation of these genes in the inflammatory cascade associated with EAC. In summary, this integrative analysis demonstrates a complex interaction between genetic and epigenetic mechanisms providing several novel insights for our understanding of molecular events in EAC. PMID:28102292

  4. Physiological and Molecular Assessment of Altered Expression of Hsc70-1 in Arabidopsis. Evidence for Pleiotropic Consequences1

    PubMed Central

    Sung, Dong Yul; Guy, Charles L.

    2003-01-01

    Hsp70s function as molecular chaperones. The protective chaperone activities of hsp70 help to confer tolerance to heat, glucose deprivation, and drought. Overexpression of hsp70s in many organisms correlates with enhanced thermotolerance, altered growth, and development. To better understand the roles of hsp70 proteins in Arabidopsis, the molecular and physiological consequences of altered expression of the major heat shock cognate, Hsc70-1, were analyzed. Extensive efforts to achieve underexpression of Hsc70-1 mRNA using a full-length antisense cDNA resulted in no viable transgenic plants, suggesting that reduced expression is lethal. Constitutive overexpression of Hsc70-1 also appeared to be deleterious to viability, growth, and development because fewer transformants were recovered, and most were dwarfed with altered root systems. Despite being dwarfed, the overexpression plants progressed normally through four selected developmental stages. Heat treatment revealed that Hsc70-1 overexpression plants were more tolerant to heat shock (44°C for 10 min). The elevated basal levels of HSC70-1 in transgenic plants led to delayed heat shock response of several heat shock genes. The data in this study suggest that tight regulation of Hsc70-1 expression is critical for the viability of Arabidopsis and that the functions of HSC70-1 contribute to optimum growth, development, thermotolerance, and regulation of the heat shock response. PMID:12805626

  5. Cooperative genomic alteration network reveals molecular classification across 12 major cancer types.

    PubMed

    Zhang, Hongyi; Deng, Yulan; Zhang, Yong; Ping, Yanyan; Zhao, Hongying; Pang, Lin; Zhang, Xinxin; Wang, Li; Xu, Chaohan; Xiao, Yun; Li, Xia

    2017-01-25

    The accumulation of somatic genomic alterations that enables cells to gradually acquire growth advantage contributes to tumor development. This has the important implication of the widespread existence of cooperative genomic alterations in the accumulation process. Here, we proposed a computational method HCOC that simultaneously consider genetic context and downstream functional effects on cancer hallmarks to uncover somatic cooperative events in human cancers. Applying our method to 12 TCGA cancer types, we totally identified 1199 cooperative events with high heterogeneity across human cancers, and then constructed a pan-cancer cooperative alteration network. These cooperative events are associated with genomic alterations of some high-confident cancer drivers, and can trigger the dysfunction of hallmark associated pathways in a co-defect way rather than single alterations. We found that these cooperative events can be used to produce a prognostic classification that can provide complementary information with tissue-of-origin. In a further case study of glioblastoma, using 23 cooperative events identified, we stratified patients into molecularly relevant subtypes with a prognostic significance independent of the Glioma-CpG Island Methylator Phenotype (GCIMP). In summary, our method can be effectively used to discover cancer-driving cooperative events that can be valuable clinical markers for patient stratification.

  6. Cooperative genomic alteration network reveals molecular classification across 12 major cancer types

    PubMed Central

    Zhang, Hongyi; Deng, Yulan; Zhang, Yong; Ping, Yanyan; Zhao, Hongying; Pang, Lin; Zhang, Xinxin; Wang, Li; Xu, Chaohan; Xiao, Yun; Li, Xia

    2017-01-01

    The accumulation of somatic genomic alterations that enables cells to gradually acquire growth advantage contributes to tumor development. This has the important implication of the widespread existence of cooperative genomic alterations in the accumulation process. Here, we proposed a computational method HCOC that simultaneously consider genetic context and downstream functional effects on cancer hallmarks to uncover somatic cooperative events in human cancers. Applying our method to 12 TCGA cancer types, we totally identified 1199 cooperative events with high heterogeneity across human cancers, and then constructed a pan-cancer cooperative alteration network. These cooperative events are associated with genomic alterations of some high-confident cancer drivers, and can trigger the dysfunction of hallmark associated pathways in a co-defect way rather than single alterations. We found that these cooperative events can be used to produce a prognostic classification that can provide complementary information with tissue-of-origin. In a further case study of glioblastoma, using 23 cooperative events identified, we stratified patients into molecularly relevant subtypes with a prognostic significance independent of the Glioma-CpG Island Methylator Phenotype (GCIMP). In summary, our method can be effectively used to discover cancer-driving cooperative events that can be valuable clinical markers for patient stratification. PMID:27899621

  7. Molecular and Structural Basis of Inner Core Lipopolysaccharide Alterations in Escherichia coli

    PubMed Central

    Klein, Gracjana; Müller-Loennies, Sven; Lindner, Buko; Kobylak, Natalia; Brade, Helmut; Raina, Satish

    2013-01-01

    It is well established that lipopolysaccharide (LPS) often carries nonstoichiometric substitutions in lipid A and in the inner core. In this work, the molecular basis of inner core alterations and their physiological significance are addressed. A new inner core modification of LPS is described, which arises due to the addition of glucuronic acid on the third heptose with a concomitant loss of phosphate on the second heptose. This was shown by chemical and structural analyses. Furthermore, the gene whose product is responsible for the addition of this sugar was identified in all Escherichia coli core types and in Salmonella and was designated waaH. Its deduced amino acid sequence exhibits homology to glycosyltransferase family 2. The transcription of the waaH gene is positively regulated by the PhoB/R two-component system in a growth phase-dependent manner, which is coordinated with the transcription of the ugd gene explaining the genetic basis of this modification. Glucuronic acid modification was observed in E. coli B, K12, R2, and R4 core types and in Salmonella. We also show that the phosphoethanolamine (P-EtN) addition on heptose I in E. coli K12 requires the product of the ORF yijP, a new gene designated as eptC. Incorporation of P-EtN is also positively regulated by PhoB/R, although it can occur at a basal level without a requirement for any regulatory inducible systems. This P-EtN modification is essential for resistance to a variety of factors, which destabilize the outer membrane like the addition of SDS or challenge to sublethal concentrations of Zn2+. PMID:23372159

  8. Dynamical Localization in Molecular Systems.

    NASA Astrophysics Data System (ADS)

    Wang, Xidi

    In the first four chapters of this thesis we concentrate on the Davydov model which describes the vibrational energy quanta of Amide I bonds (C=O bonds on the alpha -helix) coupled to the acoustic phonon modes of the alpha-helix backbone in the form of a Frohlich Hamiltonian. Following a brief introduction in chapter one, in chapter two we formulate the dynamics of vibrational quanta at finite temperature by using coherent state products. The fluctuation-dissipation relation is derived. At zero temperature, in the continuum limit, we recover the original results of Davydov. We also achieve good agreement with numerical simulations. In chapter three, the net contraction of the lattice is calculated exactly at any temperature, and its relation to the so -call "topological stability" of the Davydov soliton is discussed. In the second section of the chapter three we calculate the overtone spectra of crystalline acetanilide (according to some opinions ACN provides experimental evidence for the existence of Davydov solitons). Good agreement with experimental data has been obtained. In chapter four we study the self-trapped vibrational excitations by the Quantum Monte Carlo technique. For a single excitation, the temperature dependence of different physical observables is calculated. The quasi-particle which resembles the Davydov soliton has been found to be fairly narrow using the most commonly used data for the alpha -helix; at temperatures above a few Kelvin, the quasi-particle reaches its smallest limit (extends over three sites), which implies diffusive motion of the small polaron-like quasi-particle at high temperatures. For the multi-excitation case, bound pairs and clusters of excitations are found at low temperatures; they gradually dissociate when the temperature of the system is increased as calculated from the density-density correlation function. In the last chapter of this thesis, we study a more general model of dynamical local modes in molecular systems

  9. Fine oil combustion particle bioavailable constituents induce molecular profiles of oxidative stress, altered function, and cellular injury in cardiomyocytes.

    PubMed

    Knuckles, Travis L; Dreher, Kevin L

    2007-11-01

    Epidemiological studies have shown a positive association between exposure to air particulate matter (PM) pollution and adverse cardiovascular health effects in susceptible subpopulations such as those with pre-existing cardiovascular disease. The mechanism(s) through which pulmonary deposited PM, particularly fine PM2.5, PM with mass median aerodynamic diameter <2.5 microm, affects the cardiovascular system is currently not known and remains a major focus of investigation. In the present study, the transcriptosome and transcription factor proteome were examined in rat neonatal cardiomyocyte (RCM) cultures, following an acute exposure to bioavailable constituents of PM2.5 oil combustion particles designated residual oil fly ash leachate (ROFA-L). Out of 3924 genes examined, 38 genes were suppressed and 44 genes were induced following a 1-h exposure to 3.5 microg/ml of a particle-free leachate of ROFA (ROFA-L). Genomic alterations in pathways related to IGF-1, VEGF, IL-2, PI3/AKT, cardiovascular disease, and free radical scavenging, among others, were detected 1 h postexposure to ROFA-L. Global gene expression was altered in a manner consistent with cardiac myocyte electrophysiological remodeling, cellular oxidative stress, and apoptosis. ROFA-L altered the transcription factor proteome by suppressing activity of 24 and activating 40 transcription factors out of a total of 149. Genomic alterations were found to correlate with changes in transcription factor proteome. These acute changes indicate pathological molecular alterations, which may lead to possible chronic alterations to the cardiac myocyte. These data also potentially relate underlying cardiovascular effects from occupational exposure to ROFA and identify how particles from specific emission sources may mediate ambient PM cardiac effects.

  10. How do roots alter signals of molecular proxies in terrestrial archives?

    NASA Astrophysics Data System (ADS)

    Wiesenberg, G. L.; Gocke, M. I.

    2016-12-01

    Terrestrial archives such as sediment-paleosol sequences and recent soil profiles have been frequently used for environmental and paleoenvironmental studies. One prominent tool is the use of molecular proxies from the lipid fraction due to their relative persistence and their well known suitability to trace paleoenvironmental developments as well as human activities. However, excavations of sediment-paleosol sequences often reveal the presence of roots or biopores that might have been formed during any later stage of pedogenesis or sediment accumulation, potentially altering the signal of molecular proxies. In the current study, we compile recent soils and paleosols as well as several meter thick sediment-paleosol sequences in order to trace the influence by post-pedogenic/sedimentary root penetration on molecular composition. Therefore, we documented root frequencies during field sampling campaigns and collected root (remains) with their surrounding material to assess the extension of root-derived overprint. While only suberin analysis enables identification of root-derived biomass in the vicinity of living or ancient roots, other biomarkers such as alkanes and fatty acids can derive from the primary vegetation and are commonly assumed to be only aboveground litter-derived. Further, miroorganisms and root-derived biomass contribute to lipid assemblage in soils and sediments. Therefore, their source identification and attribution to root-origin is more difficult, as also promoted degradation in the vicinity of roots can alter the biomarker signal. In the surrounding of visible root remains, we could identify root-derived overprint of up to >8cm distance, whereas this is mainly attributed to finer side roots around visible root remains. Furthermore, alteration can strongly overprint the sedimentary signal due to long-lasting overprint, especially in nutrient-rich horizons, such as paleosols. To enable proper paleoenvironmental reconstructions in terrestrial

  11. A computerized system for portrayal of landscape alterations

    Treesearch

    A. E. Stevenson; J. A. Conley; J. B. Carey

    1979-01-01

    The growing public awareness of and participation in the visual resource decision process has stimulated interest to find improved means of accurately and realistically displaying proposed alterations. The traditional artist renderings often lack the accuracy and objectivity needed for critical decisions. One approach, using computer graphics, led to the MOSAIC system...

  12. Gravity-induced cellular and molecular processes in plants studied under altered gravity conditions

    NASA Astrophysics Data System (ADS)

    Vagt, Nicole; Braun, Markus

    -rupting the actomyosin system did not impair the sedimentation of statoliths and did not prevent the activation of gravireceptors. However, experiments in microgravity and inhibitor experiments have demonstrated that the actomyosin system optimizes the statolith-receptor interactions by keeping the sedimented statoliths in motion causing a consistent activation of different gravireceptor molecules. Thereby, a triggered gravitropic signal is created which is the basis for a highly sensitive control and readjustment mechanism. In addition, the results of recent parabolic flight studies on the effects of altered gravity conditions on the gene expres-sion pattern of Arabidopsis seedlings support these findings and provide new insight into the molecular basis of the plants response to different acceleration conditions. The work was financially supported by DLR on behalf of Bundesministerium für Wirtschaft und Technologie (50WB0815).

  13. Molecular alterations in hepatocellular carcinoma associated with hepatitis B and hepatitis C infections

    PubMed Central

    Izzo, Francesco; Buonaguro, Franco M.

    2016-01-01

    Chronic infections with hepatitis B (HBV) and hepatitis C viruses (HCV) are the leading cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide. Both viruses encode multifunctional regulatory proteins activating several oncogenic pathways, which induce accumulation of multiple genetic alterations in the infected hepatocytes. Gene mutations in HBV- and HCV-induced HCCs frequently impair the TP53, Wnt/b-catenin, RAS/RAF/MAPK kinase and AKT/mTOR pathways, which represent important anti-cancer targets. In this review, we highlight the molecular mechanisms underlying the pathogenesis of primary liver cancer, with particular emphasis on the host genetic variations identified by high-throughput technologies. In addition, we discuss the importance of genetic alterations, such as mutations in the telomerase reverse transcriptase (TERT) promoter, for the diagnosis, prognosis, and tumor stratification for development of more effective treatment approaches. PMID:26943571

  14. Petroleum alteration by thermochemical sulfate reduction - A comprehensive molecular study of aromatic hydrocarbons and polar compounds

    NASA Astrophysics Data System (ADS)

    Walters, Clifford C.; Wang, Frank C.; Qian, Kuangnan; Wu, Chunping; Mennito, Anthony S.; Wei, Zhibin

    2015-03-01

    Thermochemical sulfate reduction (TSR) alters petroleum composition as it proceeds towards the complete oxidation of hydrocarbons to CO2. The effects of TSR on the molecular and isotopic composition of volatile species are well known; however, the non-volatile higher molecular weight aromatic and polar species have not been well documented. To address this deficiency, a suite of onshore Gulf coast oils and condensates generated from and accumulating in Smackover carbonates was assembled to include samples that experienced varying levels of TSR alteration and in reservoir thermal cracking. The entire molecular composition of aromatic hydrocarbons and NSO species were characterized and semi-quantified using comprehensive GC × GC (FID and CSD) and APPI-FTICR-MS. The concentration of thiadiamondoids is a reliable indicator of the extent of TSR alteration. Once generated by TSR, thiadiamondoids remain thermally stable in all but the most extreme reservoir temperatures (>180 °C). Hydrocarbon concentrations and distributions are influenced by thermal cracking and TSR. With increasing TSR alteration, oils become enriched in monoaromatic hydrocarbons and the distribution of high molecular weight aromatic hydrocarbons shifts towards more condensed species with a decrease in the number of alkyl carbons. Organosulfur compounds are created by the TSR process. In addition to the increase in benzothiophenes and dibenzothiophenes noted in previous studies, TSR generates condensed species containing one or more sulfur atoms that likely are composed of a single or multiple thiophenic cores. We hypothesize that these species are generated from the partial oxidation of PAHs and dealkylation reactions, followed by sulfur incorporation and condensation reactions. The organosulfur species remaining in the TSR altered oils are "proto-solid bitumen" moieties that upon further condensation, oxidation or sulfur incorporation result in highly sulfur enriched solid bitumen, which is

  15. Novel molecular events associated with altered steroidogenesis induced by exposure to atrazine in the intact and castrate male rat

    EPA Science Inventory

    Toxicology is increasingly focused on molecular events comprising adverse outcome pathways. Atrazine activates the hypothalamic-pituitary adrenal axis, but relationships to gonadal alterations are unknown. We characterized hormone profiles and adrenal (intact and castrate) and te...

  16. Novel molecular events associated with altered steroidogenesis induced by exposure to atrazine in the intact and castrate male rat

    EPA Science Inventory

    Toxicology is increasingly focused on molecular events comprising adverse outcome pathways. Atrazine activates the hypothalamic-pituitary adrenal axis, but relationships to gonadal alterations are unknown. We characterized hormone profiles and adrenal (intact and castrate) and te...

  17. Molecular Characterization of Somatic Alterations in Dukes’ B and C Colorectal Cancers by Targeted Sequencing

    PubMed Central

    Abdul, Shafina-Nadiawati; Ab Mutalib, Nurul-Syakima; Sean, Khor S.; Syafruddin, Saiful E.; Ishak, Muhiddin; Sagap, Ismail; Mazlan, Luqman; Rose, Isa M.; Abu, Nadiah; Mokhtar, Norfilza M.; Jamal, Rahman

    2017-01-01

    -β, and PI3K signaling. We reported the alteration profiles in each of the patient which has the potential to affect the clinical decision. We believe that this study will add further to the understanding of CRC molecular landscape. PMID:28769798

  18. Morphological and Molecular Alterations in 1,2 Dimethylhydrazine and Azoxymethane Induced Colon Carcinogenesis in Rats

    PubMed Central

    Perše, Martina; Cerar, Anton

    2011-01-01

    The dimethyhydrazine (DMH) or azoxymethane (AOM) model is a well-established, well-appreciated, and widely used model of experimental colon carcinogenesis. It has many morphological as well as molecular similarities to human sporadic colorectal cancer (CC), which are summarized and discussed in this paper. In addition, the paper combines present knowledge of morphological and molecular features in the multistep development of CC recognized in the DMH/AOM rat model. This understanding is necessary in order to accurately identify and interpret alterations that occur in the colonic mucosa when evaluating natural or pharmacological compounds in DMH/AOM rat colon carcinogenesis. The DMH/AOM model provides a wide range of options for investigating various initiating and environmental factors, the role of specific dietary and genetic factors, and therapeutic options in CC. The limitations of this model and suggested areas in which more research is required are also discussed. PMID:21253581

  19. Alterations of molecular and behavioral responses to cocaine by selective inhibition of Elk-1 phosphorylation.

    PubMed

    Besnard, Antoine; Bouveyron, Nicolas; Kappes, Vincent; Pascoli, Vincent; Pagès, Christiane; Heck, Nicolas; Vanhoutte, Peter; Caboche, Jocelyne

    2011-10-05

    Activation of the extracellular signal-regulated kinase (ERK) signaling pathway in the striatum is crucial for molecular adaptations and long-term behavioral alterations induced by cocaine. In response to cocaine, ERK controls the phosphorylation levels of both mitogen and stress-activated protein kinase 1 (MSK-1), a nuclear kinase involved in histone H3 (Ser10) and cAMP response element binding protein phosphorylation, and Elk-1, a transcription factor involved in serum response element (SRE)-driven gene regulations. We recently characterized the phenotype of msk-1 knock-out mice in response to cocaine. Herein, we wanted to address the role of Elk-1 phosphorylation in cocaine-induced molecular, morphological, and behavioral responses. We used a cell-penetrating peptide, named TAT-DEF-Elk-1 (TDE), which corresponds to the DEF docking domain of Elk-1 toward ERK and inhibits Elk-1 phosphorylation induced by ERKs without modifying ERK or MSK-1 in vitro. The peptide was injected in vivo before cocaine administration in mice. Immunocytochemical, molecular, morphological, and behavioral studies were performed. The TDE inhibited Elk-1 and H3 (Ser10) phosphorylation induced by cocaine, sparing ERK and MSK-1 activation. Consequently, TDE altered cocaine-induced regulation of genes bearing SRE site(s) in their promoters, including c-fos, zif268, ΔFosB, and arc/arg3.1 (activity-regulated cytoskeleton-associated protein). In a chronic cocaine administration paradigm, TDE reversed cocaine-induced increase in dendritic spine density. Finally, the TDE delayed the establishment of cocaine-induced psychomotor sensitization and conditioned-place preference. We conclude that Elk-1 phosphorylation downstream from ERK is a key molecular event involved in long-term neuronal and behavioral adaptations to cocaine.

  20. Molecular Substrate Alteration by Solar Wind Radiation Documented on Flown Genesis Mission Array Materials

    NASA Technical Reports Server (NTRS)

    Calaway, Michael J.; Stansbery, Eileen K.

    2006-01-01

    The Genesis spacecraft sampling arrays were exposed to various regimes of solar wind during flight that included: 313.01 days of high-speed wind from coronal holes, 335.19 days of low-speed inter-stream wind, 191.79 days of coronal mass ejections, and 852.83 days of bulk solar wind at Lagrange 1 orbit. Ellipsometry measurements taken at NASA s Johnson Space Center show that all nine flown array materials from the four Genesis regimes have been altered by solar wind exposure during flight. These measurements show significant changes in the optical constant for all nine ultra-pure materials that flew on Genesis when compared with their non-flight material standard. This change in the optical constant (n and k) of the material suggests that the molecular structure of the all nine ultra-pure materials have been altered by solar radiation. In addition, 50 samples of float-zone and czochralski silicon bulk array ellipsometry results were modeled with an effective medium approximation layer (EMA substrate layer) revealing a solar radiation molecular damage zone depth below the SiO2 native oxide layer ranging from 392 to 613 . This bulk solar wind radiation penetration depth is comparable to the depth of solar wind implantation depth of Mg measured by SIMS and SARISA.

  1. Histopathological cutaneous alterations in systemic sclerosis: a clinicopathological study

    PubMed Central

    2011-01-01

    Introduction The aims of the present study were to identify histopathological parameters which are linked to local clinical skin disease at two distinct anatomical sites in systemic sclerosis (SSc) patients with skin involvement (limited cutaneous systemic sclerosis (lcSSc) or diffuse cutaneous systemic sclerosis (dcSSc)) and to determine the sensitivity of SSc specific histological alterations, focusing on SSc patients without clinical skin involvement (limited SSc (lSSc)). Methods Histopathological alterations were systematically scored in skin biopsies of 53 consecutive SSc patients (dorsal forearm and upper inner arm) and 18 controls (upper inner arm). Clinical skin involvement was evaluated using the modified Rodnan skin score. In patients with lcSSc or dcSSc, associations of histopathological parameters with local clinical skin involvement were determined by generalised estimation equation modelling. Results The hyalinised collagen score, the myofibroblast score, the mean epidermal thickness, the mononuclear cellular infiltration and the frequency of focal exocytosis differed significantly between biopsies with and without local clinical skin involvement. Except for mononuclear cellular infiltration, all of the continuous parameters correlated with the local clinical skin score at the dorsal forearm. Parakeratosis, myofibroblasts and intima proliferation were present in a minority of the SSc biopsies, but not in controls. No differences were found between lSSc and controls. Conclusions Several histopathological parameters are linked to local clinical skin disease. SSc-specific histological alterations have a low diagnostic sensitivity. PMID:21356083

  2. Crack cocaine inhalation induces schizophrenia-like symptoms and molecular alterations in mice prefrontal cortex.

    PubMed

    Areal, Lorena Bianchine; Herlinger, Alice Laschuk; Pelição, Fabrício Souza; Martins-Silva, Cristina; Pires, Rita Gomes Wanderley

    2017-03-06

    Crack cocaine (crack) addiction represents a major social and health burden, especially seeing as users are more prone to engage in criminal and violent acts. Crack users show a higher prevalence of psychiatric comorbidities - particularly antisocial personality disorders - when compared to powder cocaine users. They also develop cognitive deficits related mainly to executive functions, including working memory. It is noteworthy that stimulant drugs can induce psychotic states, which appear to mimic some symptoms of schizophrenia among users. Social withdraw and executive function deficits are, respectively, negative and cognitive symptoms of schizophrenia mediated by reduced dopamine (DA) tone in the prefrontal cortex (PFC) of patients. That could be explained by an increased expression of D2R short isoform (D2S) in the PFC of such patients and/or by hypofunctioning NMDA receptors in this region. Reduced DA tone has already been described in the PFC of mice exposed to crack smoke. Therefore, it is possible that behavioral alterations presented by crack users result from molecular and biochemical neuronal alterations akin to schizophrenia. Accordingly, we found that upon crack inhalation mice have shown decreased social interaction and working memory deficits analogous to schizophrenia's symptoms, along with increased D2S/D2L expression ratio and decreased expression of NR1, NR2A and NR2B NMDA receptor subunits in the PFC. Herein we propose two possible mechanisms to explain the reduced DA tone in the PFC elicited by crack consumption in mice, bringing also the first direct evidence that crack use may result in schizophrenia-like neurochemical, molecular and behavioral alterations.

  3. Molecular weight fibrinogen variants alter gene expression and functional characteristics of human endothelial cells.

    PubMed

    Weijers, E M; van Wijhe, M H; Joosten, L; Horrevoets, A J G; de Maat, M P M; van Hinsbergh, V W M; Koolwijk, P

    2010-12-01

    Fibrin is a temporary matrix that not only seals a wound, but also provides a temporary matrix structure for invading cells during wound healing. Two naturally occurring fibrinogen variants, high molecular weight (HMW) and low molecular weight (LMW) fibrinogen, display different properties in supporting angiogenesis in vivo and in vitro. This study was aimed at investigating the functional characteristics and molecular mechanisms of human microvascular endothelial cells (HMVECs) cultured on HMW and LMW fibrin matrices. HMVECs on HMW fibrin matrices showed increased proliferation and tube formation as compared with their counterparts on unfractionated and LMW fibrin. Degradation of HMW fibrin was markedly enhanced by the presence of HMVECs, that of LMW fibrin was enhanced only slightly. However, the expression levels of fibrinolysis-regulating proteins and integrins were similar. Subsequent microarray analysis revealed that the expression of 377 genes differed significantly between HMVECs cultured on HMW fibrin and those cultured on LMW fibrin. Among these genes, UNC5B, DLL4 and the DLL4-Notch downstream targets Hey1, Hey2 and Hes1 showed increased expression in HMVECs on LMW fibrin. However, pharmacologic and genetic (DLL4 small interfering RNA) inhibition of DLL4-Notch signaling blunted rather than enhanced proliferation and tube formation by HMVECs on both fibrin variants. Heterogeneity in naturally occurring fibrinogen strongly influences endothelial cell proliferation and tube formation, and causes alterations in gene expression, including that of DLL4-Notch. The higher fibrinolytic sensitivity of HMW fibrin in the presence of HMVECs contributes to increased tube formation. Although the expression of DLL4-Notch was altered, it did not explain the enhanced tube formation in HMW fibrin. This study provides new perspectives for biological and tissue engineering applications. © 2010 International Society on Thrombosis and Haemostasis.

  4. Skeletal muscle molecular alterations precede whole-muscle dysfunction in NYHA Class II heart failure patients.

    PubMed

    Godard, Michael P; Whitman, Samantha A; Song, Yao-Hua; Delafontaine, Patrice

    2012-01-01

    Heart failure (HF), a debilitating disease in a growing number of adults, exerts structural and neurohormonal changes in both cardiac and skeletal muscles. However, these alterations and their affected molecular pathways remain uncharacterized. Disease progression is known to transform skeletal muscle fiber composition by unknown mechanisms. In addition, perturbation of specific hormonal pathways, including those involving skeletal muscle insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-5 (IGFB-5) appears to occur, likely affecting muscle metabolism and regeneration. We hypothesized that changes in IGF-1 and IGFB-5 mRNA levels correlate with the transformation of single-skeletal muscle fiber myosin heavy chain isoforms early in disease progression, making these molecules valuable markers of skeletal muscle changes in heart failure. To investigate these molecules during "early" events in HF patients, we obtained skeletal muscle biopsies from New York Heart Association (NYHA) Class II HF patients and controls for molecular analyses of single fibers, and we also quantified isometric strength and muscle size. There were more (P < 0.05) single muscle fibers coexpressing two or more myosin heavy chains in the HF patients (30% ± 7%) compared to the control subjects (13% ± 2%). IGF-1 and IGFBP-5 expression was fivefold and 15-fold lower in patients with in HF compared to control subjects (P < 0.05), respectively. Strikingly, there was a correlation in IGF-1 expression and muscle cross-sectional area (P < 0.05) resulting in a decrease in whole-muscle quality (P < 0.05) in the HF patients, despite no significant decrease in isometric strength or whole-muscle size. These data indicate that molecular alterations in myosin heavy chain isoforms, IGF-1, and IGFB-5 levels precede the gross morphological and functional deficits that have previously been associated with HF, and may be used as a predictor of functional outcome in patients.

  5. Fragment Molecular Orbital Nonadiabatic Molecular Dynamics for Condensed Phase Systems.

    PubMed

    Nebgen, Ben; Prezhdo, Oleg V

    2016-09-15

    A method for efficiently simulating nonadiabatic molecular dynamics (NAMD) of nanoscale and condensed phase systems is developed and tested. The electronic structure, including force and nonadiabatic coupling, are obtained with the fragment molecular orbital (FMO) approximation, which provides significant computational savings by splitting the system into fragments and computing electronic properties of each fragment subject to the external field due to other all other fragments. The efficiency of the developed technique is demonstrated by studying the effect of explicit solvent molecules on excited state relaxation in the Fe(CO)4 complex. The relaxation in the gas phase occurs on a 50 fs time scale, which is in excellent agreement with previously recorded femtosecond pump-probe spectroscopy. Adding a solvation shell of ethanol molecules to the simulation results in an increase in the excited state lifetime to 100 fs, in agreement with recent femtosecond X-ray spectroscopy measurements.

  6. Genetic and molecular alterations in olfactory neuroblastoma: implications for pathogenesis, prognosis and treatment

    PubMed Central

    Czapiewski, Piotr; Kunc, Michał; Haybaeck, Johannes

    2016-01-01

    Olfactory neuroblastoma (ONB, Esthesioneuroblastoma) is an infrequent neoplasm of the head and neck area derived from olfactory neuroepithelium. Despite relatively good prognosis a subset of patients shows recurrence, progression and/or metastatic disease, which requires additional treatment. However, neither prognostic nor predictive factors are well specified. Thus, we performed a literature search for the currently available data on disturbances in molecular pathways, cytogenetic changes and results gained by next generation sequencing (NGS) approaches in ONB in order to gain an overview of genetic alterations which might be useful for treating patients with ONB. We present briefly ONB molecular pathogenesis and propose potential therapeutic targets and prognostic factors. Possible therapeutic targets in ONB include: receptor tyrosine kinases (c-kit, PDGFR-b, TrkB; EGFR); somatostatin receptor; FGF-FGFR1 signaling; Sonic hedgehog pathway; apoptosis-related pathways (Bcl-2, TRAIL) and neoangiogenesis (VEGF; KDR). Furthermore, we compare high- and low-grade ONB, and describe its frequent mimicker: sinonasal neuroendocrine carcinoma. ONB is often a therapeutic challenge, so our goal should be the implementation of acquired knowledge into clinical practice, especially at pretreated, recurrent and metastatic stages. Moreover, the multicenter molecular studies are needed to increase the amount of available data. PMID:27256979

  7. New Developments in Salivary Gland Pathology: Clinically Useful Ancillary Testing and New Potentially Targetable Molecular Alterations.

    PubMed

    Griffith, Christopher C; Schmitt, Alessandra C; Little, James L; Magliocca, Kelly R

    2017-03-01

    Accurate diagnosis of salivary gland tumors can be challenging because of the many diagnostic entities, the sometimes extensive morphologic overlap, and the rarity of most tumor types. Ancillary testing is beginning to ameliorate some of these challenges through access to newer immunohistochemical stains and fluorescence in situ hybridization probes, which can limit differential diagnostic considerations in some cases. These ancillary testing strategies are especially useful in small biopsy samples, including aspiration cytology. Molecular techniques are also expanding our understanding of salivary gland tumor pathology and are helping to identify potential targets that may improve treatment for some of these tumors. Here, we summarize the clinical use of new immunohistochemical markers in our practice and review the current understanding of chromosomal rearrangements in salivary gland tumor pathology, emphasizing the prospects for exploiting molecular alterations in salivary gland tumors for diagnosis and targeted therapy. We find that immunohistochemistry and fluorescence in situ hybridization are powerful tools toward the diagnosis of salivary gland tumors, especially when used in a systematic manner based on morphologic differential-diagnostic considerations. As new targeted therapies emerge, it will become increasingly vital to incorporate appropriate molecular testing into the pathologic evaluation of salivary gland cancers.

  8. Molecular Alterations in Patients with Pulmonary Adenocarcinoma Presenting with Malignant Pleural Effusion at the First Diagnosis.

    PubMed

    Rodriguez, Erika F; Shabihkhani, Maryam; Carter, Jamal; Maleki, Zahra

    2017-01-01

    The aim of this study was to report cytologic and molecular features of pulmonary adenocarcinoma patients presenting with a malignant pleural effusion at the first diagnosis. Patients who had a cytopathologic diagnosis conclusive for lung adenocarcinoma for the first time on their pleural fluid specimen, and molecular testing done, were studied. The control group consisted of patients with a malignant pleural effusion that developed during disease progression. We identified 18 patients (9 males and 9 females). Micropapillary and/or solid adenocarcinoma type features predominated among cytologic specimens (n = 15), while acinar patterns predominated in controls. Survival was not significantly different from that of the control group (mean 13.8 vs. 13.9 months, respectively; p = 0.61). Ten (55%) cases had mutations in EGFR (n = 6; 60%), KRAS (n = 3; 30%), or ALK translocation (n = 1; 10%). No mutations were identified in BRAF, AKT, ERBB2, NRAS, or PIK3CA (tested in 7 patients). Patients positive for the tested mutations had a better overall survival than patients negative for the mutations (mean survival 16.2 vs. 6.05 months, respectively; p = 0.006, log-rank test). Ten (84%) control patients were positive for mutations in EGFR (n = 5; 42%), KRAS (n = 4; 34%), or ALK translocation (n = 1; 8.4%). In our series, a micropapillary-like and solid-like morphology, common in cytologic specimens, and alterations in EGFR were the most frequent identifiable molecular changes. © 2017 S. Karger AG, Basel.

  9. Multichannel perimetric alterations in systemic lupus erythematosus treated with hydroxychloroquine.

    PubMed

    Piñero, David P; Monllor, Begoña; Camps, Vicente J; de Fez, Dolores

    Systemic lupus erythematosus (SLE) is a multiorgan autoimmune disease of unknown etiology with many clinical manifestations. We report the first case of SLE in which visual alterations were evaluated with multichannel perimetry. Some achromatic and color vision alterations may be present in SLE, especially when treated with hydroxychloroquine. The sensitivity losses detected in the chromatic channels in the central zone of the visual field were consistent with the results of the FM 100 Hue color test. Likewise, the multichannel perimetry detected sensitivity losses in the parafoveal area for both chromatic channels, especially for the blue-yellow. Copyright © 2016 Spanish General Council of Optometry. Published by Elsevier España, S.L.U. All rights reserved.

  10. High Molecular Weight Barley β-Glucan Alters Gut Microbiota Toward Reduced Cardiovascular Disease Risk.

    PubMed

    Wang, Yanan; Ames, Nancy P; Tun, Hein M; Tosh, Susan M; Jones, Peter J; Khafipour, Ehsan

    2016-01-01

    The physiological cholesterol-lowering benefits of β-glucan have been well documented, however, whether modulation of gut microbiota by β-glucan is associated with these physiological effects remains unknown. The objectives of this study were therefore to determine the impact of β-glucan on the composition of gut microbiota in mildly hypercholesterolemic individuals and to identify if the altered microbiota are associated with bioactivity of β-glucan in improving risk factors of cardiovascular disease (CVD). Using a randomized, controlled crossover study design, individuals received for 5-week either a treatment breakfast containing 3 g high molecular weight (HMW), 3 g low molecular weight (LMW), 5 g LMW barley β-glucan, or wheat and rice. The American Heart Association (AHA) diet served as the background diet for all treatment groups. Phases were separated by 4-week washout periods. Fecal samples were collected at the end of each intervention phase and subjected to Illumina sequencing of 16S rRNA genes. Results revealed that at the phylum level, supplementation of 3 g/d HMW β-glucan increased Bacteroidetes and decreased Firmicutes abundances compared to control (P < 0.001). At the genus level, consumption of 3 g/d HMW β-glucan increased Bacteroides (P < 0.003), tended to increase Prevotella (P < 0.1) but decreased Dorea (P < 0.1), whereas diets containing 5 g LMW β-glucan and 3 g LMW β-glucan failed to alter the gut microbiota composition. Bacteroides, Prevotella, and Dorea composition correlated (P < 0.05) with shifts of CVD risk factors, including body mass index, waist circumference, blood pressure, as well as triglyceride levels. Our data suggest that consumption of HMW β-glucan favorably alters the composition of gut microbiota and this altered microbiota profile associates with a reduction of CVD risk markers. Together, our study suggests that β-glucan induced shifts in gut microbiota in a MW-dependent manner and that might be one of the

  11. High Molecular Weight Barley β-Glucan Alters Gut Microbiota Toward Reduced Cardiovascular Disease Risk

    PubMed Central

    Wang, Yanan; Ames, Nancy P.; Tun, Hein M.; Tosh, Susan M.; Jones, Peter J.; Khafipour, Ehsan

    2016-01-01

    The physiological cholesterol-lowering benefits of β-glucan have been well documented, however, whether modulation of gut microbiota by β-glucan is associated with these physiological effects remains unknown. The objectives of this study were therefore to determine the impact of β-glucan on the composition of gut microbiota in mildly hypercholesterolemic individuals and to identify if the altered microbiota are associated with bioactivity of β-glucan in improving risk factors of cardiovascular disease (CVD). Using a randomized, controlled crossover study design, individuals received for 5-week either a treatment breakfast containing 3 g high molecular weight (HMW), 3 g low molecular weight (LMW), 5 g LMW barley β-glucan, or wheat and rice. The American Heart Association (AHA) diet served as the background diet for all treatment groups. Phases were separated by 4-week washout periods. Fecal samples were collected at the end of each intervention phase and subjected to Illumina sequencing of 16S rRNA genes. Results revealed that at the phylum level, supplementation of 3 g/d HMW β-glucan increased Bacteroidetes and decreased Firmicutes abundances compared to control (P < 0.001). At the genus level, consumption of 3 g/d HMW β-glucan increased Bacteroides (P < 0.003), tended to increase Prevotella (P < 0.1) but decreased Dorea (P < 0.1), whereas diets containing 5 g LMW β-glucan and 3 g LMW β-glucan failed to alter the gut microbiota composition. Bacteroides, Prevotella, and Dorea composition correlated (P < 0.05) with shifts of CVD risk factors, including body mass index, waist circumference, blood pressure, as well as triglyceride levels. Our data suggest that consumption of HMW β-glucan favorably alters the composition of gut microbiota and this altered microbiota profile associates with a reduction of CVD risk markers. Together, our study suggests that β-glucan induced shifts in gut microbiota in a MW-dependent manner and that might be one of the

  12. Characterizing Molecular Interactions in Chemical Systems.

    PubMed

    Günther, David; Boto, Roberto A; Contreras-Garcia, Juila; Piquemal, Jean-Philip; Tierny, Julien

    2014-12-01

    Interactions between atoms have a major influence on the chemical properties of molecular systems. While covalent interactions impose the structural integrity of molecules, noncovalent interactions govern more subtle phenomena such as protein folding, bonding or self assembly. The understanding of these types of interactions is necessary for the interpretation of many biological processes and chemical design tasks. While traditionally the electron density is analyzed to interpret the quantum chemistry of a molecular system, noncovalent interactions are characterized by low electron densities and only slight variations of them--challenging their extraction and characterization. Recently, the signed electron density and the reduced gradient, two scalar fields derived from the electron density, have drawn much attention in quantum chemistry since they enable a qualitative visualization of these interactions even in complex molecular systems and experimental measurements. In this work, we present the first combinatorial algorithm for the automated extraction and characterization of covalent and noncovalent interactions in molecular systems. The proposed algorithm is based on a joint topological analysis of the signed electron density and the reduced gradient. Combining the connectivity information of the critical points of these two scalar fields enables to visualize, enumerate, classify and investigate molecular interactions in a robust manner. Experiments on a variety of molecular systems, from simple dimers to proteins or DNA, demonstrate the ability of our technique to robustly extract these interactions and to reveal their structural relations to the atoms and bonds forming the molecules. For simple systems, our analysis corroborates the observations made by the chemists while it provides new visual and quantitative insights on chemical interactions for larger molecular systems.

  13. The sympathetic nervous system alterations in human hypertension.

    PubMed

    Grassi, Guido; Mark, Allyn; Esler, Murray

    2015-03-13

    Several articles have dealt with the importance and mechanisms of the sympathetic nervous system alterations in experimental animal models of hypertension. This review addresses the role of the sympathetic nervous system in the pathophysiology and therapy of human hypertension. We first discuss the strengths and limitations of various techniques for assessing the sympathetic nervous system in humans, with a focus on heart rate, plasma norepinephrine, microneurographic recording of sympathetic nerve traffic, and measurements of radiolabeled norepinephrine spillover. We then examine the evidence supporting the importance of neuroadrenergic factors as promoters and amplifiers of human hypertension. We expand on the role of the sympathetic nervous system in 2 increasingly common forms of secondary hypertension, namely hypertension associated with obesity and with renal disease. With this background, we examine interventions of sympathetic deactivation as a mode of antihypertensive treatment. Particular emphasis is given to the background and results of recent therapeutic approaches based on carotid baroreceptor stimulation and radiofrequency ablation of the renal nerves.

  14. Genetic and molecular alterations in pancreatic cancer: Implications for personalized medicine

    PubMed Central

    Fang, Yantian; Yao, Qizhi; Chen, Zongyou; Xiang, Jianbin; William, Fisher E.; Gibbs, Richard A.; Chen, Changyi

    2013-01-01

    Recent advances in human genomics and biotechnologies have profound impacts on medical research and clinical practice. Individual genomic information, including DNA sequences and gene expression profiles, can be used for prediction, prevention, diagnosis, and treatment for many complex diseases. Personalized medicine attempts to tailor medical care to individual patients by incorporating their genomic information. In a case of pancreatic cancer, the fourth leading cause of cancer death in the United States, alteration in many genes as well as molecular profiles in blood, pancreas tissue, and pancreas juice has recently been discovered to be closely associated with tumorigenesis or prognosis of the cancer. This review aims to summarize recent advances of important genes, proteins, and microRNAs that play a critical role in the pathogenesis of pancreatic cancer, and to provide implications for personalized medicine in pancreatic cancer. PMID:24172537

  15. Reaction dynamics in polyatomic molecular systems

    SciTech Connect

    Miller, W.H.

    1993-12-01

    The goal of this program is the development of theoretical methods and models for describing the dynamics of chemical reactions, with specific interest for application to polyatomic molecular systems of special interest and relevance. There is interest in developing the most rigorous possible theoretical approaches and also in more approximate treatments that are more readily applicable to complex systems.

  16. Altered molecular profile in thyroid cancers from patients affected by the Three Mile Island nuclear accident.

    PubMed

    Goldenberg, David; Russo, Mariano; Houser, Kenneth; Crist, Henry; Derr, Jonathan B; Walter, Vonn; Warrick, Joshua I; Sheldon, Kathryn E; Broach, James; Bann, Darrin V

    2017-07-01

    In 1979, Three Mile Island (TMI) nuclear power plant experienced a partial meltdown with release of radioactive material. The effects of the accident on thyroid cancer (TC) in the surrounding population remain unclear. Radiation-induced TCs have a lower incidence of single nucleotide oncogenic driver mutations and higher incidence of gene fusions. We used next generation sequencing (NGS) to identify molecular signatures of radiation-induced TC in a cohort of TC patients residing near TMI during the time of the accident. Case series. We identified 44 patients who developed papillary thyroid carcinoma between 1974 and 2014. Patients who developed TC between 1984 and 1996 were at risk for radiation-induced TC, patients who developed TC before 1984 or after 1996 were the control group. We used targeted NGS of paired tumor and normal tissue from each patient to identify single nucleotide oncogenic driver mutations. Oncogenic gene fusions were identified using quantitative reverse transcription polymerase chain reaction. We identified 15 patients in the at-risk group and 29 patients in the control group. BRAFV600E mutations were identified in 53% patients in the at-risk group and 83% patients in the control group. The proportion of patients with BRAF mutations in the at-risk group was significantly lower than predicted by the The Cancer Genome Atlas cohort. Gene fusion or somatic copy number alteration drivers were identified in 33% tumors in the at-risk group and 14% of tumors in the control group. Findings were consistent with observations from other radiation-exposed populations. These data raise the possibility that radiation released from TMI may have altered the molecular profile of TC in the population surrounding TMI. 4 Laryngoscope, 127:S1-S9, 2017. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

  17. Frequent HLA class I alterations in human prostate cancer: molecular mechanisms and clinical relevance.

    PubMed

    Carretero, Francisco Javier; Del Campo, Ana Belen; Flores-Martín, Jose Francisco; Mendez, Rosa; García-Lopez, Cesar; Cozar, Jose Manuel; Adams, Victoria; Ward, Stephen; Cabrera, Teresa; Ruiz-Cabello, Francisco; Garrido, Federico; Aptsiauri, Natalia

    2016-01-01

    Reduced expression of HLA class I is an important immune escape mechanism from cytotoxic T cells described in various types of malignancy. It often correlates with poor prognosis and resistance to therapy. However, current knowledge about the frequency, underlying molecular mechanisms, and prognostic value of HLA class I and II alterations in prostate cancer (PC) is limited. Immunohistochemical analysis demonstrated that 88 % of the 42 studied cryopreserved prostate tumors have at least one type of HLA alteration as compared to adjacent normal prostate epithelium or benign hyperplasia. Total loss of HLA-I expression found in 50 % of tumors showed an association with increased incidence of tumor relapse, perineural invasion, and high D'Amico risk. The remaining HLA-I-positive tumors demonstrated locus and allelic losses detected in 26 and 12 % of samples, respectively. Loss of heterozygosity at chromosome 6 was detected in 32 % of the studied tumors. Molecular analysis revealed a reduced expression of B2M, TAP2, tapasin and NLRC5 mRNA in microdissected HLA-I-negative tumors. Analysis of twelve previously unreported cell lines derived from neoplastic and normal epithelium of cancerous prostate revealed different types of HLA-I aberration, ranging from locus and/or allelic downregulation to a total absence of HLA-I expression. The high incidence of HLA-I loss observed in PC, caused by both regulatory and structural defects, is associated with more aggressive disease development and may pose a real threat to patient health by increasing cancer progression and resistance to T-cell-based immunotherapy.

  18. Chronic ethanol intake leads to structural and molecular alterations in the rat endometrium.

    PubMed

    Martinez, Marcelo; Milton, Flora A; Pinheiro, Patricia Fernanda F; Almeida-Francia, Camila C D; Cagnon-Quitete, Valeria H A; Tirapelli, Luiz F; Padovani, Carlos Roberto; Chuffa, Luiz Gustavo A; Martinez, Francisco Eduardo

    2016-05-01

    We described the effects of low- and high-dose ethanol intake on the structure and apoptosis signaling of the uterine endometrium of UChA and UChB rats (animals with voluntary ethanol consumption). Thirty adult female rats, 90 days old, were divided into three groups (n = 10/group): UChA rats fed with 10% (v/v) ethanol ad libitum (free choice for water or ethanol) drinking < 1.9 g/kg/day; UChB rats fed with 10% (v/v) ethanol ad libitum (free choice for water or ethanol) drinking from 2 to 5 g/kg/day; control rats without ethanol (only water). After 120 days of treatment, rats displaying estrus were euthanized. Uterine epithelial cells of the UCh rats showed dilated cisterns of the rough endoplasmic reticulum, presence of lipid droplets, altered nuclear chromatin, and disrupted mitochondria. The UCh rats exhibited intense atrophied epithelial cells with smaller areas and perimeters of cytoplasm and nuclei. The endometrium of UChA rats showed higher levels of caspase-3 while Xiap and Bcl2 varied from moderate to weak. Both UChA and UChB rats exhibited a stronger immunoreaction to Ki-67 and IGFR-1 on epithelial and stromal cells. Chronic ethanol intake leads to structural and molecular alterations in the uterine endometrium of UCh rats, regardless of low- or high-dose consumption, promoting reproductive disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Leukemia-Associated Mutations in Nucleophosmin Alter Recognition by CRM1: Molecular Basis of Aberrant Transport

    PubMed Central

    Arregi, Igor; Falces, Jorge; Olazabal-Herrero, Anne; Alonso-Mariño, Marián; Taneva, Stefka G.; Rodríguez, José A.; Urbaneja, María A.; Bañuelos, Sonia

    2015-01-01

    Nucleophosmin (NPM) is a nucleocytoplasmic shuttling protein, normally enriched in nucleoli, that performs several activities related to cell growth. NPM mutations are characteristic of a subtype of acute myeloid leukemia (AML), where mutant NPM seems to play an oncogenic role. AML-associated NPM mutants exhibit altered subcellular traffic, being aberrantly located in the cytoplasm of leukoblasts. Exacerbated export of AML variants of NPM is mediated by the nuclear export receptor CRM1, and due, in part, to a mutationally acquired novel nuclear export signal (NES). To gain insight on the molecular basis of NPM transport in physiological and pathological conditions, we have evaluated the export efficiency of NPM in cells, and present new data indicating that, in normal conditions, wild type NPM is weakly exported by CRM1. On the other hand, we have found that AML-associated NPM mutants efficiently form complexes with CRM1HA (a mutant CRM1 with higher affinity for NESs), and we have quantitatively analyzed CRM1HA interaction with the NES motifs of these mutants, using fluorescence anisotropy and isothermal titration calorimetry. We have observed that the affinity of CRM1HA for these NESs is similar, which may help to explain the transport properties of the mutants. We also describe NPM recognition by the import machinery. Our combined cellular and biophysical studies shed further light on the determinants of NPM traffic, and how it is dramatically altered by AML-related mutations. PMID:26091065

  20. A comparison of molecular alterations in environmental and genetic rat models of ADHD: a pilot study.

    PubMed

    DasBanerjee, Tania; Middleton, Frank A; Berger, David F; Lombardo, John P; Sagvolden, Terje; Faraone, Stephen V

    2008-12-05

    Attention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral disorder in school-aged children. In addition to genetic factors, environmental influences or gene x environmental interactions also play an important role in ADHD. One example of a well studied environmental risk factor for ADHD is exposure to polychlorinated biphenyls (PCBs). In this study, we investigated whether the well-established genetic model of ADHD based on the spontaneously hypertensive rat (SHR) and a well established PCB-based model of ADHD exhibited similar molecular changes in brain circuits involved in ADHD. The brains from 28 male rats (8 SHR, 8 Sprague-Dawley (SD) controls, 8 Wistar/Kyoto (WKY) controls, and 4 PCB-exposed SD rats) were harvested at postnatal days (PNDs) 55-65 and RNA was isolated from six brain regions of interest. The RNA was analyzed for differences in expression of a set of 308 probe sets interrogating 218 unique genes considered highly relevant to ADHD or epigenetic gene regulation using the Rat RAE230 2.0 GeneChip (Affymetrix). Selected observations were confirmed by real-time quantitative RT-PCR. The results show that the expression levels of genes Gnal, COMT, Adrbk1, Ntrk2, Hk1, Syt11, and Csnk1a1 were altered in both the SHR rats and the PCB-exposed SD rats. Arrb2, Stx12, Aqp6, Syt1, Ddc, and Pgk1 expression levels were changed only in the PCB-exposed SD rats. Genes with altered expression only in the SHRs included Oprm1, Calcyon, Calmodulin, Lhx1, and Hes6. The epigenetic genes Crebbp, Mecp2, and Hdac5 are significantly altered in both models. The data provide strong evidence that genes and environment can affect different set of genes in two different models of ADHD and yet result in the similar disease-like symptoms. Copyright 2008 Wiley-Liss, Inc.

  1. A Comparison of Molecular Alterations in Environmental and Genetic Rat Models of ADHD: a pilot study

    PubMed Central

    DasBanerjee, Tania; Middleton, Frank A.; Berger, David F.; Lombardo, John P.; Sagvolden, Terje; Faraone, Stephen V.

    2008-01-01

    Attention Deficit Hyperactivity Disorder (ADHD) is the most common neurobehavioral disorder in school-aged children. In addition to genetic factors, environmental influences or gene × environmental interactions also play an important role in ADHD. One example of a well studied environmental risk factor for ADHD is exposure to polychlorinated biphenyls (PCBs). In this study, we investigated whether the well-established genetic model of ADHD based on the Spontaneously Hypertensive Rat (SHR) and a well established PCB-based model of ADHD exhibited similar molecular changes in brain circuits involved in ADHD. The brains from 28 male rats (8 SHR, 8 Sprague-Dawley (SD) controls, 8 Wistar-Kyoto (WKY) controls, and 4 PCB-exposed SD rats) were harvested at postnatal day 55-65 and RNA was isolated from six brain regions of interest. The RNA was analyzed for differences in expression of a set of 308 probe sets interrogating 218 unique genes considered highly relevant to ADHD or epigenetic gene regulation using the Rat RAE 230 2.0 GeneChip (Affymetrix). Selected observations were confirmed by real time quantitative RT-PCR. The results show that the expression levels of genes Gnal, COMT, Adrbk1, Ntrk2, Hk1, Syt11 and Csnk1a1 were altered in both the SHR rats and the PCB-exposed SD rats. Arrb2, Stx12, Aqp6, Syt1, Ddc and Pgk1 expression levels were changed only in the PCB-exposed SD rats. Genes with altered expression only in the SHRs included Oprm1, Calcyon, Calmodulin, Lhx1 and Hes6. The epigenetic genes Crebbp, Mecp2 and Hdac5 are significantly altered in both models. The data provide strong evidence that genes and environment can affect different set of genes in two different models of ADHD and yet result in the similar disease-like symptoms. PMID:18937310

  2. Cross-cancer profiling of molecular alterations within the human autophagy interaction network

    PubMed Central

    Lebovitz, Chandra B; Robertson, A Gordon; Goya, Rodrigo; Jones, Steven J; Morin, Ryan D; Marra, Marco A; Gorski, Sharon M

    2015-01-01

    Aberrant activation or disruption of autophagy promotes tumorigenesis in various preclinical models of cancer, but whether the autophagy pathway is a target for recurrent molecular alteration in human cancer patient samples is unknown. To address this outstanding question, we surveyed 211 human autophagy-associated genes for tumor-related alterations to DNA sequence and RNA expression levels and examined their association with patient survival outcomes in multiple cancer types with sequence data from The Cancer Genome Atlas consortium. We found 3 (RB1CC1/FIP200, ULK4, WDR45/WIPI4) and one (ATG7) core autophagy genes to be under positive selection for somatic mutations in endometrial carcinoma and clear cell renal carcinoma, respectively, while 29 autophagy regulators and pathway interactors, including previously identified KEAP1, NFE2L2, and MTOR, were significantly mutated in 6 of the 11 cancer types examined. Gene expression analyses revealed that GABARAPL1 and MAP1LC3C/LC3C transcripts were less abundant in breast cancer and non-small cell lung cancers than in matched normal tissue controls; ATG4D transcripts were increased in lung squamous cell carcinoma, as were ATG16L2 transcripts in kidney cancer. Unsupervised clustering of autophagy-associated mRNA levels in tumors stratified patient overall survival in 3 of 9 cancer types (acute myeloid leukemia, clear cell renal carcinoma, and head and neck cancer). These analyses provide the first comprehensive resource of recurrently altered autophagy-associated genes in human tumors, and highlight cancer types and subtypes where perturbed autophagy may be relevant to patient overall survival. PMID:26208877

  3. 44 CFR 6.71 - Federal Register notice of establishment of new system or alteration of existing system.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... establishment of new system or alteration of existing system. 6.71 Section 6.71 Emergency Management and... PRIVACY ACT OF 1974 Report on New Systems and Alterations of Existing Systems § 6.71 Federal Register notice of establishment of new system or alteration of existing system. Notice of the proposed...

  4. 44 CFR 6.71 - Federal Register notice of establishment of new system or alteration of existing system.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... establishment of new system or alteration of existing system. 6.71 Section 6.71 Emergency Management and... PRIVACY ACT OF 1974 Report on New Systems and Alterations of Existing Systems § 6.71 Federal Register notice of establishment of new system or alteration of existing system. Notice of the proposed...

  5. Vapor-liquid equilibrium of ethanol-water system in the presence of molecular sieves

    SciTech Connect

    Abu Al-Rub, F.A.; Banat, F.A.; Jumah, R.

    1999-09-01

    Adsorptive distillation is a new process to separate liquid mixtures in a packed distillation column. It depends on using active packing material instead of inert packing material in a packed distillation column. The active packing material can affect the intermolecular forces among the system components and thus alter its vapor-liquid equilibrium (VLE). The VLE of the ethanol-water system at 1 atm was studied using a circulation still in the absence and in the presence of different amounts of 4 {angstrom} molecular sieves. The results obtained showed that the VLE of the system was altered in the presence of the molecular sieves, the azeotropic point of the system (at 89.7 mol% ethanol in the normal case) was eliminated and considerable separation was achieved for a mixture of azeotropic composition, and the alteration in the VLE of a given binary mixture is a function of the pore size and the amount of the molecular sieves.

  6. [Metastasis tumors of the central nervous system: molecular biology].

    PubMed

    Bello, M Josefa; González-Gómez, P; Rey, J A

    2004-12-01

    Metastases in the nervous system represent an important and growing problem in the clinical practice, being the cause of a great mortality in the developed countries. This article reviews the few data available on the molecular mechanisms involved in the pathogenesis of these tumours, leading to oncogene activation, inactivation of tumour suppressor genes, not only by the classical mechanisms, but also by the tumour cell epigenetic balance alteration. We conclude that all this knowledge will lead in the future to a better diagnosis, treatment and clinic evolution of these patients.

  7. Glycans In The Immune system and The Altered Glycan Theory of Autoimmunity: A Critical Review

    PubMed Central

    Maverakis, Emanual; Kim, Kyoungmi; Shimoda, Michiko; Gershwin, M. Eric; Patel, Forum; Wilken, Reason; Raychaudhuri, Siba; Ruhaak, L. Renee; Lebrilla, Carlito B.

    2015-01-01

    Herein we will review the role of glycans in determining the functionality and specificity of various components of the immune system. Specific topics covered include: the specific glycosylation sites of IgE, IgM, IgD, IgE, IgA, and IgG; how glycans can encode “self” identity by functioning as either danger associated molecular patterns (DAMPs) or self-associated molecular patterns (SAMPs); the role of glycans as markers of protein integrity and age; how the glycocalyx can dictate the migration pattern of immune cells; and how the combination of Fc N-glycans and Ig isotype dictate the effector function of immunoglobulins. We speculate that the latter may be responsible for the well-documented association between alterations of the serum glycome and autoimmunity. Due to technological limitations, the extent of these autoimmune-associated glycan alterations and their role in disease pathophysiology has not been fully elucidated to date. Thus, we also review the current technologies available for glycan analysis, placing an emphasis on Multiple Reaction Monitoring (MRM), a rapid high-throughput technology that has great potential for glycan biomarker research. Finally, we put forth The Altered Glycan Theory of Autoimmunity, which states that each autoimmune disease will have a unique glycan signature characterized by the site-specific relative abundances of individual glycan structures on immune cells and serum proteins, especially the site-specific glycosylation patterns of specific antibody classes and subclasses. PMID:25578468

  8. Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: a critical review.

    PubMed

    Maverakis, Emanual; Kim, Kyoungmi; Shimoda, Michiko; Gershwin, M Eric; Patel, Forum; Wilken, Reason; Raychaudhuri, Siba; Ruhaak, L Renee; Lebrilla, Carlito B

    2015-02-01

    Herein we will review the role of glycans in the immune system. Specific topics covered include: the glycosylation sites of IgE, IgM, IgD, IgE, IgA, and IgG; how glycans can encode "self" identity by functioning as either danger associated molecular patterns (DAMPs) or self-associated molecular patterns (SAMPs); the role of glycans as markers of protein integrity and age; how the glycocalyx can dictate the migration pattern of immune cells; and how the combination of Fc N-glycans and Ig isotype dictate the effector function of immunoglobulins. We speculate that the latter may be responsible for the well-documented association between alterations of the serum glycome and autoimmunity. Due to technological limitations, the extent of these autoimmune-associated glycan alterations and their role in disease pathophysiology has not been fully elucidated. Thus, we also review the current technologies available for glycan analysis, placing an emphasis on Multiple Reaction Monitoring (MRM), a rapid high-throughput technology that has great potential for glycan biomarker research. Finally, we put forth The Altered Glycan Theory of Autoimmunity, which states that each autoimmune disease will have a unique glycan signature characterized by the site-specific relative abundances of individual glycan structures on immune cells and extracellular proteins, especially the site-specific glycosylation patterns of the different immunoglobulin(Ig) classes and subclasses.

  9. Molecular alterations in gastric cancer with special reference to the early-onset subtype.

    PubMed

    Skierucha, Małgorzata; Milne, Anya Na; Offerhaus, G Johan A; Polkowski, Wojciech P; Maciejewski, Ryszard; Sitarz, Robert

    2016-02-28

    Currently, gastric cancer (GC) is one of the most frequently diagnosed neoplasms, with a global burden of 723000 deaths in 2012. It is the third leading cause of cancer-related death worldwide. There are numerous possible factors that stimulate the pro-carcinogenic activity of important genes. These factors include genetic susceptibility expressed in a single-nucleotide polymorphism, various acquired mutations (chromosomal instability, microsatellite instability, somatic gene mutations, epigenetic alterations) and environmental circumstances (e.g., Helicobcter pylori infection, EBV infection, diet, and smoking). Most of the aforementioned pathways overlap, and authors agree that a clear-cut pathway for GC may not exist. Thus, the categorization of carcinogenic events is complicated. Lately, it has been claimed that research on early-onset gastric carcinoma (EOGC) and hereditary GC may contribute towards unravelling some part of the mystery of the GC molecular pattern because young patients are less exposed to environmental carcinogens and because carcinogenesis in this setting may be more dependent on genetic factors. The comparison of various aspects that differ and coexist in EOGCs and conventional GCs might enable scientists to: distinguish which features in the pathway of gastric carcinogenesis are modifiable, discover specific GC markers and identify a specific target. This review provides a summary of the data published thus far concerning the molecular characteristics of GC and highlights the outstanding features of EOGC.

  10. Modified oleic cottonseeds show altered content, composition and tissue-specific distribution of triacylglycerol molecular species.

    PubMed

    Horn, Patrick J; Sturtevant, Drew; Chapman, Kent D

    2014-01-01

    Targeted increases in monounsaturated (oleic acid) fatty acid content of refined cottonseed oil could support improved human nutrition and cardiovascular health. Genetic modifications of cottonseed fatty acid composition have been accomplished using several different molecular strategies. Modification of oleic acid content in cottonseed embryos using a dominant-negative protein approach, while successful in effecting change in the desired fatty acid composition, resulted in reduced oil content and seed viability. Here these changes in fatty acid composition were associated with changes in dominant molecular species of triacylglycerols (TAGs) and their spatial distributions within embryo tissues. A combination of mass spectrometry (MS)-based lipidomics approaches, including MS imaging of seed cryo-sections, revealed that cotton embryos expressing a non-functional allele of a Brassica napus delta-12 desaturase showed altered accumulation of TAG species, especially within cotyledonary tissues. While lipid analysis of seed extracts could demonstrate detailed quantitative changes in TAG species in transgenics, the spatial contribution of metabolite compartmentation could only be visualized by MS imaging. Our results suggest tissue-specific differences in TAG biosynthetic pathways within cotton embryos, and indicate the importance of considering the location of metabolites in tissues in addition to their identification and quantification when developing a detailed view of cellular metabolism. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  11. Molecular alterations in gastric cancer with special reference to the early-onset subtype

    PubMed Central

    Skierucha, Małgorzata; Milne, Anya NA; Offerhaus, G Johan A; Polkowski, Wojciech P; Maciejewski, Ryszard; Sitarz, Robert

    2016-01-01

    Currently, gastric cancer (GC) is one of the most frequently diagnosed neoplasms, with a global burden of 723000 deaths in 2012. It is the third leading cause of cancer-related death worldwide. There are numerous possible factors that stimulate the pro-carcinogenic activity of important genes. These factors include genetic susceptibility expressed in a single-nucleotide polymorphism, various acquired mutations (chromosomal instability, microsatellite instability, somatic gene mutations, epigenetic alterations) and environmental circumstances (e.g., Helicobcter pylori infection, EBV infection, diet, and smoking). Most of the aforementioned pathways overlap, and authors agree that a clear-cut pathway for GC may not exist. Thus, the categorization of carcinogenic events is complicated. Lately, it has been claimed that research on early-onset gastric carcinoma (EOGC) and hereditary GC may contribute towards unravelling some part of the mystery of the GC molecular pattern because young patients are less exposed to environmental carcinogens and because carcinogenesis in this setting may be more dependent on genetic factors. The comparison of various aspects that differ and coexist in EOGCs and conventional GCs might enable scientists to: distinguish which features in the pathway of gastric carcinogenesis are modifiable, discover specific GC markers and identify a specific target. This review provides a summary of the data published thus far concerning the molecular characteristics of GC and highlights the outstanding features of EOGC. PMID:26937134

  12. Association of Fusobacterium nucleatum with immunity and molecular alterations in colorectal cancer.

    PubMed

    Nosho, Katsuhiko; Sukawa, Yasutaka; Adachi, Yasushi; Ito, Miki; Mitsuhashi, Kei; Kurihara, Hiroyoshi; Kanno, Shinichi; Yamamoto, Itaru; Ishigami, Keisuke; Igarashi, Hisayoshi; Maruyama, Reo; Imai, Kohzoh; Yamamoto, Hiroyuki; Shinomura, Yasuhisa

    2016-01-14

    The human intestinal microbiome plays a major role in human health and diseases, including colorectal cancer. Colorectal carcinogenesis represents a heterogeneous process with a differing set of somatic molecular alterations, influenced by diet, environmental and microbial exposures, and host immunity. Fusobacterium species are part of the human oral and intestinal microbiota. Metagenomic analyses have shown an enrichment of Fusobacterium nucleatum (F. nucleatum) in colorectal carcinoma tissue. Using 511 colorectal carcinomas from Japanese patients, we assessed the presence of F. nucleatum. Our results showed that the frequency of F. nucleatum positivity in the Japanese colorectal cancer was 8.6% (44/511), which was lower than that in United States cohort studies (13%). Similar to the United States studies, F. nucleatum positivity in Japanese colorectal cancers was significantly associated with microsatellite instability (MSI)-high status. Regarding the immune response in colorectal cancer, high levels of infiltrating T-cell subsets (i.e., CD3+, CD8+, CD45RO+, and FOXP3+ cells) have been associated with better patient prognosis. There is also evidence to indicate that molecular features of colorectal cancer, especially MSI, influence T-cell-mediated adaptive immunity. Concerning the association between the gut microbiome and immunity, F. nucleatum has been shown to expand myeloid-derived immune cells, which inhibit T-cell proliferation and induce T-cell apoptosis in colorectal cancer. This finding indicates that F. nucleatum possesses immunosuppressive activities by inhibiting human T-cell responses. Certain microRNAs are induced during the macrophage inflammatory response and have the ability to regulate host-cell responses to pathogens. MicroRNA-21 increases the levels of IL-10 and prostaglandin E2, which suppress antitumor T-cell-mediated adaptive immunity through the inhibition of the antigen-presenting capacities of dendritic cells and T-cell proliferation in

  13. Association of Fusobacterium nucleatum with immunity and molecular alterations in colorectal cancer

    PubMed Central

    Nosho, Katsuhiko; Sukawa, Yasutaka; Adachi, Yasushi; Ito, Miki; Mitsuhashi, Kei; Kurihara, Hiroyoshi; Kanno, Shinichi; Yamamoto, Itaru; Ishigami, Keisuke; Igarashi, Hisayoshi; Maruyama, Reo; Imai, Kohzoh; Yamamoto, Hiroyuki; Shinomura, Yasuhisa

    2016-01-01

    The human intestinal microbiome plays a major role in human health and diseases, including colorectal cancer. Colorectal carcinogenesis represents a heterogeneous process with a differing set of somatic molecular alterations, influenced by diet, environmental and microbial exposures, and host immunity. Fusobacterium species are part of the human oral and intestinal microbiota. Metagenomic analyses have shown an enrichment of Fusobacterium nucleatum (F. nucleatum) in colorectal carcinoma tissue. Using 511 colorectal carcinomas from Japanese patients, we assessed the presence of F. nucleatum. Our results showed that the frequency of F. nucleatum positivity in the Japanese colorectal cancer was 8.6% (44/511), which was lower than that in United States cohort studies (13%). Similar to the United States studies, F. nucleatum positivity in Japanese colorectal cancers was significantly associated with microsatellite instability (MSI)-high status. Regarding the immune response in colorectal cancer, high levels of infiltrating T-cell subsets (i.e., CD3+, CD8+, CD45RO+, and FOXP3+ cells) have been associated with better patient prognosis. There is also evidence to indicate that molecular features of colorectal cancer, especially MSI, influence T-cell-mediated adaptive immunity. Concerning the association between the gut microbiome and immunity, F. nucleatum has been shown to expand myeloid-derived immune cells, which inhibit T-cell proliferation and induce T-cell apoptosis in colorectal cancer. This finding indicates that F. nucleatum possesses immunosuppressive activities by inhibiting human T-cell responses. Certain microRNAs are induced during the macrophage inflammatory response and have the ability to regulate host-cell responses to pathogens. MicroRNA-21 increases the levels of IL-10 and prostaglandin E2, which suppress antitumor T-cell-mediated adaptive immunity through the inhibition of the antigen-presenting capacities of dendritic cells and T-cell proliferation in

  14. Molecular alterations in partially-encapsulated or well-circumscribed follicular variant of papillary thyroid carcinoma.

    PubMed

    Howitt, Brooke E; Jia, Yonghui; Sholl, Lynette M; Barletta, Justine A

    2013-10-01

    Studies have described an encapsulated and an infiltrative form of the follicular variant of papillary thyroid carcinoma (FVPTC). Encapsulated FVPTCs have been reported to have virtually no recurrence risk or metastatic potential and to harbor RAS mutations but not BRAF mutations. In contrast, infiltrative tumors have significant metastatic potential, a risk of recurrence, and a BRAF mutation frequency of approximately 25%. In our experience, a substantial number of FVPTCs are neither fully encapsulated nor infiltrative, but instead are partially encapsulated (PE) or well circumscribed (WC). We have previously reported that PE/WC FVPTCs behave in an indolent fashion similar to encapsulated tumors. The purpose of the current study was to evaluate the molecular alterations in PE/WC FVPTC. We identified 28 PE/WC FVPTCs resected consecutively at our institution. Targeted mutation analysis of 41 genes including members of the RAS and RAF families was performed on DNA extracted from formalin-fixed, paraffin-embedded blocks using single-base extension chemistry and mass spectrometry. Lymph node metastases were absent in all cases with sampled lymph nodes, and no patients developed tumor recurrences (median follow-up time, 72.8 months). Overall, 13 cases (46%) harbored RAS mutations, including seven (25%) with NRAS mutations (p.Gln61Arg) and six (21%) with HRAS mutations (five had p.Gln61Arg and one had a p.Gln61Lys substitution). No PE/WC FVPTCs had BRAF mutations. The results of this study confirm our previous finding that PE/WC FVPTCs pursue an indolent clinical course. Additionally, we found that PE/WC tumors have a similar molecular profile to that of encapsulated FVPTCs with frequent RAS mutations (46%) and no BRAF mutations. These molecular results provide further evidence that PE/WC and encapsulated FVPTCs are biologically similar and should be distinguished from more aggressive infiltrative FVPTCs.

  15. Method and Apparatus Providing Deception and/or Altered Operation in an Information System Operating System

    DOEpatents

    Cohen, Fred; Rogers, Deanna T.; Neagoe, Vicentiu

    2008-10-14

    A method and/or system and/or apparatus providing deception and/or execution alteration in an information system. In specific embodiments, deceptions and/or protections are provided by intercepting and/or modifying operation of one or more system calls of an operating system.

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

    PubMed

    Do, Hainam; Troisi, Alessandro

    2015-10-14

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

  17. MOLECULAR BONDING SYSTEM - INNOVATIVE TECHNOLOGY EVALUATION REPORT

    EPA Science Inventory

    This document presents an evaluation of the Molecular Bonding System (MBS) and its ability to chemically stabilize three metals-contaminated wstes/soils during a SITe demo. The MBS process treated approximately 500 tons each of soil/Fill, Slag, and Miscellaneous Smelter Waste wit...

  18. MOLECULAR BONDING SYSTEM - INNOVATIVE TECHNOLOGY EVALUATION REPORT

    EPA Science Inventory

    This document presents an evaluation of the Molecular Bonding System (MBS) and its ability to chemically stabilize three metals-contaminated wstes/soils during a SITe demo. The MBS process treated approximately 500 tons each of soil/Fill, Slag, and Miscellaneous Smelter Waste wit...

  19. Molecular-beam gas-sampling system

    NASA Technical Reports Server (NTRS)

    Young, W. S.; Knuth, E. L.

    1972-01-01

    A molecular beam mass spectrometer system for rocket motor combustion chamber sampling is described. The history of the sampling system is reviewed. The problems associated with rocket motor combustion chamber sampling are reported. Several design equations are presented. The results of the experiments include the effects of cooling water flow rates, the optimum separation gap between the end plate and sampling nozzle, and preliminary data on compositions in a rocket motor combustion chamber.

  20. Characterization of high-molecular-weight glutenin subunits from Eremopyrum bonaepartis and identification of a novel variant with unusual high molecular weight and altered cysteine residues.

    PubMed

    Jiang, Qian-Tao; Zhang, Xiao-Wei; Ma, Jian; Wei, Long; Zhao, Shan; Zhao, Quan-Zhi; Qi, Peng-Fei; Lu, Zhen-Xiang; Zheng, You-Liang; Wei, Yu-Ming

    2014-04-01

    We characterized two high-molecular-weight glutenin subunit (HMW-GS) variants from Eremopyrum bonaepartis, determined their complete open reading frames, and further expressed them in a bacterial system. The variants have many novel structural features compared with typical subunits encoded by Glu-1 loci: 1Fx3.7 and 1Fy1.5 exhibit hybrid properties of x- and y-type subunits. In addition, unusual molecular mass and altered number and distribution of cysteine residues were unique features of HMW-GSs encoded by Glu-F1 from E. bonaepartis. The mature 1Fx3.7 subunit has a full length of 1,223 amino acid residues, making it the largest subunit found thus far, while 1Fy1.5 is just 496 residues. In addition, the mutated PGQQ repeat motif was found in the repetitive region of 1Fx3.7. Although it has a similar molecular mass to that previously reported for 1Dx2.2, 1Dx2.2* and 1S(sh)x2.9 subunits, 1Fx3.7 appears to have had a different evolutionary history. The N-terminal and repetitive regions have a total of four additional cysteine residues, giving 1Fx3.7 a total of eight cysteines, while 1Fy1.5 has only six cysteines because the GHCPTSPQQ nonapeptide at the end of the repetitive region is deleted. With its extra cysteine residues and the longest repetitive region, features that are relevant to good wheat quality, the 1Fx3.7 subunit gene could be an excellent candidate for applications in wheat quality improvement.

  1. Physiological and molecular alterations in plants exposed to high [CO2] under phosphorus stress.

    PubMed

    Pandey, Renu; Zinta, Gaurav; AbdElgawad, Hamada; Ahmad, Altaf; Jain, Vanita; Janssens, Ivan A

    2015-01-01

    Atmospheric [CO2] has increased substantially in recent decades and will continue to do so, whereas the availability of phosphorus (P) is limited and unlikely to increase in the future. P is a non-renewable resource, and it is essential to every form of life. P is a key plant nutrient controlling the responsiveness of photosynthesis to [CO2]. Increases in [CO2] typically results in increased biomass through stimulation of net photosynthesis, and hence enhance the demand for P uptake. However, most soils contain low concentrations of available P. Therefore, low P is one of the major growth-limiting factors for plants in many agricultural and natural ecosystems. The adaptive responses of plants to [CO2] and P availability encompass alterations at morphological, physiological, biochemical and molecular levels. In general low P reduces growth, whereas high [CO2] enhances it particularly in C3 plants. Photosynthetic capacity is often enhanced under high [CO2] with sufficient P supply through modulation of enzyme activities involved in carbon fixation such as ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). However, high [CO2] with low P availability results in enhanced dry matter partitioning towards roots. Alterations in below-ground processes including root morphology, exudation and mycorrhizal association are influenced by [CO2] and P availability. Under high P availability, elevated [CO2] improves the uptake of P from soil. In contrast, under low P availability, high [CO2] mainly improves the efficiency with which plants produce biomass per unit P. At molecular level, the spatio-temporal regulation of genes involved in plant adaptation to low P and high [CO2] has been studied individually in various plant species. Genome-wide expression profiling of high [CO2] grown plants revealed hormonal regulation of biomass accumulation through complex transcriptional networks. Similarly, differential transcriptional regulatory networks are involved in P

  2. THE SYMPATHETIC NERVOUS SYSTEM ALTERATIONS IN HUMAN HYPERTENSION

    PubMed Central

    Grassi, Guido; Mark, Allyn; Esler, Murray

    2015-01-01

    A number of articles have dealt with the importance and mechanisms of the sympathetic nervous system alterations in experimental animal models of hypertension. This review addresses the role of the sympathetic nervous system in the pathophysiology and therapy of human hypertension. We first discuss the strengths and limitations of various techniques for assessing the sympathetic nervous system in humans, with a focus on heart rate, plasma norepinephrine, microneurographic recording of sympathetic nerve traffic, and measurements of radiolabeled norepinephrine spillover. We then examine the evidence supporting the importance of neuroadrenergic factors as “promoters” and “amplifiers” of human hypertension. We expand on the role of the sympathetic nervous system in two increasingly common forms of secondary hypertension, namely hypertension associated with obesity and with renal disease. With this background, we examine interventions of sympathetic deactivation as a mode of antihypertensive treatment. Particular emphasis is given to the background and results of recent therapeutic approaches based on carotid baroreceptor stimulation and radiofrequency ablation of the renal nerves. PMID:25767284

  3. Relaxation time in disordered molecular systems

    SciTech Connect

    Rocha, Rodrigo P.; Freire, José A.

    2015-05-28

    Relaxation time is the typical time it takes for a closed physical system to attain thermal equilibrium. The equilibrium is brought about by the action of a thermal reservoir inducing changes in the system micro-states. The relaxation time is intuitively expected to increase with system disorder. We derive a simple analytical expression for this dependence in the context of electronic equilibration in an amorphous molecular system model. We find that the disorder dramatically enhances the relaxation time but does not affect its independence of the nature of the initial state.

  4. Distinct molecular alterations in complex endometrial hyperplasia (CEH) with and without immature squamous metaplasia (squamous morules).

    PubMed

    Brachtel, Elena F; Sánchez-Estevez, Carolina; Moreno-Bueno, Gema; Prat, Jaime; Palacios, José; Oliva, Esther

    2005-10-01

    Several molecular alterations, most commonly PTEN mutations but also K-ras mutations, microsatellite instability, and beta-catenin mutations have been detected in endometrioid endometrial carcinoma (EEC). Specifically, mutations in the beta-catenin gene are seen in 15% to 20% of EECs, whereas immunohistochemical expression of beta-catenin ranges from 13% to 44%, nuclear staining being concentrated in areas of immature squamous metaplasia (squamous morules). Complex endometrial hyperplasia with atypia (CEH-A) is a well-known precursor of EEC, which can also show immature squamous metaplasia. In this study, we compared the immunohistochemical and molecular profiles of 13 CEH-A with and 11 CEH-A without squamous morules (SM) for mutations of beta-catenin, PTEN, K-ras, and microsatellite instability (MSI). In all cases of CEH-A with SM, beta-catenin immunostaining showed strong and diffuse nuclear expression in areas of SM and weak to moderate nuclear expression in the glandular component. Six different beta-catenin mutations were found in 7 of 13 cases (54%) (G34E, G34V, S33C, D32Y, S33F, D32A); however, no mutations of the PTEN or K-ras genes were identified. beta-Catenin immunostaining showed focal nuclear staining in only 2 cases of CEH-A without SM. Only 1 case had a beta-catenin mutation (S45A), which was associated with a K-ras mutation (G12D). Another 3 cases had both PTEN and K-ras mutations (C296Stop Ex 8 and G12V, 244del C Ex 7 and G12D, 251ins TGAT Ex 7 and G13D), and one had a PTEN mutation (G230E Ex 7) only. Of all 24 cases, only 1 case of CEH-A without SM showed MSI. In conclusion, marked differences in the molecular profiles regarding beta-catenin, PTEN, and K-ras mutations were observed between CEH-A with and without SM. beta-catenin mutations might represent a signaling pathway leading to a distinctive morphology in hyperplastic/neoplastic endometrium with SM. Other molecular events such as K-ras or PTEN mutations are likely to occur in CEH

  5. Method of molecular specie alteration by nonresonant laser induced dielectric breakdown

    DOEpatents

    Ronn, Avigdor M.

    1980-01-01

    Irradiation of a molecular specie by itself or in the presence of a secondary material at a pressure above a threshold value for the particular system by a laser of predetermined minimum power and having a frequency displaced from an absorption line of the specie causes severance of the weakest bond and a yield of products containing at least one dissociative fragment from said specie. A Rogowski type TEA CO.sub.2 --N.sub.2 --He laser has been used successfully on a wide variety of molecular species. Solid, liquid and gaseous end products have been obtained depending upon the starting materials. When solids have been produced they are in the form of microfine particles or microfine aggregates. A neodymium glass laser has also been used successfully.

  6. Simplified system to investigate alteration of retinal neurons in diabetes.

    PubMed

    Dong, Shuqian; Liu, Yan; Zhu, Meili; Xu, Xueliang; Le, Yun-Zheng

    2014-01-01

    Diabetic retinopathy (DR) is traditionally considered as a microvascular complication in diabetic retinas. Emerging evidences suggest that the alteration of neuronal function and the death of retinal neurons are part of DR pathology. However, surprisingly little is known about how retinal neurons behave in DR. As diabetic animals are chronicle models that are difficult and expensive to maintain, we used a chemical hypoxia model that mimics the later stage of diabetes and investigated its potential in predicting retinal cell behaviors in diabetes in an efficient manner. In this chapter, we discuss the similarities and differences between diabetic and hypoxic models and the usefulness and limitation of the cobalt-chloride-generated hypoxia system in mice for studying retinal neurobiology in diabetes.

  7. Prematurely aged children: molecular alterations leading to Hutchinson-Gilford progeria and Werner syndromes.

    PubMed

    Domínguez-Gerpe, Lourdes; Araújo-Vilar, David

    2008-12-01

    Ageing is thought to be a polygenic and stochastic process in which multiple mechanisms operate at the same time. At the level of the individual organism ageing is associated with a progressive deterioration of health and quality of life, sharing common features such as: alopecia and grey hair, loss of audition, macular degeneration, neurodegeneration, cardiovascular diseases, osteoporosis, cataract formation, type-2 diabetes, lipodystrophies; a generally increased susceptibility to infection, autoimmune disorders and diseases such as cancer; and an impaired ability to cope with stress. Recent studies of mechanisms involved in the ageing process are contributing to the identification of genes involved in longevity. Monogenic heritable disorders causing premature ageing, and animal models have contributed to the understanding of some of the characteristic organism-level features associated with human ageing. Werner syndrome and Hutchinson-Gilford progeria syndrome are the best characterized human disorders. Werner syndrome patients have a median life expectancy of 47 years with clinical conditions from the second decade of life. Hutchinson-Gilford progeria syndrome patients die at a median age of 11-13 years with clinical conditions appearing soon after birth. In both syndromes, alterations in specific genes have been identified, with mutations in the WRN and LMNA genes respectively being the most closely associated with each syndrome. Results from molecular studies strongly suggest an increase in DNA damage and cell senescence as the underlying mechanism of pathological premature ageing in these two human syndromes. The same general mechanism has also been observed in human cells undergoing the normal ageing process. In the present article the molecular mechanisms currently proposed for explaining these two syndromes, which may also partly explain the normal ageing process, are reviewed.

  8. The immune system which adversely alter thyroid functions: a review on the concept of autoimmunity.

    PubMed

    Mansourian, Azad Reza

    2010-08-15

    The immune system protect individual from many pathogens exists within our environment and in human body, by destroying them through molecular and cellular mechanism of B and T cells of immune system. Autoimmunity is an adverse relation of immune system against non- foreign substances leaving behind either alters the normal function or destroying the tissue involved. Autoimmunity occur in genetically predispose persons with familial connections. The autoimmunity to the thyroid gland mainly consists of Hashimato thyroiditis and Grave's disease, the two end of spectrum in thyroid function of hypo and hyperactivity, respectively. The thyroid stimulating hormone receptor, thyroglobuline, enzymes of thyroid hormones synthesis are targeted by autoantibodies and cell- mediated reactions. The aim of this review is to explore the studies reported on the autoimmunity to the thyroid gland.

  9. Internal density functional theory of molecular systems

    NASA Astrophysics Data System (ADS)

    Nalewajski, Roman F.

    1984-08-01

    A thermodynamiclike theory of internal equilibrium and constrained equilibrium states of individual molecular systems is formulated, based on the Legendre transformed density functional theory (LT DFT). The molecular system (nonrelativistic, field free, Born-Oppenheimer or non-Born-Oppenheimer) is treated as the closed composite thermodynamic system, consisting of very small, rigid (open) subsystems (simple systems) containing a multi-(m)-component charged fluid in the presence of an external field. The generalized Levy constrained search construction of various ``thermodynamic'' potentials of LT DFT is given and the local Maxwell relations are derived. The reduction of various second-order partial functional derivatives (system sensitivities) in terms of few independent, basic kernels is described, using the Jacobian determinants technique. The qualitative implications for the basic kernels of the theory, from the Maxwell relations and stability criteria (generalized Le Châtelier and Le Châtelier-Braun principles) are systematically examined. Finally, possible applications of the general formalism in the thermodynamic analysis of the chemical bond, molecular stability, and chemical reactivity are identified.

  10. Molecular Clouds in the Magellanic System

    NASA Astrophysics Data System (ADS)

    Chin, Y.

    Temperature, density, metallicity, and radiation field are important parameters that characterize the physical and chemical state of molecular clouds. In order to understand physics and chemistry, it is therefore necessary to observe and analyse molecular clouds in a variety of ennvironments and to combine observational data with results from model calculations. Observationally, it is possible to vary the first two parameters (temperature and density) within our Milky Way by observing clouds in different locations. The metallicity, however, does not change drastically in the plane of the Milky Way. As two of the closest galaxies, the Magellanic Clouds provide metallicities which are factors of 3 and 10 lower (Westerlund 1991). If we treat our Galaxy as a "chemically" evolved system, the Magellanic System are without doubt still in an early stage of "chemical" evolution, with elemental abundances that may resemble those that characterize larger galaxies at high redshifts. In addition, the radiation field is stronger than in the solar neighborhood. As a consequence of low metallicities and strong UV radiation field, the Magellanic Clouds are characterized by low dust-to-gas mass ratios. They are thus a "laboratory" where we can study molecular clouds with exotic boundary conditions and it is easy to foresee that detailed observations will have a great impact on our general knowledge of astrochemistry and astrophysice of interstellar clouds. To date, it is possible to carry out a detailed molecular study of Magellanic Cloud cores located at distances of 50 - 60 kpc. Two prominent molecular clouds -- one in the LMC and one in the SMC -- have been observed. Preliminary results are presented. On the other hand, searches for a variety of molecules in the LMC & SMC have been made (e.g. Johansson et al. 1994; Chin et al. 1997, 1998) so far mostly towards molecular cores associated with prominent HII regions. This does not cover, however, the entire range of physical and

  11. Long-Term Oil Contamination Alters the Molecular Ecological Networks of Soil Microbial Functional Genes

    PubMed Central

    Liang, Yuting; Zhao, Huihui; Deng, Ye; Zhou, Jizhong; Li, Guanghe; Sun, Bo

    2016-01-01

    With knowledge on microbial composition and diversity, investigation of within-community interactions is a further step to elucidate microbial ecological functions, such as the biodegradation of hazardous contaminants. In this work, microbial functional molecular ecological networks were studied in both contaminated and uncontaminated soils to determine the possible influences of oil contamination on microbial interactions and potential functions. Soil samples were obtained from an oil-exploring site located in South China, and the microbial functional genes were analyzed with GeoChip, a high-throughput functional microarray. By building random networks based on null model, we demonstrated that overall network structures and properties were significantly different between contaminated and uncontaminated soils (P < 0.001). Network connectivity, module numbers, and modularity were all reduced with contamination. Moreover, the topological roles of the genes (module hub and connectors) were altered with oil contamination. Subnetworks of genes involved in alkane and polycyclic aromatic hydrocarbon degradation were also constructed. Negative co-occurrence patterns prevailed among functional genes, thereby indicating probable competition relationships. The potential “keystone” genes, defined as either “hubs” or genes with highest connectivities in the network, were further identified. The network constructed in this study predicted the potential effects of anthropogenic contamination on microbial community co-occurrence interactions. PMID:26870020

  12. Conflicting selection alters the trajectory of molecular evolution in a tripartite bacteria-plasmid-phage interaction.

    PubMed

    Harrison, Ellie; Hall, James J P; Paterson, Steve; Spiers, Andrew J; Brockhurst, Michael A

    2017-03-01

    Bacteria engage in a complex network of ecological interactions, which includes mobile genetic elements (MGEs) such as phages and plasmids. These elements play a key role in microbial communities as vectors of horizontal gene transfer but can also be important sources of selection for their bacterial hosts. In natural communities bacteria are likely to encounter multiple MGEs simultaneously and conflicting selection among MGEs could alter the bacterial evolutionary response to each MGE. Here we test the effect of interactions with multiple MGEs on bacterial molecular evolution in the tripartite interaction between the bacterium, Pseudomonas fluorescens, the lytic bacteriophage SBW25φ2 and conjugative plasmid, pQBR103, using genome sequencing of experimentally evolved bacteria. We show that, individually, both plasmids and phages impose selection leading to bacterial evolutionary responses that are distinct from bacterial populations evolving without MGEs, but that together, plasmids and phages impose conflicting selection on bacteria, constraining the evolutionary responses observed in pairwise interactions. Our findings highlight the likely difficulties of predicting evolutionary responses to multiple selective pressures from the observed evolutionary responses to each selective pressure alone. Understanding evolution in complex microbial communities comprising many species and MGEs will require that we go beyond studies of pairwise interactions. This article is protected by copyright. All rights reserved.

  13. Acute systemic rapamycin induces neurobehavioral alterations in rats.

    PubMed

    Hadamitzky, Martin; Herring, Arne; Keyvani, Kathy; Doenlen, Raphael; Krügel, Ute; Bösche, Katharina; Orlowski, Kathrin; Engler, Harald; Schedlowski, Manfred

    2014-10-15

    Rapamycin is a drug with antiproliferative and immunosuppressive properties, widely used for prevention of acute graft rejection and cancer therapy. It specifically inhibits the activity of the mammalian target of rapamycin (mTOR), a protein kinase known to play an important role in cell growth, proliferation and antibody production. Clinical observations show that patients undergoing therapy with immunosuppressive drugs frequently suffer from affective disorders such as anxiety or depression. However, whether these symptoms are attributed to the action of the distinct compounds remains rather elusive. The present study investigated in rats neurobehavioral consequences of acute rapamycin treatment. Systemic administration of a single low dose rapamycin (3mg/kg) led to enhanced neuronal activity in the amygdala analyzed by intracerebral electroencephalography and FOS protein expression 90min after drug injection. Moreover, behavioral investigations revealed a rapamycin-induced increase in anxiety-related behaviors in the elevated plus-maze and in the open-field. The behavioral alterations correlated to enhanced amygdaloid expression of KLK8 and FKBP51, proteins that have been implicated in the development of anxiety and depression. Together, these results demonstrate that acute blockade of mTOR signaling by acute rapamycin administration not only causes changes in neuronal activity, but also leads to elevated protein expression in protein kinase pathways others than mTOR, contributing to the development of anxiety-like behavior. Given the pivotal role of the amygdala in mood regulation, associative learning, and modulation of cognitive functions, our findings raise the question whether therapy with rapamycin may induce alterations in patients neuropsychological functioning.

  14. Ultrasonographic depiction of knee joint alterations in systemic lupus erythematosus.

    PubMed

    Ossandon, A; Iagnocco, A; Alessandri, C; Priori, R; Conti, F; Valesini, G

    2009-01-01

    The aim of this study was to assess inflammatory changes within the knee joint of systemic lupus erythematosus (SLE) patients by using ultrasound (US). Rheumatoid arthritis (RA) patients and healthy subjects (HS) were evaluated as controls. US findings were correlated with disease activity parameters. Twenty-six SLE patients were enrolled in the study, 25 RA patients and 15 HS were selected as controls. US was performed by two different experienced operators, using an Agilent-HP Image point Hx machine equipped with a 10 MHz linear transducer. Power Doppler (PD) was used to determine local synovial perfusion (PFR 700-1100 Hz; gain 60-65dB; low filter). Knee joints were examined bilaterally. US findings, expressed after consensus of the 2 operators, were correlated to clinical and serological parameters of disease activity. Statistical analysis was performed by the EPISTAT program. In SLE, synovitis was found in 21 knees (40%), joint effusion in 12 (23%), synovial proliferation in 12 (23%), positive PD signal in 5 (10%) and gastrocnemius-semimembranosus bursitis in 5 (10%). No erosions were detected. There was a significant difference respect to RA for synovitis (p<0.003), synovial proliferation (p<0.002) and positive PD signal (p<0.01). No correlation was found between US alterations and SLE disease activity parameters. In the HS group 1 patient showed mild synovial proliferation. This is the first study that investigates knee joint involvement in SLE by ultrasonography. US was able to depict inflammatory alterations in the articular tissues of SLE patients, revealing some common characteristics with RA, except for the presence of erosions. We believe that US might be of help in the global evaluation of SLE patients with inflammatory joint involvement, providing relevant information to the clinician.

  15. Computational Hemodynamic Simulation of Human Circulatory System under Altered Gravity

    NASA Technical Reports Server (NTRS)

    Kim. Chang Sung; Kiris, Cetin; Kwak, Dochan

    2003-01-01

    A computational hemodynamics approach is presented to simulate the blood flow through the human circulatory system under altered gravity conditions. Numerical techniques relevant to hemodynamics issues are introduced to non-Newtonian modeling for flow characteristics governed by red blood cells, distensible wall motion due to the heart pulse, and capillary bed modeling for outflow boundary conditions. Gravitational body force terms are added to the Navier-Stokes equations to study the effects of gravity on internal flows. Six-type gravity benchmark problems are originally presented to provide the fundamental understanding of gravitational effects on the human circulatory system. For code validation, computed results are compared with steady and unsteady experimental data for non-Newtonian flows in a carotid bifurcation model and a curved circular tube, respectively. This computational approach is then applied to the blood circulation in the human brain as a target problem. A three-dimensional, idealized Circle of Willis configuration is developed with minor arteries truncated based on anatomical data. Demonstrated is not only the mechanism of the collateral circulation but also the effects of gravity on the distensible wall motion and resultant flow patterns.

  16. The Systemic Cytokine Environment Is Permanently Altered in Multiple Myeloma

    PubMed Central

    Bemis, Kyle; Belch, Andrew R.; Pilarski, Linda M.; Shively, John E.; Kirshner, Julia

    2013-01-01

    Multiple myeloma (MM) is an incurable bone marrow malignancy of the B cell lineage. Utilizing multiplex Luminex technology we measured levels of 25 cytokines in the plasma of normal donors (n = 177), those with monoclonal gammopathy of undetermined significance (n = 8), and MM patients (n = 55) with either active disease, on treatment, or in remission. The cytokine levels were compared between normal donors and MM patients as well as between various phases of MM, and discriminant analysis was used to create a predictive classification model based on the differentially expressed cytokines. Evaluating age- and gender-dependence of cytokine expression, we determined that with age there is a shift toward a pro-inflammatory environment. Moreover, we observed a strong gender bias in cytokine expression. However, the profile of differentially expressed cytokines was heavily skewed toward an anti-inflammatory, pro-tumorigenic response in patients with MM. Significantly, our predictive model placed all patients in remission in the same category as those with active disease. Thus, our study demonstrates that the homeostasis of systemic cytokines is not restored when MM patients enter remission, suggesting that once an individual has cancer, the microenvironment is permanently altered and the system is primed for a relapse. PMID:23544044

  17. Maternal bisphenol A alters fetal endocrine system: Thyroid adipokine dysfunction.

    PubMed

    Ahmed, R G

    2016-09-01

    Because bisphenol A (BPA) has been detected in animals, the aim of this study was to investigate the possible effects of maternal BPA exposure on the fetal endocrine system (thyroid-adipokine axis). BPA (20 or 40 μg/kg body weight) was orally administered to pregnant rats from gestation day (GD) 1-20. In both treated groups, the dams and their fetuses had lower serum thyroxine (T4) and triiodothyronine (T3) levels, and higher thyrotropin (TSH) level than control dams and fetuses at GD 20. Some histopathological changes in fetal thyroid glands were observed in both maternal BPA groups at embryonic day (ED) 20, including fibroblast proliferation, hyperplasia, luminal obliteration, oedema, and degeneration. These disorders resulted in the suppression of fetal serum growth hormone (GH), insulin growth factor-1 (IGF1) and adiponectin (ADP) levels, and the elevation of fetal serum leptin, insulin and tumor necrosis factor-alpha (TNFα) levels in both treated groups with respect to control. The depraved effects of both treated groups were associated with reduced maternal and fetal body weight compared to the control group. These alterations were dose dependent. Thus, BPA might penetrate the placental barrier and perturb the fetal thyroid adipokine axis to influence fat metabolism and the endocrine system. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Altered signaling in systemic juvenile idiopathic arthritis monocytes

    PubMed Central

    Macaubas, Claudia; Wong, Elizabeth; Zhang, Yujuan; Nguyen, Khoa D.; Lee, Justin; Milojevic, Diana; Shenoi, Susan; Stevens, Anne M.; Ilowite, Norman; Saper, Vivian; Lee, Tzielan; Mellins, Elizabeth D.

    2016-01-01

    Systemic juvenile idiopathic arthritis (sJIA) is characterized by systemic inflammation and arthritis. Monocytes are implicated in sJIA pathogenesis, but their role in disease is unclear. The response of sJIA monocytes to IFN may be dysregulated. We examined intracellular signaling in response to IFN type I (IFNα) and type II (IFNγ) in monocytes during sJIA activity and quiescence, in 2 patient groups. Independent of disease activity, monocytes from Group 1 (collected between 2002-2009) showed defective STAT1 phosphorylation downstream of IFNs, and expressed higher transcript levels of SOCS1, an inhibitor of IFN signaling. In the Group 2 (collected between 2011-2014), monocytes of patients with recent disease onset were IFNγ hyporesponsive, but in treated, quiescent subjects, monocytes were hyperresponsive to IFNγ. Recent changes in medication in sJIA may alter the IFN hyporesponsiveness. Impaired IFN/pSTAT1 signaling is consistent with skewing of sJIA monocytes away from an M1 phenotype and may contribute to disease pathology. PMID:26747737

  19. 32 CFR Appendix B to Part 323 - Criteria for New and Altered Record Systems

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... alterations. b. Increases in numbers of individuals due to normal growth are not considered alterations unless... scope of population covered (for example, expansion of a system of records covering a single PLFA's...

  20. 32 CFR Appendix B to Part 323 - Criteria for New and Altered Record Systems

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... alterations. b. Increases in numbers of individuals due to normal growth are not considered alterations unless... scope of population covered (for example, expansion of a system of records covering a single PLFA's...

  1. The impact of systemic cortical alterations on perception

    NASA Astrophysics Data System (ADS)

    Zhang, Zheng

    2011-12-01

    Perception is the process of transmitting and interpreting sensory information, and the primary somatosensory (SI) area in the human cortex is the main sensory receptive area for the sensation of touch. The elaborate neuroanatomical connectivity that subserves the neuronal communication between adjacent and near-adjacent regions within sensory cortex has been widely recognized to be essential to normal sensory function. As a result, systemic cortical alterations that impact the cortical regional interaction, as associated with many neurological disorders, are expected to have significant impact on sensory perception. Recently, our research group has developed a novel sensory diagnostic system that employs quantitative sensory testing methods and is able to non-invasively assess central nervous system healthy status. The intent of this study is to utilize quantitative sensory testing methods that were designed to generate discriminable perception to objectively and quantitatively assess the impacts of different conditions on human sensory information processing capacity. The correlation between human perceptions with observations from animal research enables a better understanding of the underlying neurophysiology of human perception. Additional findings on different subject populations provide valuable insight of the underlying mechanisms for the development and maintenance of different neurological diseases. During the course of the study, several protocols were designed and utilized. And this set of sensory-based perceptual metrics was employed to study the effects of different conditions (non-noxious thermal stimulation, chronic pain stage, and normal aging) on sensory perception. It was found that these conditions result in significant deviations of the subjects' tactile information processing capacities from normal values. Although the observed shift of sensory detection sensitivity could be a result of enhanced peripheral activity, the changes in the effects

  2. Intelligent systems for the molecular biologist

    SciTech Connect

    Brutlag, D.L.

    1995-12-31

    This tutorial was one of eight tutorials selected to be presented at the Third International Conference on Intelligent Systems for Molecular Biology which was held in the United Kingdom from July 16 to 19, 1995. In this paper, one objective is to identify properties of DNA sequences that determine their function, by computer-aided statistical analysis and to accurately predict its function, given a new sequence. A related problem is to predict protein structure and function from the sequence.

  3. Optical antenna for photofunctional molecular systems.

    PubMed

    Ikeda, Katsuyoshi; Uosaki, Kohei

    2012-02-06

    Optical antennas can enhance the efficiency of photon-molecule interactions. To design efficient antenna structures, it is essential to consider physicochemical aspects in addition to electromagnetic considerations. Specifically, chemical interactions between optical antennas and molecules have to be controlled to enhance the overall efficiency. For this purpose, sphere-plane nanostructures are suitable optical antennas for molecular-modified functional electrode systems when a well-defined electrode is utilized as a platform.

  4. Molecular Basis of Altered hERG1 Channel Gating Induced by Ginsenoside Rg3.

    PubMed

    Gardner, Alison; Wu, Wei; Thomson, Steven; Zangerl-Plessl, Eva-Maria; Stary-Weinzinger, Anna; Sanguinetti, Michael C

    2017-10-01

    Outward current conducted by human ether-à-go-go-related gene type 1 (hERG1) channels is a major determinant of action potential repolarization in the human ventricle. Ginsenoside 20(S)-Rg3 [Rg3; (2S,3R,4S,5S,6R)-2-[(2R,3R,4S,5S,6R)-4,5-dihydroxy-2-[[(3S,5R,8R,9R,10R,12R,13R,14R,17S)-12-hydroxy-17-[(2S)-2-hydroxy-6-methylhept-5-en-2-yl]-4,4,8,10,14-pentamethyl-2,3,5,6,7,9,11,12,13,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]-6-(hydroxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol], an alkaloid isolated from the root of Panax ginseng, slows the rate of hERG1 deactivation, induces channels to open at more negative potentials than normal, and increases current magnitude. The onset of Rg3 action is extremely fast, suggesting that it binds to an extracellular accessible site on the channel to alter its gating. Here we used a scanning mutagenesis approach to identify residues in the extracellular loops and transmembrane segments of hERG1 that might interact with Rg3. Single or multiple residues of hERG1 were mutated to Ala or Cys and the resulting mutant channels were heterologously expressed in Xenopus oocytes. The effects of Rg3 on the voltage dependence of activation and the deactivation rate of mutant channel currents were characterized using the two-microelectrode voltage clamp technique. Mutation to Ala of specific residues in the S1 (Tyr420), S2 (Leu452, Phe463), and S4 (Ile521, Lys525) segments partially inhibited the effects of Rg3 on hERG1. The double mutant Y420A/L452A nearly eliminated the effects of Rg3 on voltage-dependent channel gating but did not prevent the increase in current magnitude. These findings together with molecular modeling suggest that Rg3 alters the gating of hERG1 channels by interacting with and stabilizing the voltage sensor domain in an activated state. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  5. Synchrotron-based and globar-sourced molecular (micro)spectroscopy contributions to advances in new hulless barley (with structure alteration) research on molecular structure, molecular nutrition, and nutrient delivery.

    PubMed

    Yang, Ling; Yu, Peiqiang

    2017-01-02

    This paper aimed to review synchrotron-based and globar-sourced molecular infrared (micro)spectroscopy contributions to advances in new hulless barley (with structure alteration) research on molecular structure, molecular nutrition, and nutrient delivery in ruminants. It reviewed recent progress in barley varieties, its utilization for animal and human, inherent structure features and chemical make-up, evaluation and research methodology, breeding progress, rumen degradation, and intestinal digestion. The emphasis of this review was focused on the effect of alteration of carbohydrate traits of newly developed hulless barley on molecular structure changes and nutrient delivery and quantification of the relationship between molecular structure features and changes and truly absorbed nutrient supply to ruminants. This review provides an insight into how inherent structure changes on a molecular basis affect nutrient utilization and availability in ruminants.

  6. Accurate methods for large molecular systems.

    PubMed

    Gordon, Mark S; Mullin, Jonathan M; Pruitt, Spencer R; Roskop, Luke B; Slipchenko, Lyudmila V; Boatz, Jerry A

    2009-07-23

    Three exciting new methods that address the accurate prediction of processes and properties of large molecular systems are discussed. The systematic fragmentation method (SFM) and the fragment molecular orbital (FMO) method both decompose a large molecular system (e.g., protein, liquid, zeolite) into small subunits (fragments) in very different ways that are designed to both retain the high accuracy of the chosen quantum mechanical level of theory while greatly reducing the demands on computational time and resources. Each of these methods is inherently scalable and is therefore eminently capable of taking advantage of massively parallel computer hardware while retaining the accuracy of the corresponding electronic structure method from which it is derived. The effective fragment potential (EFP) method is a sophisticated approach for the prediction of nonbonded and intermolecular interactions. Therefore, the EFP method provides a way to further reduce the computational effort while retaining accuracy by treating the far-field interactions in place of the full electronic structure method. The performance of the methods is demonstrated using applications to several systems, including benzene dimer, small organic species, pieces of the alpha helix, water, and ionic liquids.

  7. Laboratory Information Systems in Molecular Diagnostics: Why Molecular Diagnostics Data are Different.

    PubMed

    Lee, Roy E; Henricks, Walter H; Sirintrapun, Sahussapont J

    2016-03-01

    Molecular diagnostic testing presents new challenges to information management that are yet to be sufficiently addressed by currently available information systems for the molecular laboratory. These challenges relate to unique aspects of molecular genetic testing: molecular test ordering, informed consent issues, diverse specimen types that encompass the full breadth of specimens handled by traditional anatomic and clinical pathology information systems, data structures and data elements specific to molecular testing, varied testing workflows and protocols, diverse instrument outputs, unique needs and requirements of molecular test reporting, and nuances related to the dissemination of molecular pathology test reports. By satisfactorily addressing these needs in molecular test data management, a laboratory information system designed for the unique needs of molecular diagnostics presents a compelling reason to migrate away from the current paper and spreadsheet information management that many molecular laboratories currently use. This paper reviews the issues and challenges of information management in the molecular diagnostics laboratory.

  8. The sensitivity of an immature vestibular system to altered gravity.

    PubMed

    Gabriel, Martin; Frippiat, Jean-Pol; Frey, Herbert; Horn, Eberhard R

    2012-07-01

    Stimulus deprivation or stimulus augmentation can induce long-lasting modifications to sensory and motor systems. If deprivation is effective only during a limited period of life this phase is called "critical period." A critical period was described for the development of the roll-induced vestibuloocular reflex (rVOR) of Xenopus laevis using spaceflights. Spaceflight durations and basic conditions of Xenopus' development did not make it possible to answer the question whether exposure of the immature vestibular organ to weightlessness affects rVOR development. The embryonic development of Pleurodeles waltl is slow enough to solve this problem because the rVOR cannot be induced before 15 dpf. Stage 20-21 embryos (4 dpf) were exposed to microgravity during a 10-day spaceflight, or to 3g hypergravity following the same time schedule. After termination of altered gravity, the rVOR was recorded twice in most animals. The main observations were as follows: (1) after the first rVOR appearance at stage 37 (16 dpf), both rVOR gain and amplitude increased steadily up to saturation levels of 0.22 and 20°, respectively. (2) Three days after termination of microgravity, flight and ground larvae showed no rVOR; 1 day later, the rVOR could be induced only in ground larvae. Differences disappeared after 3 weeks. (3) For 10 days after 3g exposure, rVOR development was similar to that of 1g-controls but 3 weeks later, 3g-larvae showed a larger rVOR than 1g-controls. These observations indicate that the immature vestibular system is transiently sensitive to microgravity exposure and that exposure of the immature vestibular system to hypergravity leads to a slowly growing vestibular sensitization.

  9. Modulation by metformin of molecular and histopathological alterations in the lung of cigarette smoke-exposed mice

    PubMed Central

    Izzotti, Alberto; Balansky, Roumen; D'Agostini, Francesco; Longobardi, Mariagrazia; Cartiglia, Cristina; Micale, Rosanna T; La Maestra, Sebastiano; Camoirano, Anna; Ganchev, Gancho; Iltcheva, Marietta; Steele, Vernon E; De Flora, Silvio

    2014-01-01

    The anti-diabetic drug metformin is endowed with anti-cancer properties. Epidemiological and experimental studies, however, did not provide univocal results regarding its role in pulmonary carcinogenesis. We used Swiss H mice of both genders in order to detect early molecular alterations and tumors induced by mainstream cigarette smoke. Based on a subchronic toxicity study, oral metformin was used at a dose of 800 mg/kg diet, which is 3.2 times higher than the therapeutic dose in humans. Exposure of mice to smoke for 4 months, starting at birth, induced a systemic clastogenic damage, formation of DNA adducts, oxidative DNA damage, and extensive downregulation of microRNAs in lung after 10 weeks. Preneoplastic lesions were detectable after 7.5 months in both lung and urinary tract along with lung tumors, both benign and malignant. Modulation by metformin of 42 of 1281 pulmonary microRNAs in smoke-free mice highlighted a variety of mechanisms, including modulation of AMPK, stress response, inflammation, NFκB, Tlr9, Tgf, p53, cell cycle, apoptosis, antioxidant pathways, Ras, Myc, Dicer, angiogenesis, stem cell recruitment, and angiogenesis. In smoke-exposed mice, metformin considerably decreased DNA adduct levels and oxidative DNA damage, and normalized the expression of several microRNAs. It did not prevent smoke-induced lung tumors but inhibited preneoplastic lesions in both lung and kidney. In conclusion, metformin was able to protect the mouse lung from smoke-induced DNA and microRNA alterations and to inhibit preneoplastic lesions in lung and kidney but failed to prevent lung adenomas and malignant tumors induced by this complex mixture. PMID:24683044

  10. The Effectiveness of Natural Diarylheptanoids against Trypanosoma cruzi: Cytotoxicity, Ultrastructural Alterations and Molecular Modeling Studies.

    PubMed

    Sueth-Santiago, Vitor; Moraes, Julliane de B B; Sobral Alves, Eliomara Sousa; Vannier-Santos, Marcos André; Freire-de-Lima, Célio G; Castro, Rosane N; Mendes-Silva, Gustavo Peron; Del Cistia, Catarina de Nigris; Magalhães, Luma Godoy; Andricopulo, Adriano Defini; Sant Anna, Carlos Mauricio R; Decoté-Ricardo, Debora; Freire de Lima, Marco Edilson

    Curcumin (CUR) is the major constituent of the rhizomes of Curcuma longa and has been widely investigated for its chemotherapeutic properties. The well-known activity of CUR against Leishmania sp., Trypanosoma brucei and Plasmodium falciparum led us to investigate its activity against Trypanosoma cruzi. In this work, we tested the cytotoxic effects of CUR and other natural curcuminoids on different forms of T. cruzi, as well as the ultrastructural changes induced in epimastigote form of the parasite. CUR was verified as the curcuminoid with more significant trypanocidal properties (IC50 10.13 μM on epimastigotes). Demethoxycurcumin (DMC) was equipotent to CUR (IC50 11.07 μM), but bisdemethoxycurcumin (BDMC) was less active (IC50 45.33 μM) and cyclocurcumin (CC) was inactive. In the experiment with infected murine peritoneal macrophages all diarylheptanoids were more active than the control in the inhibition of the trypomastigotes release. The electron microscopy images showed ultrastructural changes associated with the cytoskeleton of the parasite, indicating tubulin as possible target of CUR in T. cruzi. The results obtained by flow cytometry analysis of DNA content of the parasites treated with natural curcuminoids suggested a mechanism of action on microtubules related to the paclitaxel`s mode of action. To better understand the mechanism of action highlighted by electron microscopy and flow cytometry experiments we performed the molecular docking of natural curcuminoids on tubulin of T. cruzi in a homology model and the results obtained showed that the observed interactions are in accordance with the IC50 values found, since there CUR and DMC perform similar interactions at the binding site on tubulin while BDMC do not realize a hydrogen bond with Lys163 residue due to the absence of methoxyl groups. These results indicate that trypanocidal properties of CUR may be related to the cytoskeletal alterations.

  11. The Effectiveness of Natural Diarylheptanoids against Trypanosoma cruzi: Cytotoxicity, Ultrastructural Alterations and Molecular Modeling Studies

    PubMed Central

    Sueth-Santiago, Vitor; Moraes, Julliane de B. B.; Sobral Alves, Eliomara Sousa; Vannier-Santos, Marcos André; Freire-de-Lima, Célio G.; Castro, Rosane N.; Mendes-Silva, Gustavo Peron; Del Cistia, Catarina de Nigris; Magalhães, Luma Godoy; Andricopulo, Adriano Defini; Sant´Anna, Carlos Mauricio R.; Decoté-Ricardo, Debora; Freire de Lima, Marco Edilson

    2016-01-01

    Curcumin (CUR) is the major constituent of the rhizomes of Curcuma longa and has been widely investigated for its chemotherapeutic properties. The well-known activity of CUR against Leishmania sp., Trypanosoma brucei and Plasmodium falciparum led us to investigate its activity against Trypanosoma cruzi. In this work, we tested the cytotoxic effects of CUR and other natural curcuminoids on different forms of T. cruzi, as well as the ultrastructural changes induced in epimastigote form of the parasite. CUR was verified as the curcuminoid with more significant trypanocidal properties (IC50 10.13 μM on epimastigotes). Demethoxycurcumin (DMC) was equipotent to CUR (IC50 11.07 μM), but bisdemethoxycurcumin (BDMC) was less active (IC50 45.33 μM) and cyclocurcumin (CC) was inactive. In the experiment with infected murine peritoneal macrophages all diarylheptanoids were more active than the control in the inhibition of the trypomastigotes release. The electron microscopy images showed ultrastructural changes associated with the cytoskeleton of the parasite, indicating tubulin as possible target of CUR in T. cruzi. The results obtained by flow cytometry analysis of DNA content of the parasites treated with natural curcuminoids suggested a mechanism of action on microtubules related to the paclitaxel`s mode of action. To better understand the mechanism of action highlighted by electron microscopy and flow cytometry experiments we performed the molecular docking of natural curcuminoids on tubulin of T. cruzi in a homology model and the results obtained showed that the observed interactions are in accordance with the IC50 values found, since there CUR and DMC perform similar interactions at the binding site on tubulin while BDMC do not realize a hydrogen bond with Lys163 residue due to the absence of methoxyl groups. These results indicate that trypanocidal properties of CUR may be related to the cytoskeletal alterations. PMID:27658305

  12. Articular Joint Lubricants during Osteoarthritis and Rheumatoid Arthritis Display Altered Levels and Molecular Species

    PubMed Central

    Liebisch, Gerhard; Zhang, Ruiyan; Siebert, Hans-Christian; Wilhelm, Jochen; Kaesser, Ulrich; Dettmeyer, Reinhard B.; Klein, Heiko; Ishaque, Bernd; Rickert, Markus; Schmitz, Gerd; Schmidt, Tannin A.; Steinmeyer, Juergen

    2015-01-01

    Background Hyaluronic acid (HA), lubricin, and phospholipid species (PLs) contribute independently or together to the boundary lubrication of articular joints that is provided by synovial fluid (SF). Our study is the first reporting quantitative data about the molecular weight (MW) forms of HA, lubricin, and PLs in SF from cohorts of healthy donors, patients with early (eOA)- or late (lOA)-stage osteoarthritis (OA), and patients with active rheumatoid arthritis (RA). Methods We used human SF from unaffected controls, eOA, lOA, and RA. HA and lubricin levels were measured by enzyme-linked immunosorbent assay. PLs was quantified by electrospray ionization tandem mass spectrometry. Fatty acids (FAs) were analyzed by gas chromatography, coupled with mass spectrometry. The MW distribution of HA was determined by agarose gel electrophoresis. Results Compared with control SF, the concentrations of HA and lubricin were lower in OA and RA SF, whereas those of PLs were higher in OA and RA SF. Moreover, the MW distribution of HA shifted toward the lower ranges in OA and RA SF. We noted distinct alterations between cohorts in the relative distribution of PLs and the degree of FA saturation and chain lengths of FAs. Conclusions The levels, composition, and MW distribution of all currently known lubricants in SF—HA, lubricin, PLs—vary with joint disease and stage of OA. Our study is the first delivering a comprehensive view about all joint lubricants during health and widespread joint diseases. Thus, we provide the framework to develop new optimal compounded lubricants to reduce joint destruction. PMID:25933137

  13. Molecular and Spectroscopic Characterization of Water Extractable Organic Matter from Thermally Altered Soils Reveal Insight into Disinfection Byproduct Precursors.

    PubMed

    Cawley, Kaelin M; Hohner, Amanda K; Podgorski, David C; Cooper, William T; Korak, Julie A; Rosario-Ortiz, Fernando L

    2017-01-17

    To characterize the effects of thermal-alteration on water extractable organic matter (WEOM), soil samples were heated in a laboratory at 225, 350, and 500 °C. Next, heated and unheated soils were leached, filtered, and analyzed for dissolved organic carbon (DOC) concentration, optical properties, molecular size distribution, molecular composition, and disinfection byproduct (DBP) formation following the addition of chlorine. The soils heated to 225 °C leached the greatest DOC and had the highest C- and N-DBP precursor reactivity per unit carbon compared to the unheated material or soils heated to 350 or 500 °C. The molecular weight of the soluble compounds decreased with increasing heating temperature. Compared to the unheated soil leachates, all DBP yields were higher for the leachates of soils heated to 225 °C. However, only haloacetonitrile yields (μg/mgC) were higher for leachates of the soils heated to 350 °C, whereas trihalomethane, haloacetic acid and chloropicrin yields were lower compared to unheated soil leachates. Soluble N-containing compounds comprised a high number of molecular formulas for leachates of heated soils, which may explain the higher yield of haloacetonitriles for heated soil leachates. Overall, heating soils altered the quantity, quality, and reactivity of the WEOM pool. These results may be useful for inferring how thermal alteration of soil by wildfire can affect water quality.

  14. High concordance of molecular tumor alterations between pre-operative curettage and hysterectomy specimens in patients with endometrial carcinoma.

    PubMed

    Stelloo, Ellen; Nout, Remi A; Naves, Lisanne C L M; Ter Haar, Natalja T; Creutzberg, Carien L; Smit, Vincent T H B M; Bosse, Tjalling

    2014-05-01

    Molecular alterations in endometrial cancer have been shown to be prognostically significant but have not yet been implemented in the current clinical risk assessment. Few studies have investigated the reliability of molecular alterations in pre-operative specimens. Therefore, the objective was to determine whether molecular analysis of pre-operative endometrial cancer samples accurately reflects those alterations in the subsequent hysterectomy specimens. Paired pre-operative and hysterectomy specimens of 48 patients diagnosed with endometrial carcinoma, 42 endometrioid (EEC) and 6 non-endometrioid (NEEC) carcinomas, were analyzed for immunohistochemical expression of p53, PTEN and β-catenin. Tumor DNA was isolated and analyzed for microsatellite instability (MSI), TP53 mutations and somatic hot spot mutations in 13 genes. In EEC patients, loss of PTEN, nuclear β-catenin and p53-mutant expression was found in 43%, 7% and 12%, respectively. No nuclear β-catenin was found in 5 of 6 NEEC patients, all serous cancers, whereas a p53-mutant expression was present in all serous cases. MSI was found in 19.5%, all EEC. Concordance for PTEN, β-catenin, p53 expression and MSI status was found in 79%, 92%, 79% and 93.5%, respectively. We detected 65 hot spot mutations in 39/48 (81%) tumors. Overall concordance of the GynCarta multigene analysis was 99.8%. The results confirm the reliability of immunohistochemical and DNA-based techniques in the evaluation of molecular alterations in pre-operative endometrial specimens and high concordance rates with the definitive hysterectomy specimens. The resulting molecular signature provides initial pre-operative diagnostic information on the status of oncogenic pathways, which may contribute to individualized treatment strategies. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Accounting for intra-molecular vibrational modes in open quantum system description of molecular systems.

    PubMed

    Roden, Jan; Strunz, Walter T; Whaley, K Birgitta; Eisfeld, Alexander

    2012-11-28

    Electronic-vibrational dynamics in molecular systems that interact with an environment involve a large number of degrees of freedom and are therefore often described by means of open quantum system approaches. A popular approach is to include only the electronic degrees of freedom into the system part and to couple these to a non-Markovian bath of harmonic vibrational modes that is characterized by a spectral density. Since this bath represents both intra-molecular and external vibrations, it is important to understand how to construct a spectral density that accounts for intra-molecular vibrational modes that couple further to other modes. Here, we address this problem by explicitly incorporating an intra-molecular vibrational mode together with the electronic degrees of freedom into the system part and using the Fano theory for a resonance coupled to a continuum to derive an "effective" bath spectral density, which describes the contribution of intra-molecular modes. We compare this effective model for the intra-molecular mode with the method of pseudomodes, a widely used approach in simulation of non-Markovian dynamics. We clarify the difference between these two approaches and demonstrate that the respective resulting dynamics and optical spectra can be very different.

  16. Race-specific molecular alterations correlate with differential outcomes for black and white endometrioid endometrial cancer patients.

    PubMed

    Bateman, Nicholas W; Dubil, Elizabeth A; Wang, Guisong; Hood, Brian L; Oliver, Julie M; Litzi, Tracy A; Gist, Glenn D; Mitchell, David A; Blanton, Brian; Phippen, Neil T; Tian, Chunqiao; Zahn, Christopher M; Cohn, David E; Havrilesky, Laura J; Berchuck, Andrew; Shriver, Craig D; Darcy, Kathleen M; Hamilton, Chad A; Conrads, Thomas P; Maxwell, G Larry

    2017-06-27

    The objective of this study was to identify molecular alterations associated with disease outcomes for white and black patients with endometrioid endometrial cancer (EEC). EEC samples from black (n = 17) and white patients (n = 13) were analyzed by proteomics (liquid chromatography-tandem mass spectrometry) and transcriptomics (RNA-seq). Coordinate alterations were validated with RNA-seq data from black (n = 49) and white patients (n = 216). Concordantly altered candidates were further tested for associations with race-specific progression-free survival (PFS) in black (n = 64) or white patients (n = 267) via univariate and multivariate Cox regression modeling and log-rank testing. Discovery analyses revealed significantly altered candidate proteins and transcripts between black and white patients, suggesting modulation of tumor cell viability in black patients and cell death signaling in black and white patients. Eighty-nine candidates were validated as altered between these patient cohorts, and a subset significantly correlated with differential PFS. White-specific PFS candidates included serpin family A member 4 (SERPINA4; hazard ratio [HR], 0.89; Wald P value = .02), integrin subunit α3 (ITGA3; HR, 0.76; P = .03), and Bet1 Golgi vesicular membrane trafficking protein like (BET1L; HR, 0.48; P = .04). Black-specific PFS candidates included family with sequence similarity 228 member B (FAM228B; HR, 0.13; P = .001) and HEAT repeat containing 6 (HEATR6; HR, 4.94; P = .047). Several candidates were also associated with overall survival (SERPINA4 and ITGA3) as well as PFS independent of disease stage, grade and myometrial invasion (SERPINA4, BET1L and FAM228B). This study has identified and validated molecular alterations in tumors from black and white EEC patients, including candidates significantly associated with altered disease outcomes within these patient cohorts. Cancer 2017. © 2017 American Cancer Society. © 2017 American Cancer Society.

  17. Altered Systemic Adipokines in Patients with Chronic Urticaria.

    PubMed

    Trinh, Hoang Kim Tu; Pham, Duy Le; Ban, Ga-Young; Lee, Hyun-Young; Park, Hae-Sim; Ye, Young-Min

    2016-01-01

    Increasing evidence suggests that adipokines affect immune responses and chronic urticaria (CU) is associated with an altered immune response related to chronic systemic inflammation. Our objectives were to investigate whether adipokines are involved in CU pathogenesis and to outline relationships between adipokines and urticaria severity and quality of life. Serum adiponectin, leptin, lipocalin-2 (LCN2), interleukin (IL)-10, IL-6, and tumor necrosis factor (TNF)-α concentrations were measured by enzyme-linked immunosorbent assays in 191 CU patients and 89 healthy controls. The effect of LCN2 on N-formyl-methionine-leucine-phenylalanine (fMLP)-induced neutrophil chemotaxis was assessed using migration assays. CU severity was assessed based on the urticaria activity score (UAS). To explore relationships between adipokines and UAS and the chronic urticaria-specific quality of life (CU-QoL) questionnaire, a structural equation model was used. Mean levels of serum LCN2, TNF-α, IL-6, and IL-10 were significantly higher in CU patients than in controls. Adiponectin levels were significantly lower in patients with CU than in controls. While serum IL-6 levels were significantly higher in refractory CU patients, compared to responsive CU individuals, LCN2 levels were significantly lower. LCN2 inhibited fMLP-induced neutrophil migration. LCN2 showed a direct relationship with UAS (β = -0.274, p < 0.001), and UAS was found to contribute to CU-QoL (β = 0.417, p < 0.001). Our results highlighted an imbalance in pro- and anti-inflammatory adipokines in CU patients. We suggest that LCN2 could be a differential marker for disease activity and the clinical responses to antihistamine treatment in CU patients. Modulation of systemic inflammation may be a therapeutic strategy for treating severe, refractory CU. © 2016 S. Karger AG, Basel.

  18. Phonon Overlaps in Molecular Quantum Dot Systems

    NASA Astrophysics Data System (ADS)

    Chang, Connie; Sethna, James

    2004-03-01

    We model the amplitudes and frequencies of the vibrational sidebands for the new molecular quantum dot systems. We calculate the Franck-Condon phonon overlaps in the 3N-dimensional configuration sapce. We solve the general case where the vibrational frequencies and eigenmodes change during the transition. We perform PM3 and DFT calculations for the case of the dumb bell-shaped C140 molecule. We find that the strongest amplitudes are associated with the 11 meV stretch mode, in agreement with experiment. The experimental amplitudes vary from molecule to molecule; indicating that the molecular overlaps are environment dependent. We explore overlaps in the presence of external electric fields from image charges and counter ions.

  19. Structural and functional alteration of blood vessels caused by cigarette smoking: an overview of molecular mechanisms.

    PubMed

    Rahman, Mohammad M; Laher, Ismail

    2007-10-01

    Smoking is a significant independent risk factor for cardiovascular disease and is a leading cause of structural and functional alterations of the cardiovascular system. Most clinical and experimental investigations of the pathophysiology of cigarette smoking have studied the effects of smoke as a whole, while a few studies focused on specific components of cigarette smoke, e.g. nicotine and carbon monoxide, which are only 2 of the more than 4,000 different chemicals present in cigarette smoke. The findings point to some discrepancies when the effects of whole smoke are compared to nicotine alone, while there is almost uniform agreement that both active and passive smoking have detrimental effects on the cardiovascular system, although a milder effect was suggested for the latter. This review focuses on findings from clinical and experimental studies on the vascular effects of active and passive cigarette smoking and nicotine exposure. The findings are discussed in terms of tissue (conduit vs. resistance arteries and veins), species, age, gender and dosage. Although the exact pathophysiology of cigarette smoking has not been unveiled, cigarette smoking causes injury to the vascular endothelium, produces superoxide anions, reduces production and bioavailability of nitric oxide (NO), increases production and release of endothelin, causes endothelial dysfunction, thrombosis, atherosclerosis, infarction, coronary artery disease (CAD), stroke and death.

  20. Molecular ecology of anaerobic reactor systems.

    PubMed

    Hofman-Bang, J; Zheng, D; Westermann, P; Ahring, B K; Raskin, L

    2003-01-01

    Anaerobic reactor systems are essential for the treatment of solid and liquid wastes and constitute a core facility in many waste treatment plants. Although much is known about the basic metabolism in different types of anaerobic reactors, little is known about the microbes responsible for these processes. Only a few percent of Bacteria and Archaea have so far been isolated, and almost nothing is known about the dynamics and interactions between these and other microorganisms. This lack of knowledge is most clearly exemplified by the sometimes unpredictable and unexplainable failures and malfunctions of anaerobic digesters occasionally experienced, leading to sub-optimal methane production and wastewater treatment. Using a variety of molecular techniques, we are able to determine which microorganisms are active, where they are active, and when they are active, but we still need to determine why and what they are doing. As genetic manipulations of anaerobes have been shown in only a few species permitting in-situ gene expression studies, the only way to elucidate the function of different microbes is to correlate the metabolic capabilities of isolated microbes in pure culture to the abundance of each microbe in anaerobic reactor systems by rRNA probing. This chapter focuses on various molecular techniques employed and problems encountered when elucidating the microbial ecology of anaerobic reactor systems. Methods such as quantitative dot blot/fluorescence in-situ probing using various specific nucleic acid probes are discussed and exemplified by studies of anaerobic granular sludge, biofilm and digester systems.

  1. Time-resolved optical imaging provides a molecular snapshot of altered metabolic function in living human cancer cell models

    NASA Astrophysics Data System (ADS)

    Sud, Dhruv; Zhong, Wei; Beer, David G.; Mycek, Mary-Ann

    2006-05-01

    A fluorescence lifetime imaging microscopy (FLIM) method was developed and applied to investigate metabolic function in living human normal esophageal (HET-1) and Barrett’s adenocarcinoma (SEG-1) cells. In FLIM, image contrast is based on fluorophore excited state lifetimes, which reflect local biochemistry and molecular activity. Unique FLIM system attributes, including variable ultrafast time gating (≥ 200 ps), wide spectral tunability (337.1 - 960 nm), large temporal dynamic range (≥ 600 ps), and short data acquisition and processing times (15 s), enabled the study of two key molecules consumed at the termini of the oxidative phosphorylation pathway, NADH and oxygen, in living cells under controlled and calibrated environmental conditions. NADH is an endogenous cellular fluorophore detectable in living human tissues that has been shown to be a quantitative biomarker of dysplasia in the esophagus. Lifetime calibration of an oxygen-sensitive, ruthenium-based cellular stain enabled in vivo oxygen level measurements with a resolution of 8 μM over the entire physiological range (1 - 300 μM). Starkly higher intracellular oxygen and NADH levels in living SEG-1 vs. HET-1 cells were detected by FLIM and attributed to altered metabolic pathways in malignant cells.

  2. Can Molecular Hippocampal Alterations Explain Behavioral Differences in Prenatally Stressed Rats?

    EPA Science Inventory

    Studies in both humans and animals have shown that prenatal stress can alter cognitive function and other neurological behaviors in adult offspring. One possible underlying mechanism for this may lie with alterations in hippocampal gene expression. The present study examined geno...

  3. The Optical Bichromatic Force in Molecular Systems

    NASA Astrophysics Data System (ADS)

    Aldridge, Leland M.; Galica, Scott E.; Eyler, Edward E.

    2015-06-01

    The bichromatic optical force (BCF), which can greatly exceed radiative forces, seems ideal for laser slowing and cooling of molecules because it minimizes the effects of radiative decay. However, it relies on sustained coherences between optically coupled states, and molecules, with their many sublevels and decay pathways, present new challenges in maintaining these coherences compared with simple atoms. We have conducted extensive numerical simulations of BCFs in model molecular systems based on the B leftrightarrow X transition in CaF, and have begun experimental tests in a molecular beam. In our modeling, the effects of fine and hyperfine structure are examined using a simplified level scheme that is still sufficiently complete to include the major pathways leading to loss or decoherence. To circumvent optical pumping into coherent dark states we explore two possible schemes: (1) a skewed dc magnetic field, and (2) rapid optical polarization switching. The effects of repumping to compensate for out-of-system radiative decay are also examined. Our results verify that the BCF is a promising method for creating large forces in molecular beams while minimizing out-of-system radiative losses, and provide detailed guidance for experimental designs. Compared to a two-level atom, the peak force is reduced by about an order of magnitude, but there is little reduction in the velocity range over which the force is effective. Our experiments on deflection and slowing using the CaF B leftrightarrow X, (0-0) transition, still at an early stage, include studies of both the P11(1.5)/^PQ12(0.5) branch, a quasi-cycling configuration with extensive hfs, and the R11(0.5)/^RQ21(0.5) branch, which has a much simpler hfs but requires rotational repumping. Supported by the National Science Foundation

  4. Molecular Imaging System for Monitoring Tumor Angiogenesis

    NASA Astrophysics Data System (ADS)

    Aytac, Esra; Burcin Unlu, Mehmet

    2012-02-01

    In cancer, non-invasive imaging techniques that monitor molecular processes associated with the tumor angiogenesis could have a central role in the evaluation of novel antiangiogenic and proangiogenic therapies as well as early detection of the disease. Matrix metalloproteinases (MMP) can serve as specific biological targets for imaging of angiogenesis since expression of MMPs is required for angiogenesis and has been found to be upregulated in every type of human cancer and correlates with stage, invasive, metastatic properties and poor prognosis. However, for most cancers it is still unknown when, where and how MMPs are involved in the tumor angiogenesis [1]. Development of high-resolution, high sensitivity imaging techniques in parallel with the tumor models could prove invaluable for assessing the physical location and the time frame of MMP enzymatic acitivity. The goal of this study is to understand where, when and how MMPs are involved in the tumor angiogenesis. We will accomplish this goal by following two objectives: to develop a high sensitivity, high resolution molecular imaging system, to develop a virtual tumor simulator that can predict the physical location and the time frame of the MMP activity. In order to achieve our objectives, we will first develop a PAM system and develop a mathematical tumor model in which the quantitative data obtained from the PAM can be integrated. So, this work will develop a virtual tumor simulator and a molecular imaging system for monitoring tumor angiogenesis. 1.Kessenbrock, K., V. Plaks, and Z. Werb, MMP:regulators of the tumor microenvironment. Cell, 2010. 141(1)

  5. Microelectromechanical systems integrating molecular spin crossover actuators

    NASA Astrophysics Data System (ADS)

    Manrique-Juarez, Maria D.; Rat, Sylvain; Mathieu, Fabrice; Saya, Daisuke; Séguy, Isabelle; Leïchlé, Thierry; Nicu, Liviu; Salmon, Lionel; Molnár, Gábor; Bousseksou, Azzedine

    2016-08-01

    Silicon MEMS cantilevers coated with a 200 nm thin layer of the molecular spin crossover complex [Fe(H2B(pz)2)2(phen)] (H2B(pz)2 = dihydrobis(pyrazolyl)borate and phen = 1,10-phenantroline) were actuated using an external magnetic field and their resonance frequency was tracked by means of integrated piezoresistive detection. The light-induced spin-state switching of the molecules from the ground low spin to the metastable high spin state at 10 K led to a well-reproducible shift of the cantilever's resonance frequency (Δfr = -0.52 Hz). Control experiments at different temperatures using coated as well as uncoated devices along with simple calculations support the assignment of this effect to the spin transition. This latter translates into changes in mechanical behavior of the cantilever due to the strong spin-state/lattice coupling. A guideline for the optimization of device parameters is proposed so as to efficiently harness molecular scale movements for large-scale mechanical work, thus paving the road for nanoelectromechanical systems (NEMS) actuators based on molecular materials.

  6. Molecular Marker Systems for Oenothera Genetics

    PubMed Central

    Rauwolf, Uwe; Golczyk, Hieronim; Meurer, Jörg; Herrmann, Reinhold G.; Greiner, Stephan

    2008-01-01

    The genus Oenothera has an outstanding scientific tradition. It has been a model for studying aspects of chromosome evolution and speciation, including the impact of plastid nuclear co-evolution. A large collection of strains analyzed during a century of experimental work and unique genetic possibilities allow the exchange of genetically definable plastids, individual or multiple chromosomes, and/or entire haploid genomes (Renner complexes) between species. However, molecular genetic approaches for the genus are largely lacking. In this study, we describe the development of efficient PCR-based marker systems for both the nuclear genome and the plastome. They allow distinguishing individual chromosomes, Renner complexes, plastomes, and subplastomes. We demonstrate their application by monitoring interspecific exchanges of genomes, chromosome pairs, and/or plastids during crossing programs, e.g., to produce plastome–genome incompatible hybrids. Using an appropriate partial permanent translocation heterozygous hybrid, linkage group 7 of the molecular map could be assigned to chromosome 9·8 of the classical Oenothera map. Finally, we provide the first direct molecular evidence that homologous recombination and free segregation of chromosomes in permanent translocation heterozygous strains is suppressed. PMID:18791241

  7. Microelectromechanical systems integrating molecular spin crossover actuators

    SciTech Connect

    Manrique-Juarez, Maria D.; Rat, Sylvain; Salmon, Lionel; Molnár, Gábor; Bousseksou, Azzedine E-mail: azzedine.bousseksou@lcc-toulouse.fr; Mathieu, Fabrice; Saya, Daisuke; Séguy, Isabelle; Leïchlé, Thierry; Nicu, Liviu E-mail: azzedine.bousseksou@lcc-toulouse.fr

    2016-08-08

    Silicon MEMS cantilevers coated with a 200 nm thin layer of the molecular spin crossover complex [Fe(H{sub 2}B(pz){sub 2}){sub 2}(phen)] (H{sub 2}B(pz){sub 2} = dihydrobis(pyrazolyl)borate and phen = 1,10-phenantroline) were actuated using an external magnetic field and their resonance frequency was tracked by means of integrated piezoresistive detection. The light-induced spin-state switching of the molecules from the ground low spin to the metastable high spin state at 10 K led to a well-reproducible shift of the cantilever's resonance frequency (Δf{sub r} = −0.52 Hz). Control experiments at different temperatures using coated as well as uncoated devices along with simple calculations support the assignment of this effect to the spin transition. This latter translates into changes in mechanical behavior of the cantilever due to the strong spin-state/lattice coupling. A guideline for the optimization of device parameters is proposed so as to efficiently harness molecular scale movements for large-scale mechanical work, thus paving the road for nanoelectromechanical systems (NEMS) actuators based on molecular materials.

  8. TP53 alterations in pancreatic acinar cell carcinoma: new insights into the molecular pathology of this rare cancer.

    PubMed

    La Rosa, Stefano; Bernasconi, Barbara; Frattini, Milo; Tibiletti, Maria Grazia; Molinari, Francesca; Furlan, Daniela; Sahnane, Nora; Vanoli, Alessandro; Albarello, Luca; Zhang, Lizhi; Notohara, Kenji; Casnedi, Selenia; Chenard, Marie-Pierre; Adsay, Volkan; Asioli, Sofia; Capella, Carlo; Sessa, Fausto

    2016-03-01

    The molecular alterations of pancreatic acinar cell carcinomas (ACCs) are poorly understood and have been reported as being different from those in ductal adenocarcinomas. Loss of TP53 gene function in the pathogenesis of ACCs is controversial since contradictory findings have been published. A comprehensive analysis of the different possible genetic and epigenetic mechanisms leading to TP53 alteration in ACC has never been reported and hence the role of TP53 in the pathogenesis and/or progression of ACC remains unclear. We investigated TP53 alterations in 54 tumor samples from 44 patients, including primary and metastatic ACC, using sequencing analysis, methylation-specific multiplex ligation probe amplification, fluorescence in situ hybridization, and immunohistochemistry. TP53 mutations were found in 13 % of primary ACCs and in 31 % of metastases. Primary ACCs and metastases showed the same mutational profile, with the exception of one case, characterized by a wild-type sequence in the primary carcinoma and a mutation in the corresponding metastasis. FISH analysis revealed deletion of the TP53 region in 53 % of primary ACCs and in 50 % of metastases. Promoter hypermethylation was found in one case. The molecular alterations correlated well with the immunohistochemical findings. A statistically significant association was found between the combination of mutation of one allele and loss of the other allele of TP53 and worse survival.

  9. Molecular interactions alter clay and polymer structure in polymer clay nanocomposites.

    PubMed

    Sikdar, Debashis; Katti, Kalpana S; Katti, Dinesh R

    2008-04-01

    In this work, using photoacoustic Fourier transform infrared spectroscopy (FTIR) we have studied the structural distortion of clay crystal structure in organically modified montmorillonite (OMMT) and polymer clay nanocomposites (PCN). To study the effect of organic modifiers on the distortion of crystal structure of clay, we have synthesized OMMTs and PCNs containing same polymer and clay but with three different organic modifiers (12-aminolauric acid, n-dodecylamine, and 1,12-diaminododecane), and conducted the FTIR study on these PCNs. Our previous molecular dynamics (MD) study on these PCNs reveals that significant nonbonded interactions (van der Waals, electrostatic interactions) exist between the different constituents (polymer, organic modifier, and clay) of nanocomposites. Previous work based on X-ray diffraction (XRD) and differential scanning calorimetry (DSC) on the same set of PCNs shows that crystallinity of polymer in PCNs have changed significantly in comparison to those in pristine polymer; and, the nonbonded interactions between different constituents of PCN are responsible for the change in crystal structure of polymer in PCN. In this work to evaluate the structural distortion of crystal structure of clay in OMMTs and PCNs, the positions of bands corresponding to different modes of vibration of Si-O bonds are determined from the deconvolution of broad Si-O bands in OMMTs and PCNs obtained from FTIR spectra. Intensity and area under the Si-O bands are indicative of orientation of clay crystal structures in OMMTs and PCNs. Significant changes in the Si-O bands are observed from each vibration mode in OMMTs and PCNs containing three different organic modifiers indicating that organic modifiers influence the structural orientation of silica tetrahedra in OMMTs and PCNs. Deconvolution of Si-O bands in OMMTs indicate a band at approximately 1200 cm(-1) that is orientation-dependent Si-O band. The specific changes in intensity and area under this band for

  10. 78 FR 63211 - Privacy Act of 1974; Report of an Altered CMS System of Records Notice

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-23

    ... HUMAN SERVICES Centers for Medicare & Medicaid Services Privacy Act of 1974; Report of an Altered CMS... requirements of the Privacy Act of 1974 (5 U.S.C. 552a), CMS proposes several alterations to the existing... of Records in the System'', ``Authority for Maintenance of the System'', ``System...

  11. Systems Pharmacology in Small Molecular Drug Discovery

    PubMed Central

    Zhou, Wei; Wang, Yonghua; Lu, Aiping; Zhang, Ge

    2016-01-01

    Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity), target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level. PMID:26901192

  12. Systems Pharmacology in Small Molecular Drug Discovery.

    PubMed

    Zhou, Wei; Wang, Yonghua; Lu, Aiping; Zhang, Ge

    2016-02-18

    Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity), target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level.

  13. Energy transformation in molecular electronic systems

    SciTech Connect

    Kasha, M.

    1985-07-25

    Our new optical pumping spectroscopy (steady state, and double-laser pulse) allows the production and study of the unstable rare tautomer in its ground and excited states, including picosecond dynamic studies. Molecules under study here included 7-azaindole (model for biological purines), 3-hydroxyflavone (model for plant flavones), lumichrome, and other heterocyclics. New detailed molecular mechanisms for proton transfer are derived, especially with catalytic assisting molecules. A new proton-transfer laser of extraordinary efficiency has become a side dividend, possibly worth of industrial development. The excited and highly reactive singlet molecular oxygen species /sup 1/..delta../sub g/) has proven to be ubiquitous in chemical peroxide systems and in physically excited sensitizer-oxygen systems. Hyperbaric oxygen mechanisms in biology probably involve singlet oxygen. We have undertaken a spectroscopic study of tris - dibenzoylmethane chelates of Al, Gd, Eu, and Yb trivalent ions. These chelates offer a variety of electronic behaviors, from Z-effects on ..pi..-electron spin-orbital coupling (Al, Gd) to Weissman intramolecular energy transfer to 4f mestable levels (Eu, Gd). Elegant new spectroscopic resolution at 77K permits separation of tautomeric, parasitic self-absorption, dissociation, and cage effects to be resolved. 18 refs., 4 figs.

  14. Energy transformation in molecular electronic systems

    NASA Astrophysics Data System (ADS)

    Kasha, M.

    1985-07-01

    Our new optical pumping spectroscopy allows the production and study of the unstable rate tautomer in its ground and excited states, including picosecond dynamic studies. Molecules under study here included 7-azaindole 3-hydroxyflavone, lumichrome, and other heterocyclics. New detailed molecular mechanisms for proton transfer are derived, especially with catalytic assisting molecules. A new proton-transfer laser of extraordinary efficiency has become a side dividend, possibly worthy of industrial development. The excited and highly reactive singlet molecular oxygen species (1) DELTA sub g has proven to be ubiquitous in chemical peroxide systems and in physically excited sensitizer-oxygen systems. Hyperbaric oxygen mechanisms in biology probably involve singlet oxygen. We have undertaken a spectroscopic study of trisdibenzoylmethane chelates of Al, Gd, Eu, and Yb trivalent ions. These chelates offer a variety of electronic behaviors, from Z-effects on (PI)--electron spin-orbital coupling (Al, Gd) to Weissman intramolecular energy transfer to 4f mestable levels (Eu, Gd). Elegant new spectroscopic resolution at 77K permits separation of tautomeric, parasitic self-absorption, dissociation, and cage effects to be resolved.

  15. 44 CFR 6.72 - Effective date of new system of records or alteration of an existing system of records.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 44 Emergency Management and Assistance 1 2014-10-01 2014-10-01 false Effective date of new system of records or alteration of an existing system of records. 6.72 Section 6.72 Emergency Management and... PRIVACY ACT OF 1974 Report on New Systems and Alterations of Existing Systems § 6.72 Effective date of new...

  16. 44 CFR 6.72 - Effective date of new system of records or alteration of an existing system of records.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 44 Emergency Management and Assistance 1 2013-10-01 2013-10-01 false Effective date of new system of records or alteration of an existing system of records. 6.72 Section 6.72 Emergency Management and... PRIVACY ACT OF 1974 Report on New Systems and Alterations of Existing Systems § 6.72 Effective date of new...

  17. 44 CFR 6.72 - Effective date of new system of records or alteration of an existing system of records.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 44 Emergency Management and Assistance 1 2012-10-01 2011-10-01 true Effective date of new system of records or alteration of an existing system of records. 6.72 Section 6.72 Emergency Management and... PRIVACY ACT OF 1974 Report on New Systems and Alterations of Existing Systems § 6.72 Effective date of new...

  18. 44 CFR 6.72 - Effective date of new system of records or alteration of an existing system of records.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 44 Emergency Management and Assistance 1 2011-10-01 2011-10-01 false Effective date of new system of records or alteration of an existing system of records. 6.72 Section 6.72 Emergency Management and... PRIVACY ACT OF 1974 Report on New Systems and Alterations of Existing Systems § 6.72 Effective date of new...

  19. 44 CFR 6.72 - Effective date of new system of records or alteration of an existing system of records.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 44 Emergency Management and Assistance 1 2010-10-01 2010-10-01 false Effective date of new system of records or alteration of an existing system of records. 6.72 Section 6.72 Emergency Management and... PRIVACY ACT OF 1974 Report on New Systems and Alterations of Existing Systems § 6.72 Effective date of new...

  20. Orthogonal photoswitching in a multifunctional molecular system

    PubMed Central

    Lerch, Michael M.; Hansen, Mickel J.; Velema, Willem A.; Szymanski, Wiktor; Feringa, Ben L.

    2016-01-01

    The wavelength-selective, reversible photocontrol over various molecular processes in parallel remains an unsolved challenge. Overlapping ultraviolet-visible spectra of frequently employed photoswitches have prevented the development of orthogonally responsive systems, analogous to those that rely on wavelength-selective cleavage of photo-removable protecting groups. Here we report the orthogonal and reversible control of two distinct types of photoswitches in one solution, that is, a donor–acceptor Stenhouse adduct (DASA) and an azobenzene. The control is achieved by using three different wavelengths of irradiation and a thermal relaxation process. The reported combination tolerates a broad variety of differently substituted photoswitches. The presented system is also extended to an intramolecular combination of photoresponsive units. A model application for an intramolecular combination of switches is presented, in which the DASA component acts as a phase-transfer tag, while the azobenzene moiety independently controls the binding to α-cyclodextrin. PMID:27401266

  1. Molecular systems in a strong magnetic field

    NASA Astrophysics Data System (ADS)

    Turbiner, Alexander V.

    2007-04-01

    Brief overview of one-two electron molecular systems made out of protons and/or α-particles in a strong magnetic field B≤4.414×1013 G is presented. A particular emphasis is given to the one-electron exotic ions H 3 ++ (pppe), He 2 3+ (α α e) and to two-electron ionsH 3 + (pppee), He 2 ++ (α α ee). Quantitative studies in a strong magnetic field are very complicated technically. Novel approach to the few-electron Coulomb systems in magnetic field, which provides accurate results, based on variational calculus with physically relevant trial functions is briefly described.

  2. [Novel bioconversion systems using a yeast molecular display system].

    PubMed

    Shibasaki, Seiji

    2010-11-01

    The budding yeast Saccharomyces cerevisiae has been used for the process of fermentation as well as for studies in biochemistry and molecular biology as a eukaryotic model cell or tool for the analysis of gene functions. Thus, yeast is essential in industries and researches. Yeast cells have a cell wall, which is one characteristic that helps distinguish yeast cells from other eukaryotic cells such as mammalian cells. We have developed a molecular display system using the protein of the yeast cell wall as an anchor for foreign proteins. Yeast cells have been designed for use in sensing and metal adsorption, and have been used in vaccines and for screening novel proteins. Currently, yeast is used not only as a tool for analyzing gene or protein function but also in molecular display technology. The phage display system, which is at the forefront of molecular display technologies, is a powerful tool for screening ligands bound to a target molecule and for analyzing protein-protein interactions; however, in some cases, eukaryotic proteins are not easily expressed by this system. On the other hand, yeast cells have the ability to express eukaryotic proteins and proliferate; thus, these cells display various proteins. Yeast cells are more appropriate for white biotechnology. In this review, displays of enzymes that are important in bioconversion, such as lipases and β-glucosidases, are going to be introduced.

  3. Environmentally Induced Epigenetic Transgenerational Inheritance of Altered Sertoli Cell Transcriptome and Epigenome: Molecular Etiology of Male Infertility

    PubMed Central

    Guerrero-Bosagna, Carlos; Savenkova, Marina; Haque, Md. Muksitul; Nilsson, Eric; Skinner, Michael K.

    2013-01-01

    Environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of adult onset disease, including testis disease and male infertility. The current study was designed to determine the impact of an altered sperm epigenome on the subsequent development of an adult somatic cell (Sertoli cell) that influences the onset of a specific disease (male infertility). A gestating female rat (F0 generation) was exposed to the agriculture fungicide vinclozolin during gonadal sex determination and then the subsequent F3 generation progeny used for the isolation of Sertoli cells and assessment of testis disease. As previously observed, enhanced spermatogenic cell apoptosis was observed. The Sertoli cells provide the physical and nutritional support for the spermatogenic cells. Over 400 genes were differentially expressed in the F3 generation control versus vinclozolin lineage Sertoli cells. A number of specific cellular pathways were identified to be transgenerationally altered. One of the key metabolic processes affected was pyruvate/lactate production that is directly linked to spermatogenic cell viability. The Sertoli cell epigenome was also altered with over 100 promoter differential DNA methylation regions (DMR) modified. The genomic features and overlap with the sperm DMR were investigated. Observations demonstrate that the transgenerational sperm epigenetic alterations subsequently alters the development of a specific somatic cell (Sertoli cell) epigenome and transcriptome that correlates with adult onset disease (male infertility). The environmentally induced epigenetic transgenerational inheritance of testis disease appears to be a component of the molecular etiology of male infertility. PMID:23555832

  4. Environmentally induced epigenetic transgenerational inheritance of altered Sertoli cell transcriptome and epigenome: molecular etiology of male infertility.

    PubMed

    Guerrero-Bosagna, Carlos; Savenkova, Marina; Haque, Md Muksitul; Nilsson, Eric; Skinner, Michael K

    2013-01-01

    Environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of adult onset disease, including testis disease and male infertility. The current study was designed to determine the impact of an altered sperm epigenome on the subsequent development of an adult somatic cell (Sertoli cell) that influences the onset of a specific disease (male infertility). A gestating female rat (F0 generation) was exposed to the agriculture fungicide vinclozolin during gonadal sex determination and then the subsequent F3 generation progeny used for the isolation of Sertoli cells and assessment of testis disease. As previously observed, enhanced spermatogenic cell apoptosis was observed. The Sertoli cells provide the physical and nutritional support for the spermatogenic cells. Over 400 genes were differentially expressed in the F3 generation control versus vinclozolin lineage Sertoli cells. A number of specific cellular pathways were identified to be transgenerationally altered. One of the key metabolic processes affected was pyruvate/lactate production that is directly linked to spermatogenic cell viability. The Sertoli cell epigenome was also altered with over 100 promoter differential DNA methylation regions (DMR) modified. The genomic features and overlap with the sperm DMR were investigated. Observations demonstrate that the transgenerational sperm epigenetic alterations subsequently alters the development of a specific somatic cell (Sertoli cell) epigenome and transcriptome that correlates with adult onset disease (male infertility). The environmentally induced epigenetic transgenerational inheritance of testis disease appears to be a component of the molecular etiology of male infertility.

  5. Alteration mineralogy of the Dixie Valley geothermal system, Nevada

    SciTech Connect

    Lutz, S.J.; Moore, J.N.; Benoit, D.

    1996-12-31

    Petrographic studies along the Stillwater fault zone in Dixie Valley, Nevada document a variety of overlapping alteration assemblages that represent different physical and chemical conditions. At depth in the northern portion of the Dixie Valley geothermal field, wairakite, illite-smectite, and chalcedonic quartz are present in the hanging wall where measured, static and flowing temperatures are close to 248{degrees}C. Although the presence of wairakite is consistent with the observed temperatures, both the illite-smectite and chalcedonic quartz suggest lower temperature conditions. In outcrop, samples from the footwall of the Stillwater fault contain quartz, kaolin, smectite, dolomite, biotite, and epidote. Crosscutting relationships indicate that quartz and kaolin postdate formation of older biotite and epidote veins. The superposition of lower temperature assemblages (kaolin, dolomite, smectite) upon higher temperature minerals (biotite, epidote) characterizes the alteration in the footwall, whereas, the superposition of higher temperature minerals (wairakite) upon lower temperature phases (chalcedonic quartz, illite-smectite) is characteristic of the alteration in the geothermal reservoir within the hanging wall. This retrograde and prograde progression of alteration should be expected along this active normal fault as the footwall is uplifted and exhumed through time, and simultaneously, the hanging wall is down dropped.

  6. Altered interregional molecular associations of the serotonin transporter in attention deficit/hyperactivity disorder assessed with PET.

    PubMed

    Vanicek, Thomas; Kutzelnigg, Alexandra; Philippe, Cecile; Sigurdardottir, Helen L; James, Gregory M; Hahn, Andreas; Kranz, Georg S; Höflich, Anna; Kautzky, Alexander; Traub-Weidinger, Tatjana; Hacker, Marcus; Wadsak, Wolfgang; Mitterhauser, Markus; Kasper, Siegfried; Lanzenberger, Rupert

    2017-02-01

    Altered serotonergic neurotransmission has been found to cause impulsive and aggressive behavior, as well as increased motor activity, all exemplifying key symptoms of ADHD. The main objectives of this positron emission tomography (PET) study were to investigate the serotonin transporter binding potential (SERT BPND ) in patients with ADHD and to assess associations of SERT BPND between the brain regions. 25 medication-free patients with ADHD (age ± SD; 32.39 ± 10.15; 10 females) without any psychiatric comorbidity and 25 age and sex matched healthy control subjects (33.74 ± 10.20) were measured once with PET and the highly selective and specific radioligand [(11) C]DASB. SERT BPND maps in nine a priori defined ROIs exhibiting high SERT binding were compared between groups by means of a linear mixed model. Finally, adopted from structural and functional connectivity analyses, we performed correlational analyses using regional SERT binding potentials to examine molecular interregional associations between all selected ROIs. We observed significant differences in the interregional correlations between the precuneus and the hippocampus in patients with ADHD compared to healthy controls, using SERT BPND of the investigated ROIs (P < 0.05; Bonferroni corrected). When correlating SERT BPND and age in the ADHD and the healthy control group, we confirmed an age-related decline in brain SERT binding in the thalamus and insula (R(2)  = 0.284, R(2)  = 0.167, Ps < 0.05; Bonferroni corrected). The results show significantly different interregional molecular associations of the SERT expression for the precuneus with hippocampus in patients with ADHD, indicating presumably altered functional coupling. Altered interregional coupling between brain regions might be a sensitive approach to demonstrate functional and molecular alterations in psychiatric conditions. Hum Brain Mapp 38:792-802, 2017. © 2016 Wiley Periodicals, Inc.

  7. Long-term variation in above and belowground plant inputs alters soil organic matter biogeochemistry at the molecular-level

    NASA Astrophysics Data System (ADS)

    Simpson, M. J.; Pisani, O.; Lin, L.; Lun, O.; Simpson, A.; Lajtha, K.; Nadelhoffer, K. J.

    2015-12-01

    The long-term fate of soil carbon reserves with global environmental change remains uncertain. Shifts in moisture, altered nutrient cycles, species composition, or rising temperatures may alter the proportions of above and belowground biomass entering soil. However, it is unclear how long-term changes in plant inputs may alter the composition of soil organic matter (SOM) and soil carbon storage. Advanced molecular techniques were used to assess SOM composition in mineral soil horizons (0-10 cm) after 20 years of Detrital Input and Removal Treatment (DIRT) at the Harvard Forest. SOM biomarkers (solvent extraction, base hydrolysis and cupric (II) oxide oxidation) and both solid-state and solution-state nuclear magnetic resonance (NMR) spectroscopy were used to identify changes in SOM composition and stage of degradation. Microbial activity and community composition were assessed using phospholipid fatty acid (PLFA) analysis. Doubling aboveground litter inputs decreased soil carbon content, increased the degradation of labile SOM and enhanced the sequestration of aliphatic compounds in soil. The exclusion of belowground inputs (No roots and No inputs) resulted in a decrease in root-derived components and enhanced the degradation of leaf-derived aliphatic structures (cutin). Cutin-derived SOM has been hypothesized to be recalcitrant but our results show that even this complex biopolymer is susceptible to degradation when inputs entering soil are altered. The PLFA data indicate that changes in soil microbial community structure favored the accelerated processing of specific SOM components with littler manipulation. These results collectively reveal that the quantity and quality of plant litter inputs alters the molecular-level composition of SOM and in some cases, enhances the degradation of recalcitrant SOM. Our study also suggests that increased litterfall is unlikely to enhance soil carbon storage over the long-term in temperate forests.

  8. Altered expression of ganglioside GM3 molecular species and a potential regulatory role during myoblast differentiation.

    PubMed

    Go, Shinji; Go, Shiori; Veillon, Lucas; Ciampa, Maria Grazia; Mauri, Laura; Sato, Chihiro; Kitajima, Ken; Prinetti, Alessandro; Sonnino, Sandro; Inokuchi, Jin-Ichi

    2017-04-28

    Gangliosides (sialic acid-containing glycosphingolipids) help regulate many important biological processes, including cell proliferation, signal transduction, and differentiation, via formation of functional microdomains in plasma membranes. The structural diversity of gangliosides arises from both the ceramide moiety and glycan portion. Recently, differing molecular species of a given ganglioside are suggested to have distinct biological properties and regulate specific and distinct biological events. Elucidation of the function of each molecular species is important and will provide new insights into ganglioside biology. Gangliosides are also suggested to be involved in skeletal muscle differentiation; however, the differential roles of ganglioside molecular species remain unclear. Here we describe striking changes in quantity and quality of gangliosides (particularly GM3) during differentiation of mouse C2C12 myoblast cells and key roles played by distinct GM3 molecular species at each step of the process. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. 75 FR 5606 - Privacy Act of 1974; Report of an Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-03

    ... Services Administration proposes to establish an altered system of records: ``Campus Based Branch Program... HUMAN SERVICES Health Resources and Services Administration Privacy Act of 1974; Report of an Altered System of Records AGENCY: Department of Health and Human Services (HHS), Health Resources and...

  10. 76 FR 4451 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ... Services proposes to alter System of Records, 09-20-0112, ``Fellowship Program and Guest Researcher Records...-0112, ``, Fellowship Program and Guest Researcher Records, HHS/CDC/AHRC.'' This system is utilized by... Resources Center (AHRC) Fellowship Program And Guest Researcher Records Report of Modified or Altered...

  11. Analysis of HLA class I alterations in tumors: choosing a strategy based on known patterns of underlying molecular mechanisms.

    PubMed

    Cabrera, T; Maleno, I; Collado, A; Lopez Nevot, M A; Tait, B D; Garrido, F

    2007-04-01

    The application of peptide-based immunotherapy in the treatment of cancer has known limitations in patients with loss or downregulation of human leukocyte antigen (HLA) class I expression on tumor cells. These alterations diminish the ability of cancer cells to present tumor peptides to T cells and therefore lead to failure of peptide-based cancer vaccination. Abnormal expression of HLA class I molecules in malignant cells is a frequent event that ranges from total loss of class I molecules to partial loss of HLA-specific haplotypes or alleles. Different mechanisms underlie these alterations and might require different therapeutic approaches. A complete characterization of molecular defects may suggest strategies for the selection and follow-up of patients undergoing T-cell based immunotherapy. Moreover, a precise identification of the mechanism leading to HLA class I defects in patients with cancer will help develop new, personalized patient-tailored treatment protocols. Here, we describe several examples showing the necessity and feasibility of making detailed individual analysis of HLA alteration mechanisms based on previously described molecular patterns in different types of malignancy. We recommend using this approach, at least in some patients, to enhance the therapeutic benefit of cancer immunotherapy.

  12. The Molecular Interface Between the SUMO and Ubiquitin Systems.

    PubMed

    Staudinger, Jeff L

    2017-01-01

    The SUMO conjugation system regulates key cellular processes including cell growth, division, mitochondrial dynamics, and the maintenance of genome stability in eukaryotic cells. The ubiquitin conjugation system regulates the stability of a myriad of vital cellular proteins in a signal-dependent manner by targeting them for destruction via the proteasome-mediated degradation pathway. Recent research efforts have unveiled an evolutionarily conserved and fundamental molecular interface between the SUMO and ubiquitin systems. A coordinated and integrated interaction between these two pathways plays a key role in adapting the SUMO-related stress response to alterations in sub-cellular protein localization, specific protein recruitment strategies, and the regulation of stress-inducible protein stability. This chapter will describe the interconnected and interdependent role of the SUMO and ubiquitin systems in mediating DNA damage repair and the genesis and the resolution of inflammatory-related diseases such as cancer. New insights regarding the interdependence of these two important post-translational modifications with nuclear receptor superfamily members will also be highlighted.

  13. Microgravity-induced alterations in signal transduction in cells of the immune system

    NASA Astrophysics Data System (ADS)

    Paulsen, Katrin; Thiel, Cora; Timm, Johanna; Schmidt, Peter M.; Huber, Kathrin; Tauber, Svantje; Hemmersbach, Ruth; Seibt, Dieter; Kroll, Hartmut; Grote, Karl-Heinrich; Zipp, Frauke; Schneider-Stock, Regine; Cogoli, Augusto; Hilliger, Andre; Engelmann, Frank; Ullrich, Oliver

    2010-11-01

    Since decades it is known that the activity of cells of the immune system is severely dysregulated in microgravity, however, the underlying molecular aspects have not been elucidated yet. The identification of gravity-sensitive molecular mechanisms in cells of the immune system is an important and indispensable prerequisite for the development of counteractive measures to prevent or treat disturbed immune cell function of astronauts during long-term space missions. Moreover, their sensitivity to altered gravity renders immune cells an ideal model system to understand if and how gravity on Earth is required for normal mammalian cell function and signal transduction. We investigated the effect of simulated weightlessness (2D clinostat) and of real microgravity (parabolic flights) on key signal pathways in a human monocytic and a T lymphocyte cell line. We found that cellular responses to microgravity strongly depend on the cell-type and the conditions in which the cells are subjected to microgravity. In Jurkat T cells, enhanced phosphorylation of the MAP kinases ERK-1/2, MEK and p38 and inhibition of nuclear translocation of NF-kB were the predominant responses to simulated weightlessness, in either stimulated or non-stimulated cells. In contrast, non-stimulated monocytic U937 cells responded to simulated weightlessness with enhanced overall tyrosine-phosphorylation and activation of c-jun, whereas PMA-stimulated U937 cells responded the opposite way with reduced tyrosine-phosphorylation and reduced activation of c-jun, compared with PMA-stimulated 1 g controls. P53 protein was phosphorylated rapidly in microgravity. The identification of gravi-sensitive mechanisms in cells of the immune system will not only enable us to understand and prevent the negative effects of long time exposure to microgravity on Astronauts, but could also lead to novel therapeutic targets in general.

  14. Skeletal muscle plasticity: cellular and molecular responses to altered physical activity paradigms

    NASA Technical Reports Server (NTRS)

    Baldwin, Kenneth M.; Haddad, Fadia

    2002-01-01

    The goal of this article is to examine our current understanding of the chain of events known to be involved in the adaptive process whereby specific genes and their protein products undergo altered expression; specifically, skeletal muscle adaptation in response to altered loading states will be discussed, with a special focus on the regulation of the contractile protein, myosin heavy chain gene expression. This protein, which is both an important structural and regulatory protein comprising the contractile apparatus, can be expressed as different isoforms, thereby having an impact on the functional diversity of the muscle. Because the regulation of the myosin gene family is under the control of a complex set of processes including, but not limited to, activity, hormonal, and metabolic factors, this protein will serve as a cellular "marker" for studies of muscle plasticity in response to various mechanical perturbations in which the quantity and type of myosin isoform, along with other important cellular proteins, are altered in expression.

  15. Skeletal muscle plasticity: cellular and molecular responses to altered physical activity paradigms

    NASA Technical Reports Server (NTRS)

    Baldwin, Kenneth M.; Haddad, Fadia

    2002-01-01

    The goal of this article is to examine our current understanding of the chain of events known to be involved in the adaptive process whereby specific genes and their protein products undergo altered expression; specifically, skeletal muscle adaptation in response to altered loading states will be discussed, with a special focus on the regulation of the contractile protein, myosin heavy chain gene expression. This protein, which is both an important structural and regulatory protein comprising the contractile apparatus, can be expressed as different isoforms, thereby having an impact on the functional diversity of the muscle. Because the regulation of the myosin gene family is under the control of a complex set of processes including, but not limited to, activity, hormonal, and metabolic factors, this protein will serve as a cellular "marker" for studies of muscle plasticity in response to various mechanical perturbations in which the quantity and type of myosin isoform, along with other important cellular proteins, are altered in expression.

  16. Skeletal muscle plasticity: cellular and molecular responses to altered physical activity paradigms.

    PubMed

    Baldwin, Kenneth M; Haddad, Fadia

    2002-11-01

    The goal of this article is to examine our current understanding of the chain of events known to be involved in the adaptive process whereby specific genes and their protein products undergo altered expression; specifically, skeletal muscle adaptation in response to altered loading states will be discussed, with a special focus on the regulation of the contractile protein, myosin heavy chain gene expression. This protein, which is both an important structural and regulatory protein comprising the contractile apparatus, can be expressed as different isoforms, thereby having an impact on the functional diversity of the muscle. Because the regulation of the myosin gene family is under the control of a complex set of processes including, but not limited to, activity, hormonal, and metabolic factors, this protein will serve as a cellular "marker" for studies of muscle plasticity in response to various mechanical perturbations in which the quantity and type of myosin isoform, along with other important cellular proteins, are altered in expression.

  17. Does aging alter the molecular substrate of ionotropic neurotransmitter receptors in the rostral ventral lateral medulla? - A short communication.

    PubMed

    Pawar, Hitesh N; Balivada, Sivasai; Kenney, Michael J

    2017-03-02

    Aging alters sympathetic nervous system (SNS) regulation, although central mechanisms are not well understood. In young rats the rostral ventral lateral medulla (RVLM) is critically involved in central SNS regulation and RVLM neuronal activity is mediated by a balance of excitatory and inhibitory ionotropic neurotransmitters and receptors, providing the foundation for hypothesizing that with advanced age the molecular substrate of RVLM ionotropic receptors is characterized by upregulated excitatory and downregulated inhibitory receptor subunits. This hypothesis was tested by comparing the relative mRNA expression and protein concentration of RVLM excitatory (NMDA and AMPA) and inhibitory (GABA and glycinergic) ionotropic neurotransmitter receptor subunits in young and aged Fischer (F344) rats. Brains were removed from anesthetized rats and the RVLM-containing area was micropunched and extracted RNA and protein were subsequently used for TaqMan qRT-PCR gene expression and quantitative ELISA analyses. Bilateral chemical inactivation of RVLM neurons and peripheral ganglionic blockade on visceral sympathetic nerve discharge (SND) was determined in additional experiments. The relative gene expression of RVLM NMDA and AMPA glutamate-gated receptor subunits and protein concentration of select receptor subunits did not differ between young and aged rats, and there were no age-related differences in the expression of RVLM ionotropic GABAA and Gly receptors, or of protein concentration of select GABAA subunits. RVLM muscimol microinjections significantly reduced visceral SND by 70±2% in aged F344 rats. Collectively these findings from this short communication support a functional role for the RVLM in regulation of sympathetic nerve outflow in aged rats, but provide no evidence for an ionotropic RVLM receptor-centric framework explaining age-associated changes in SNS regulation.

  18. Adaptations of the vestibular system to short and long-term exposures to altered gravity

    NASA Astrophysics Data System (ADS)

    Bruce, L. L.

    2003-10-01

    Long-term space flight creates unique environmental conditions to which the vestibular system must adapt for optimal survival of a given organism. The development and maintenance of vestibular connections are controlled by environmental gravitational stimulation as well as genetically controlled molecular interactions. This paper describes the effects of hypergravity on axonal growth and dendritic morphology, respectively. Two aspects of this vestibular adaptation are examined: (1) How does long-term exposure to hypergravity affect the development of vestibular axons? (2) How does short-term exposure to extremely rapid changes in gravity, such as those that occur during shuttle launch and landing, affect dendrites of the vestibulocerebellar system? To study the effects of longterm exposures to altered gravity, embryonic rats that developed in hypergravity were compared to microgravity-exposed and control rats. Examination of the vestibular projections from epithelia devoted to linear and angular acceleration revealed that the terminal fields segregate differently in rat embryos that gestated in each of the gravitational environments.To study the effects of short-term exposures to altered gravity, mice were exposed briefly to strong vestibular stimuli and the vestibulocerebellum was examined for any resulting morphological changes. My data show that these stimuli cause intense vestibular excitation of cerebellar Purkinje cells, which induce up-regulation of clathrin-mediated endocytosis and other morphological changes that are comparable to those seen in long-term depression. This system provides a basis for studying how the vestibular environment can modify cerebellar function, allowing animals to adapt to new environments.

  19. ONTOGENETIC ALTERATIONS IN MOLECULAR AND STRUCTURAL CORRELATES OF DENDRITIC GROWTH FOLLOWING DEVELOPMENTAL EXPOSURE TO POLYCHLORINATED BIPHENYLS.

    EPA Science Inventory

    This is the first report showing both molecular and structural changes in brain following developmental exposure to a neurotoxicant. It is known that perinatal exposure to a neurotoxicant, polychlorinated biphenyls (PCBs), is associated with decreased IQ scores, impaired learnin...

  20. ONTOGENETIC ALTERATIONS IN MOLECULAR AND STRUCTURAL CORRELATES OF DENDRITIC GROWTH FOLLOWING DEVELOPMENTAL EXPOSURE TO POLYCHLORINATED BIPHENYLS.

    EPA Science Inventory

    This is the first report showing both molecular and structural changes in brain following developmental exposure to a neurotoxicant. It is known that perinatal exposure to a neurotoxicant, polychlorinated biphenyls (PCBs), is associated with decreased IQ scores, impaired learnin...

  1. Perinatal exposure to lead (Pb) induces ultrastructural and molecular alterations in synapses of rat offspring.

    PubMed

    Gąssowska, Magdalena; Baranowska-Bosiacka, Irena; Moczydłowska, Joanna; Frontczak-Baniewicz, Małgorzata; Gewartowska, Magdalena; Strużyńska, Lidia; Gutowska, Izabela; Chlubek, Dariusz; Adamczyk, Agata

    2016-12-12

    Lead (Pb), environmentally abundant heavy-metal pollutant, is a strong toxicant for the developing central nervous system. Pb intoxication in children, even at low doses, is found to affect learning and memorizing, with devastating effects on cognitive function and intellectual development. However, the precise mechanism by which Pb impairs synaptic plasticity is not fully elucidated. The purpose of this study was to investigate the effect of pre- and neonatal exposure to low dose of Pb (with Pb concentrations in whole blood below 10μg/dL) on the synaptic structure and the pre- and postsynaptic proteins expression in the developing rat brain. Furthermore, the level of brain-derived neurotrophic factor (BDNF) was analyzed. Pregnant female Wistar rats received 0.1% lead acetate (PbAc) in drinking water from the first day of gestation until weaning of the offspring, while the control animals received drinking water. During the feeding of pups, mothers from the Pb-group were continuously receiving PbAc. Pups of both groups were weaned at postnatal day 21 and then until postnatal day 28 received only drinking water. 28-day old pups were sacrificed and the ultrastructural changes as well as expression of presynaptic (VAMP1/2, synaptophysin, synaptotagmin-1, SNAP25, syntaxin-1) and postsynaptic (PSD-95) proteins were analyzed in: forebrain cortex, cerebellum and hippocampus. Our data revealed that pre- and neonatal exposure to low dose of Pb promotes pathological changes in synapses, including nerve endings swelling, blurred and thickened synaptic cleft structure as well as enhanced density of synaptic vesicles in the presynaptic area. Moreover, synaptic mitochondria were elongated, swollen or shrunken in Pb-treated animals. These structural abnormalities were accompanied by decrease in the level of key synaptic proteins: synaptotagmin-1 in cerebellum, SNAP25 in hippocampus and syntaxin-1 in cerebellum and hippocampus. In turn, increased level of synaptophysin was

  2. Perinatal exposure to lead (Pb) induces ultrastructural and molecular alterations in synapses of rat offspring.

    PubMed

    Gąssowska, Magdalena; Baranowska-Bosiacka, Irena; Moczydłowska, Joanna; Frontczak-Baniewicz, Małgorzata; Gewartowska, Magdalena; Strużyńska, Lidia; Gutowska, Izabela; Chlubek, Dariusz; Adamczyk, Agata

    2016-10-29

    Lead (Pb), environmentally abundant heavy-metal pollutant, is a strong toxicant for the developing central nervous system. Pb intoxication in children, even at low doses, is found to affect learning and memorizing, with devastating effects on cognitive function and intellectual development. However, the precise mechanism by which Pb impairs synaptic plasticity is not fully elucidated. The purpose of this study was to investigate the effect of pre- and neonatal exposure to low dose of Pb (with Pb concentrations in whole blood below 10μg/dL) on the synaptic structure and the pre- and postsynaptic proteins expression in the developing rat brain. Furthermore, the level of brain-derived neurotrophic factor (BDNF) was analyzed. Pregnant female Wistar rats received 0.1% lead acetate (PbAc) in drinking water from the first day of gestation until weaning of the offspring, while the control animals received drinking water. During the feeding of pups, mothers from the Pb-group were continuously receiving PbAc. Pups of both groups were weaned at postnatal day 21 and then until postnatal day 28 received only drinking water. 28-Day old pups were sacrificed and the ultrastructural changes as well as expression of presynaptic (VAMP1/2, synaptophysin, synaptotagmin-1, SNAP25, syntaxin-1) and postsynaptic (PSD-95) proteins were analyzed in: forebrain cortex, cerebellum and hippocampus. Our data revealed that pre- and neonatal exposure to low dose of Pb promotes pathological changes in synapses, including nerve endings swelling, blurred and thickened synaptic cleft structure as well as enhanced density of synaptic vesicles in the presynaptic area. Moreover, synaptic mitochondria were elongated, swollen or shrunken in Pb-treated animals. These structural abnormalities were accompanied by decrease in the level of key synaptic proteins: synaptotagmin-1 in cerebellum, SNAP25 in hippocampus and syntaxin-1 in cerebellum and hippocampus. In turn, increased level of synaptophysin was

  3. Endometriosis as a detrimental condition for granulosa cell steroidogenesis and development: From molecular alterations to clinical impact.

    PubMed

    Sanchez, Ana Maria; Somigliana, Edgardo; Vercellini, Paolo; Pagliardini, Luca; Candiani, Massimo; Vigano, Paola

    2016-01-01

    Endometriosis is an estrogen-dependent chronic inflammatory condition that affects women in their reproductive period. Alterations in ovarian follicle morphology and function have been documented in affected women. The local intrafollicular environment has been as well examined by various groups. In the present review, we aimed to summarize the molecular evidence supporting the idea that endometriosis can negatively influence growth, steroidogenesis and the function of the granulosa cells (GCs). Reduced P450 aromatase expression, increased intracellular ROS generation and altered WNT signaling characterize the GCs of women with endometriosis. Clear evidence for an increased level of GC apoptosis has been provided in association with the downregulation of pro-survival factors. Other potentially negative effects include decreased progesterone production, locally decreased AMH production and lower inflammatory cytokine expression, although these have been only partially clarified. The possibility that endometriosis per se may influence IVF clinical results as a consequence of the detrimental impact on the local intrafollicular environment is also discussed.

  4. Molecular imaging as a guide for the treatment of central nervous system disorders.

    PubMed

    Kim, Euitae; Howes, Oliver D; Kapur, Shitij

    2013-09-01

    Molecular imaging techniques have a number of advantages for research into the pathophysiology and treatment of central nervous system (CNS) disorders. Firstly, they provide a noninvasive means of characterizing physiological processes in the living brain, enabling molecular alterations to be linked to clinical changes. Secondly, the pathophysiological target in a given CNS disorder can be measured in animal models and in experimental human models in the same way, which enables translational research. Moreover, as molecular imaging facilitates the detection of functional change which precedes gross pathology, it is particularly useful for the early diagnosis and treatment of CNS disorders. This review considers the application of molecular imaging to CNS disorders focusing on its potential to inform the development and evaluation of treatments. We focus on schizophrenia, Parkinson's disease, depression, and dementia as major CNS disorders. We also review the potential of molecular imaging to guide new drug development for CNS disorders.

  5. Involvement of the serotonergic system in orexin-induced behavioral alterations in rats.

    PubMed

    Matsuzaki, Ichiyo; Sakurai, Takeshi; Kunii, Kaiko; Nakamura, Toshiaki; Yanagisawa, Masashi; Goto, Katsutoshi

    2002-03-15

    We have demonstrated involvement of the serotonergic system in orexin-induced behavioral responses in rats. Orexin-A and -B (hypocretin-1 and -2) significantly increased total locomotor activity when administered centrally. They also induced behavioral alterations; increasing grooming, face washing and wet dog shaking in rats. Haloperidol inhibited orexin-induced hyperlocomotion and these behavioral alterations. Serotonin antagonists, ritanserin and metergoline, did not attenuate orexin-induced hyperlocomotion but partly inhibited orexin-induced behavioral alterations. These results suggest that the dopaminergic system might be involved in orexin-induced hyperlocomotion, while both the serotonergic system as well as the dopaminergic system might be involved in orexin-induced behavioral responses.

  6. Development of Assays for Detecting Significant Prostate Cancer Based on Molecular Alterations Associated with Cancer in Non-Neoplastic Prostate Tissue

    DTIC Science & Technology

    2012-10-01

    prostate cancer ." Am J Pathol 181(1): 34-42. Li, M. and L. A. Cannizzaro (1999). "Identical clonal origin of synchronous and metachronous low-grade...significant prostate cancer based on molecular alterations associated with cancer in non-neoplastic prostate tissue PRINCIPAL INVESTIGATOR...significant prostate cancer based on molecular alterations associated with cancer in non-neoplastic prostate tissue 5a. CONTRACT NUMBER 5b. GRANT

  7. Molecular structures and metabolic characteristics of protein in brown and yellow flaxseed with altered nutrient traits.

    PubMed

    Khan, Nazir Ahmad; Booker, Helen; Yu, Peiqiang

    2014-07-16

    The objectives of this study were to investigate the chemical profiles; crude protein (CP) subfractions; ruminal CP degradation characteristics and intestinal digestibility of rumen undegraded protein (RUP); and protein molecular structures using molecular spectroscopy of newly developed yellow-seeded flax (Linum usitatissimum L.). Seeds from two yellow flaxseed breeding lines and two brown flaxseed varieties were evaluated. The yellow-seeded lines had higher (P < 0.001) contents of oil (44.54 vs 41.42% dry matter (DM)) and CP (24.94 vs 20.91% DM) compared to those of the brown-seeded varieties. The CP in yellow seeds contained lower (P < 0.01) contents of true protein subfraction (81.31 vs 92.71% CP) and more (P < 0.001) extensively degraded (70.8 vs 64.9% CP) in rumen resulting in lower (P < 0.001) content of RUP (29.2 vs 35.1% CP) than that in the brown-seeded varieties. However, the total supply of digestible RUP was not significantly different between the two seed types. Regression equations based on protein molecular structural features gave relatively good estimation for the contents of CP (R(2) = 0.87), soluble CP (R(2) = 0.92), RUP (R(2) = 0.97), and intestinal digestibility of RUP (R(2) = 0.71). In conclusion, molecular spectroscopy can be used to rapidly characterize feed protein molecular structures and predict their nutritive value.

  8. Alterations in the Striatal Dopamine System During Intravenous Methamphetamine Exposure: Effects of Contingent and Noncontingent Administration

    PubMed Central

    Laćan, Goran; Hadamitzky, Martin; Kuczenski, Ronald; Melega, William P.

    2014-01-01

    The continuing spread of methamphetamine (METH) abuse has stimulated research aimed at understanding consequences of its prolonged exposure. Alterations in nigrostriatal dopamine (DA) system parameters have been characterized in experimental studies after discontinuation of long term METH but fewer studies have included similar assessments during METH exposure. Here, we report METH plasma pharmacokinetics and striatal DA system alterations in rat after noncontingent and contingent METH administration for 7.5 weeks. Escalating METH exposure was delivered by dynamic infusion (DI) that incorporated a ‘humanized’ plasma METH half life, or by intravenous self-administration (IVSA) that included binge intakes. Kinetic modeling of DI and IVSA for 24 h periods during the final week of METH exposure showed that plasma METH levels remained between 0.7–1.5 μM. Animals were sacrificed during their last METH administration for autoradiography assessment using [3H]ligands and D2 agonist-induced [35S]GTPγS binding. DA transporter binding was decreased (DI, 34%; IVSA, 15%) while vesicular monoamine transporter binding and substantia nigra DA cell numbers were unchanged. Decreases were measured for D2 receptor (DI and IVSA, 15–20%) and [35S]GTPγS binding (DI, 35%; IVSA, 18%). These similar patterns of DI and IVSA associated decreases in striatal DA markers reflect consequences of cumulative METH exposure and not the drug delivery method. For METH IVSA, individual differences were observed, yet each animal’s total intake was similar within and across three 24 h binges. IVSA rodent models may be useful for identifying molecular mechanisms that are associated with METH binges in humans. PMID:23417852

  9. Alterations in the striatal dopamine system during intravenous methamphetamine exposure: effects of contingent and noncontingent administration.

    PubMed

    Laćan, Goran; Hadamitzky, Martin; Kuczenski, Ronald; Melega, William P

    2013-08-01

    The continuing spread of methamphetamine (METH) abuse has stimulated research aimed at understanding consequences of its prolonged exposure. Alterations in nigrostriatal dopamine (DA) system parameters have been characterized in experimental studies after discontinuation of long-term METH but fewer studies have included similar assessments during METH exposure. Here, we report METH plasma pharmacokinetics and striatal DA system alterations in rat after noncontingent and contingent METH administration for 7.5 weeks. Escalating METH exposure was delivered by dynamic infusion (DI) that incorporated a "humanized" plasma METH half life or by intravenous self-administration (IVSA) that included binge intakes. Kinetic modeling of DI and IVSA for 24 h periods during the final week of METH exposure showed that plasma METH levels remained between 0.7 and 1.5 µM. Animals were sacrificed during their last METH administration for autoradiography assessment using [³H]ligands and D2 agonist-induced [³⁵S]GTPγS binding. DA transporter binding was decreased (DI, 34%; IVSA, 15%) while vesicular monoamine transporter binding and substantia nigra DA cell numbers were unchanged. Decreases were measured for D2 receptor (DI and IVSA, 15-20%) and [³⁵S]GTPγS binding (DI, 35%; IVSA, 18%). These similar patterns of DI and IVSA associated decreases in striatal DA markers reflect consequences of cumulative METH exposure and not the drug delivery method. For METH IVSA, individual differences were observed, yet each animal's total intake was similar within and across three 24-h binges. IVSA rodent models may be useful for identifying molecular mechanisms that are associated with METH binges in humans. Copyright © 2013 Wiley Periodicals, Inc.

  10. Temperature modulates the cell wall mechanical properties of rice coleoptiles by altering the molecular mass of hemicellulosic polysaccharides

    NASA Technical Reports Server (NTRS)

    Nakamura, Yukiko; Wakabayashi, Kazuyuki; Hoson, Takayuki

    2003-01-01

    The present study was conducted to investigate the mechanism inducing the difference in the cell wall extensibility of rice (Oryza sativa L. cv. Koshihikari) coleoptiles grown under various temperature (10-50 degrees C) conditions. The growth rate and the cell wall extensibility of rice coleoptiles exhibited the maximum value at 30-40 degrees C, and became smaller as the growth temperature rose or dropped from this temperature range. The amounts of cell wall polysaccharides per unit length of coleoptile increased in coleoptiles grown at 40 degrees C, but not at other temperature conditions. On the other hand, the molecular size of hemicellulosic polysaccharides was small at temperatures where the cell wall extensibility was high (30-40 degrees C). The autolytic activities of cell walls obtained from coleoptiles grown at 30 and 40 degrees C were substantially higher than those grown at 10, 20 and 50 degrees C. Furthermore, the activities of (1-->3),(1-->4)-beta-glucanases extracted from coleoptile cell walls showed a similar tendency. When oat (1-->3),(1-->4)-beta-glucans with high molecular mass were incubated with the cell wall enzyme preparations from coleoptiles grown at various temperature conditions, the extensive molecular mass downshifts were brought about only by the cell wall enzymes obtained from coleoptiles grown at 30-40 degrees C. There were close correlations between the cell wall extensibility and the molecular mass of hemicellulosic polysaccharides or the activity of beta -glucanases. These results suggest that the environmental temperature regulates the cell wall extensibility of rice coleoptiles by modifying mainly the molecular mass of hemicellulosic polysaccharides. Modulation of the activity of beta-glucanases under various temperature conditions may be involved in the alteration of the molecular size of hemicellulosic polysaccharides.

  11. Temperature modulates the cell wall mechanical properties of rice coleoptiles by altering the molecular mass of hemicellulosic polysaccharides

    NASA Technical Reports Server (NTRS)

    Nakamura, Yukiko; Wakabayashi, Kazuyuki; Hoson, Takayuki

    2003-01-01

    The present study was conducted to investigate the mechanism inducing the difference in the cell wall extensibility of rice (Oryza sativa L. cv. Koshihikari) coleoptiles grown under various temperature (10-50 degrees C) conditions. The growth rate and the cell wall extensibility of rice coleoptiles exhibited the maximum value at 30-40 degrees C, and became smaller as the growth temperature rose or dropped from this temperature range. The amounts of cell wall polysaccharides per unit length of coleoptile increased in coleoptiles grown at 40 degrees C, but not at other temperature conditions. On the other hand, the molecular size of hemicellulosic polysaccharides was small at temperatures where the cell wall extensibility was high (30-40 degrees C). The autolytic activities of cell walls obtained from coleoptiles grown at 30 and 40 degrees C were substantially higher than those grown at 10, 20 and 50 degrees C. Furthermore, the activities of (1-->3),(1-->4)-beta-glucanases extracted from coleoptile cell walls showed a similar tendency. When oat (1-->3),(1-->4)-beta-glucans with high molecular mass were incubated with the cell wall enzyme preparations from coleoptiles grown at various temperature conditions, the extensive molecular mass downshifts were brought about only by the cell wall enzymes obtained from coleoptiles grown at 30-40 degrees C. There were close correlations between the cell wall extensibility and the molecular mass of hemicellulosic polysaccharides or the activity of beta -glucanases. These results suggest that the environmental temperature regulates the cell wall extensibility of rice coleoptiles by modifying mainly the molecular mass of hemicellulosic polysaccharides. Modulation of the activity of beta-glucanases under various temperature conditions may be involved in the alteration of the molecular size of hemicellulosic polysaccharides.

  12. The Cerebral Surfactant System and Its Alteration in Hydrocephalic Conditions

    PubMed Central

    Friedrich, Benjamin; Bernhard, Matthias K.; Gebauer, Corinna; Dieckow, Julia; Gawlitza, Matthias; Pirlich, Mandy; Saur, Dorothee; Bräuer, Lars; Bechmann, Ingo; Hoffmann, Karl-Titus; Mahr, Cynthia V.; Nestler, Ulf; Preuß, Matthias

    2016-01-01

    Introduction Pulmonary Surfactant reduces surface tension in the terminal airways thus facilitating breathing and contributes to host’s innate immunity. Surfactant Proteins (SP) A, B, C and D were recently identified as inherent proteins of the CNS. Aim of the study was to investigate cerebrospinal fluid (CSF) SP levels in hydrocephalus patients compared to normal subjects. Patients and Methods CSF SP A-D levels were quantified using commercially available ELISA kits in 126 patients (0–84 years, mean 39 years). 60 patients without CNS pathologies served as a control group. Hydrocephalus patients were separated in aqueductal stenosis (AQS, n = 24), acute hydrocephalus without aqueductal stenosis (acute HC w/o AQS, n = 16) and idiopathic normal pressure hydrocephalus (NPH, n = 20). Furthermore, six patients with pseudotumor cerebri were investigated. Results SP A—D are present under physiological conditions in human CSF. SP-A is elevated in diseases accompanied by ventricular enlargement (AQS, acute HC w/o AQS) in a significant manner (0.67, 1.21 vs 0.38 ng/ml in control, p<0.001). SP-C is also elevated in hydrocephalic conditions (AQS, acute HC w/o AQS; 0.87, 1.71 vs. 0.48 ng/ml in controls, p<0.001) and in Pseudotumor cerebri (1.26 vs. 0.48 ng/ml in controls, p<0.01). SP-B and SP-D did not show significant alterations. Conclusion The present study confirms the presence of SPs in human CSF. There are significant changes of SP-A and SP-C levels in diseases affecting brain water circulation and elevation of intracranial pressure. Cause of the alterations, underlying regulatory mechanisms, as well as diagnostic and therapeutic consequences of cerebral SP’s requires further thorough investigations. PMID:27656877

  13. Primitive Liquid Water of the Solar System in an Aqueous Altered Carbonaceous Chondrite

    NASA Technical Reports Server (NTRS)

    Tsuchiyama, A.; Miyake, A.; Kitayama, A.; Matsuno, J.; Takeuchi, A.; Uesugi, K.; Suzuki, Y.; Nakano, T.; Zolensky, M. E.

    2016-01-01

    Non-destructive 3D observations of the aqueous altered CM chondrite Sutter's Mill using scanning imaging x-ray microscopy (SIXM) showed that some of calcite and enstatite grains contain two-phase inclusion, which is most probably composed of liquid water and bubbles. This water should be primitive water responsible for aqueous alteration in an asteroid in the early solar system.

  14. 78 FR 32256 - Privacy Act of 1974; Report of an Altered CMS System of Records Notice

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-29

    ... HUMAN SERVICES Centers for Medicare & Medicaid Services Privacy Act of 1974; Report of an Altered CMS System of Records Notice AGENCY: Centers for Medicare & Medicaid Services (CMS), Department of Health and... requirements of the Privacy Act of 1974 (5 USC 552a), CMS proposes the following alterations to existing...

  15. Chronic phase advance alters circadian physiological rhythms and peripheral molecular clocks

    PubMed Central

    Wolff, Gretchen; Duncan, Marilyn J.

    2013-01-01

    Shifting the onset of light, acutely or chronically, can profoundly affect responses to infection, tumor progression, development of metabolic disease, and mortality in mammals. To date, the majority of phase-shifting studies have focused on acute exposure to a shift in the timing of the light cycle, whereas the consequences of chronic phase shifts alone on molecular rhythms in peripheral tissues such as skeletal muscle have not been studied. In this study, we tested the effect of chronic phase advance on the molecular clock mechanism in two phenotypically different skeletal muscles. The phase advance protocol (CPA) involved 6-h phase advances (earlier light onset) every 4 days for 8 wk. Analysis of the molecular clock, via bioluminescence recording, in the soleus and flexor digitorum brevis (FDB) muscles and lung demonstrated that CPA advanced the phase of the rhythm when studied immediately after CPA. However, if the mice were placed into free-running conditions (DD) for 2 wk after CPA, the molecular clock was not phase shifted in the two muscles but was still shifted in the lung. Wheel running behavior remained rhythmic in CPA mice; however, the endogenous period length of the free-running rhythm was significantly shorter than that of control mice. Core body temperature, cage activity, and heart rate remained rhythmic throughout the experiment, although the onset of the rhythms was significantly delayed with CPA. These results provide clues that lifestyles associated with chronic environmental desynchrony, such as shift work, can have disruptive effects on the molecular clock mechanism in peripheral tissues, including both types of skeletal muscle. Whether this can contribute, long term, to increased incidence of insulin resistance/metabolic disease requires further study. PMID:23703115

  16. Chemical transport in geothermal systems in Iceland: Evidence from hydrothermal alteration

    NASA Astrophysics Data System (ADS)

    Franzson, Hjalti; Zierenberg, Robert; Schiffman, Peter

    2008-06-01

    This study focuses on the chemical changes in basaltic rocks in fossil low- and high-temperature hydrothermal systems in Iceland. The method used takes into account the amount of dilution caused by vesicle and vein fillings in the rocks. The amount of dilution allows a calculation of the primary concentration of the immobile element Zr, and by multiplying the composition of the altered rock by the ratio of Zr (protolith)/Zr (altered rock) one can compute the mass addition caused by the dilution of the void fillings, and also make a direct comparison with the likely protoliths from the same areas. The samples were divided into three groups; two from Tertiary fossil high-temperature systems (Hafnarfjall, Geitafell), and the third group from a low temperature, zeolite-altered plateau basalt succession. The results show that hydrothermally altered rocks are enriched in Si, Al, Fe, Mg and Mn, and that Na, K and Ca are mobile but show either depletion or enrichment. The elements that are immobile include Zr, Y, Nb and probably Ti. The two high-temperature systems show quite similar chemical alteration trends, an observation which may apply to Icelandic fresh water high-temperature systems in general. The geochemical data show that the major changes in the altered rocks from Icelandic geothermal systems may be attributed to addition of elements during deposition of pore-filling alteration minerals. A comparison with seawater-dominated basalt-hosted hydrothermal systems shows much greater mass flux within the seawater systems, even though both systems have similar alteration assemblages. The secondary mineral assemblages seem to be controlled predominantly by the thermal stability of the alteration phases and secondarily by the composition of the hydrothermal fluids.

  17. Vismodegib, an antagonist of hedgehog signaling, directly alters taste molecular signaling in taste buds

    PubMed Central

    Yang, Hyekyung; Cong, Wei-na; Yoon, Jeong Seon; Egan, Josephine M

    2015-01-01

    Vismodegib, a highly selective inhibitor of hedgehog (Hh) pathway, is an approved treatment for basal-cell carcinoma. Patients on treatment with vismodegib often report profound alterations in taste sensation. The cellular mechanisms underlying the alterations have not been studied. Sonic Hh (Shh) signaling is required for cell growth and differentiation. In taste buds, Shh is exclusively expressed in type IV taste cells, which are undifferentiated basal cells and the precursors of the three types of taste sensing cells. Thus, we investigated if vismodegib has an inhibitory effect on taste cell turnover because of its known effects on Hh signaling. We gavaged C57BL/6J male mice daily with either vehicle or 30 mg/kg vismodegib for 15 weeks. The gustatory behavior and immunohistochemical profile of taste cells were examined. Vismodegib-treated mice showed decreased growth rate and behavioral responsivity to sweet and bitter stimuli, compared to vehicle-treated mice. We found that vismodegib-treated mice had significant reductions in taste bud size and numbers of taste cells per taste bud. Additionally, vismodegib treatment resulted in decreased numbers of Ki67- and Shh-expressing cells in taste buds. The numbers of phospholipase Cβ2- and α-gustducin-expressing cells, which contain biochemical machinery for sweet and bitter sensing, were reduced in vismodegib-treated mice. Furthermore, vismodegib treatment resulted in reduction in numbers of T1R3, glucagon-like peptide-1, and glucagon-expressing cells, which are known to modulate sweet taste sensitivity. These results suggest that inhibition of Shh signaling by vismodegib treatment directly results in alteration of taste due to local effects in taste buds. PMID:25354792

  18. Vismodegib, an antagonist of hedgehog signaling, directly alters taste molecular signaling in taste buds.

    PubMed

    Yang, Hyekyung; Cong, Wei-Na; Yoon, Jeong Seon; Egan, Josephine M

    2015-02-01

    Vismodegib, a highly selective inhibitor of hedgehog (Hh) pathway, is an approved treatment for basal-cell carcinoma. Patients on treatment with vismodegib often report profound alterations in taste sensation. The cellular mechanisms underlying the alterations have not been studied. Sonic Hh (Shh) signaling is required for cell growth and differentiation. In taste buds, Shh is exclusively expressed in type IV taste cells, which are undifferentiated basal cells and the precursors of the three types of taste sensing cells. Thus, we investigated if vismodegib has an inhibitory effect on taste cell turnover because of its known effects on Hh signaling. We gavaged C57BL/6J male mice daily with either vehicle or 30 mg/kg vismodegib for 15 weeks. The gustatory behavior and immunohistochemical profile of taste cells were examined. Vismodegib-treated mice showed decreased growth rate and behavioral responsivity to sweet and bitter stimuli, compared to vehicle-treated mice. We found that vismodegib-treated mice had significant reductions in taste bud size and numbers of taste cells per taste bud. Additionally, vismodegib treatment resulted in decreased numbers of Ki67- and Shh-expressing cells in taste buds. The numbers of phospholipase Cβ2- and α-gustducin-expressing cells, which contain biochemical machinery for sweet and bitter sensing, were reduced in vismodegib-treated mice. Furthermore, vismodegib treatment resulted in reduction in numbers of T1R3, glucagon-like peptide-1, and glucagon-expressing cells, which are known to modulate sweet taste sensitivity. These results suggest that inhibition of Shh signaling by vismodegib treatment directly results in alteration of taste due to local effects in taste buds. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

  19. Structural Alterations in a Component of Cytochrome c Oxidase and Molecular Evolution of Pathogenic Neisseria in Humans

    PubMed Central

    Aspholm, Marina; Aas, Finn Erik; Harrison, Odile B.; Quinn, Diana; Vik, Åshild; Viburiene, Raimonda; Tønjum, Tone; Moir, James; Maiden, Martin C. J.; Koomey, Michael

    2010-01-01

    Three closely related bacterial species within the genus Neisseria are of importance to human disease and health. Neisseria meningitidis is a major cause of meningitis, while Neisseria gonorrhoeae is the agent of the sexually transmitted disease gonorrhea and Neisseria lactamica is a common, harmless commensal of children. Comparative genomics have yet to yield clear insights into which factors dictate the unique host-parasite relationships exhibited by each since, as a group, they display remarkable conservation at the levels of nucleotide sequence, gene content and synteny. Here, we discovered two rare alterations in the gene encoding the CcoP protein component of cytochrome cbb 3 oxidase that are phylogenetically informative. One is a single nucleotide polymorphism resulting in CcoP truncation that acts as a molecular signature for the species N. meningitidis. We go on to show that the ancestral ccoP gene arose by a unique gene duplication and fusion event and is specifically and completely distributed within species of the genus Neisseria. Surprisingly, we found that strains engineered to express either of the two CcoP forms conditionally differed in their capacity to support nitrite-dependent, microaerobic growth mediated by NirK, a nitrite reductase. Thus, we propose that changes in CcoP domain architecture and ensuing alterations in function are key traits in successive, adaptive radiations within these metapopulations. These findings provide a dramatic example of how rare changes in core metabolic proteins can be connected to significant macroevolutionary shifts. They also show how evolutionary change at the molecular level can be linked to metabolic innovation and its reversal as well as demonstrating how genotype can be used to infer alterations of the fitness landscape within a single host. PMID:20808844

  20. Molecular detection of altered X-inactivation patterns in the diagnosis of genetic disease.

    PubMed

    Malcolm, S

    1992-01-01

    It is widely assumed that when a female carrier of a genetic disorder exhibits clinical signs of the disorder it is due to chance non-random X-inactivation in particular tissues. Recently molecular methods have become available for the analysis of X-chromosome inactivation status. These are based either on the methylation patterns of DNA from the active and inactive chromosomes or on the rescue of active X chromosomes in somatic cell hybrids. As a consequence of the molecular studies, it has become obvious that there are some special cases of non-random X-inactivation patterns. These include females carrying X-linked immunodeficiencies and, sometimes, one of a pair of identical female twins.

  1. 78 FR 64196 - Privacy Act Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-28

    ...-20, Biographical Files. SUMMARY: The Department of Commerce (Commerce) publishes this notice to..., Biographical Files. The notice of proposed amendment to this system of records was published in the Federal..., Biographical Files (78 FR 171). In that notice, the Department announced its intent to amend that system...

  2. Polyglutamine expansion alters the dynamics and molecular architecture of aggregates in dentatorubropallidoluysian atrophy.

    PubMed

    Hinz, Justyna; Lehnhardt, Lothar; Zakrzewski, Silke; Zhang, Gong; Ignatova, Zoya

    2012-01-13

    Preferential accumulation of mutant proteins in the nucleus has been suggested to be the molecular culprit that confers cellular toxicity in the neurodegenerative disorders caused by polyglutamine (polyQ) expansion. Here, we use dynamic imaging approaches, orthogonal cross-seeding, and composition analysis to examine the dynamics and structure of nuclear and cytoplasmic inclusions of atrophin-1, implicated in dentatorubropallidoluysian atrophy, a polyQ-based disease with complex clinical features. Our results reveal a large heterogeneity in the dynamics of the nuclear inclusions compared with the compact and immobile cytoplasmic aggregates. At least two types of inclusions of expanded atrophin-1 with different mobility of the molecular species and ability to exchange with the surrounding monomer pool coexist in the nucleus. Intriguingly, the enrichment of nuclear inclusions with slow dynamics parallels changes in the aggregate core architecture that are dominated by the polyQ stretch. We propose that the observed complexity in the dynamics of the nuclear inclusions provides a molecular explanation for the enhanced cellular toxicity of the nuclear aggregates in polyQ-based neurodegeneration.

  3. Polyglutamine Expansion Alters the Dynamics and Molecular Architecture of Aggregates in Dentatorubropallidoluysian Atrophy*

    PubMed Central

    Hinz, Justyna; Lehnhardt, Lothar; Zakrzewski, Silke; Zhang, Gong; Ignatova, Zoya

    2012-01-01

    Preferential accumulation of mutant proteins in the nucleus has been suggested to be the molecular culprit that confers cellular toxicity in the neurodegenerative disorders caused by polyglutamine (polyQ) expansion. Here, we use dynamic imaging approaches, orthogonal cross-seeding, and composition analysis to examine the dynamics and structure of nuclear and cytoplasmic inclusions of atrophin-1, implicated in dentatorubropallidoluysian atrophy, a polyQ-based disease with complex clinical features. Our results reveal a large heterogeneity in the dynamics of the nuclear inclusions compared with the compact and immobile cytoplasmic aggregates. At least two types of inclusions of expanded atrophin-1 with different mobility of the molecular species and ability to exchange with the surrounding monomer pool coexist in the nucleus. Intriguingly, the enrichment of nuclear inclusions with slow dynamics parallels changes in the aggregate core architecture that are dominated by the polyQ stretch. We propose that the observed complexity in the dynamics of the nuclear inclusions provides a molecular explanation for the enhanced cellular toxicity of the nuclear aggregates in polyQ-based neurodegeneration. PMID:22134925

  4. Functional alterations of the stomatognathic system in patients with allergic rhinitis: case-control study.

    PubMed

    Lemos, Catiane Maçaira de; Wilhelmsen, Niels Sales Willo; Mion, Olavo de Godoy; Mello Júnior, João Ferreira de

    2009-01-01

    Mouth breathing can cause structural and functional alterations to the stomatognathic system. The aim of this investigation was to study breathing, chewing, swallowing and speaking alterations present in patients with allergic rhinitis and associate it to rhinitis symptom intensity. 170 patients between the ages of 6 and 55 years were prospectively evaluated in this study, all of them underwent both otorhinolaryngological and speech evaluation. Data on breathing, chewing, swallowing and speaking was gathered, as well as data from the medical evaluation. The data was compared and statistically analyzed. The difference in signs and symptoms' score between GR and GC was significant. We noticed a significant difference between GR and GC in breathing, chewing and swallowing. We observed a significant association between the score of nasal obstruction and the intensity of breathing and chewing alterations. Patients with allergic rhinitis have functional alterations in their stomatognathic system and an increase in nasal obstruction scores can be considered as a indication of such alterations.

  5. Systemic leukocyte alterations are associated with invasive uterine cervical cancer.

    PubMed

    Tavares-Murta, Beatriz M; Mendonça, Maria A O; Duarte, Natália L; da Silva, Juliana A; Mutão, Taciana S; Garcia, Cristiana B; Murta, Eddie F C

    2010-10-01

    The aim of the study was to evaluate blood leukocyte counts in patients with uterine cervical neoplasia. Patients treated at a university hospital were reviewed retrospectively. Disease progression was monitored, beginning in 1990 to 2002, for at least 5 years. Blood count parameters included absolute leukocyte, neutrophil and lymphocyte counts, leukocytosis (white blood cells > 10³/μL), neutrophilia (neutrophils ≥ 70% of leukocytes), lymphopenia (lymphocytes ≤ 15% of leukocytes), and the neutrophil-lymphocyte ratio (NLR), categorized as less than 5 or 5 or greater. A total of 315 patients were enrolled: 182 (57.8%) with preinvasive neoplasia (cervical intraepithelial neoplasia [CIN] group), 95 (30.1%) with stages I to II (early group), and 38 patients (12.1%) with stages III to IV neoplasia (advanced group). Neutrophil and lymphocyte counts were elevated and reduced, respectively, at advanced stages compared with the CIN group (P < 0.05). Leukocytosis, neutrophilia, lymphopenia, and an NLR of 5 or greater were more frequent at advanced stages compared with the CIN and early-stage groups (P < 0.05). Moreover, neutrophilia was also significantly more frequent at early stage compared with the CIN group. The advanced group with neutrophilia had increased frequency of recidivism and metastasis than patients in the CIN group with neutrophilia (P < 0.05). Patients with advanced cervical cancer had significantly higher frequency of leukocyte alterations, although they may occur apart from the preinvasive stages. Overall, neutrophilia was the best indicator of cancer invasiveness.

  6. Molecular alterations in tumorigenic human bronchial and breast epithelial cells induced by high let radiation

    NASA Astrophysics Data System (ADS)

    Hei, T. K.; Zhao, Y. L.; Roy, D.; Piao, C. Q.; Calaf, G.; Hall, E. J.

    Carcinogenesis is a multi-stage process with sequence of genetic events governing the phenotypic expression of a series of transformation steps leading to the development of metastatic cancer. In the present study, immortalized human bronchial (BEP2D) and breast (MCF-10F) cells were irradiated with graded doses of either 150 keV/μm alpha particles or 1 GeV/nucleon 56Fe ions. Transformed cells developed through a series of successive steps before becoming tumorigenic in nude mice. Cell fusion studies indicated that radiation-induced tumorigenic phenotype in BEP2D cells could be completely suppressed by fusion with non-tumorigenic BEP2D cells. The differential expressions of known genes between tumorigenic bronchial and breast cells induced by alpha particles and their respective control cultures were compared using cDNA expression array. Among the 11 genes identified to be differentially expressed in BEP2D cells, three ( DCC, DNA-PK and p21 CIPI) were shown to be consistently down-regulated by 2 to 4 fold in all the 5 tumor cell lines examined. In contrast, their expressions in the fusion cell lines were comparable to control BEP2D cells. Similarly, expression levels of a series of genes were found to be altered in a step-wise manner among tumorigenic MCF-10F cells. The results are highly suggestive that functional alterations of these genes may be causally related to the carcinogenic process.

  7. 75 FR 19652 - Privacy Act of 1974; Report of an Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-15

    ... practitioners who are the subjects of databases collected and maintained by State Primary Care Offices... have access to their data. The purposes of these alterations are to update the system manager location... information for the purpose of assisting [[Page 19653

  8. Clinicopathological and molecular alterations in early gastric cancers with the microsatellite instability‐high phenotype

    PubMed Central

    Sugimoto, Ryo; Habano, Wataru; Endoh, Masaki; Eizuka, Makoto; Yamamoto, Eiichiro; Uesugi, Noriyuki; Ishida, Kazuyuki; Kawasaki, Tomonori; Matsumoto, Takayuki; Suzuki, Hiromu

    2015-01-01

    The relevance of the clinicopathological and molecular features of early gastric cancers (EGCs) having the microsatellite instability (MSI)‐high phenotype has not been clearly defined in sporadic gastric carcinogenesis. Here, we examined the clinicopathological and molecular characteristics of EGC according to MSI status in 330 patients with EGC (intestinal‐type adenocarcinoma). Tumors were classified as MSI‐high (45 cases), MSI‐low (9 cases), or microsatellite stable (MSS; 276 cases). The specimens were examined using a combination of polymerase chain reaction (PCR)‐microsatellite assays and PCR‐pyrosequencing to detect chromosomal allelic imbalances in multiple cancer‐related chromosomal loci, MSI, gene mutations (KRAS and BRAF) and methylation status [high methylation epigenome (HME), intermediate methylation epigenome and low methylation epigenome]. In addition, the expression levels of various target proteins were examined using immunohistochemistry. Interestingly, EGC with the MSI phenotype showed distinct papillary features. The expression of gastric mucin was more frequent in EGC with the MSI phenotype, while p53 overexpression was common in EGCs, irrespective of MSI status. The frequency of HME was significantly higher in EGCs with the MSI phenotype than in EGCs with the MSS phenotype. Although there was a low frequency of allelic imbalance in EGCs with the MSI phenotype, some markers of allelic imbalance were more frequently detected in EGCs with the MSI‐high phenotype than in EGCs with the MSS phenotype. KRAS and BRAF mutations were rare in EGCs. Thus, the MSI phenotype in EGC is a major precursor lesion in gastric cancer and is characterized by distinct clinicopathological and molecular features. PMID:26538087

  9. Cell Cycle Control and Adhesion Molecule Expression in Cells of the Immune System are Sensitive to Altered Gravity

    NASA Astrophysics Data System (ADS)

    Ullrich, O.; Paulsen, K.; Thiel, C.; Herrmann, K.; Sang, C.; Han, G.; Hemmersbach, R.; von der Wiesche, M.; Kroll, H.; Zhuang, F.; Grote, K. H.; Cogoli, A.; Zipp, F.; Engelmann, F.

    2008-06-01

    Life on earth developed in the presence and under the constant influence of gravity. Thus, it is a fundamental biological question, whether gravity is required for cellular functions and signal transduction in mammalian cells. Since the first Spacelab-Mission 20 years ago, it is known that activation and function of T lymphocytes is severely suppressed in microgravity, but the underlying molecular mechanisms are not elucidated. Experiments have been performed using ground-based facilities such as fast-rotating clinostat and hyper-g-centrifuges, and real microgravity provided by parabolic flights. We found that 1.) cells of the immune system responded cell type specifically to altered gravity, 2.) microgravity induced a multitude of initial alterations in signal transduction, whereas 3.) hypergravity of 1.8g did not induce any changes of the pathways tested, and that 4.) most of the initially altered pathways in microgravity adapted to "normal" levels within 15min. However, some pathways remained altered and could explain cell cycle arrest of T lymphocytes as observed in several long-term space experiments.

  10. Molecular estimation of alteration in intestinal microbial composition in Hashimoto's thyroiditis patients.

    PubMed

    Ishaq, Hafiz Muhammad; Mohammad, Imran Shair; Guo, Hui; Shahzad, Muhammad; Hou, Yin Jian; Ma, Chaofeng; Naseem, Zahid; Wu, Xiaokang; Shi, Peijie; Xu, Jiru

    2017-09-09

    The gut microbiota has a crucial effect on human health and physiology. Hypothyroid Hashimoto's thyroiditis (HT) is an autoimmune disorder manifested with environmental and genetic factors. However, it is hypothesized that intestinal microbes might play a vital role in the pathogenesis of HT. The aim of current was to investigate and characterize the gut microbial composition of HT patients both quantitatively and qualitatively. The fecal samples from 29 HT patients and 12 healthy individuals were collected. The PCR-DGGE targeted V3 site of 16S rRNA gene and real time PCR for Bifidobacterium Lactobacillus, Bacteroides vulgatus and Clostridium leptum were performed. Pyrosequencing of 16S rRNA gene with V4 location was performed on 20 randomly selected samples. The comparative analysis of diversity and richness indices revealed diversification of gut microbiota in HT as compared to control. The statistical data elucidate the alterations in phyla of HT patients which was also affirmed at the family level. We observed the declined abundance of Prevotella_9 and Dialister, while elevated genera of the diseased group included Escherichia-Shigella and Parasutterella. The alteration in gut microbial configuration was also monitored at the species level, which showed an increased abundance of E. coli in HT. Therefore, the current study is in agreement with the hypothesis that HT patients have intestinal microbial dysbiosis. The taxa statistics at species-level along with each gut microbial community were modified in HT. Thus, the current study may offer the new insights into the treatment of HT patients, disease pathway, and mechanism. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  11. Plasma zinc's alter ego is a low-molecular-weight humoral factor.

    PubMed

    Ou, Ou; Allen-Redpath, Keith; Urgast, Dagmar; Gordon, Margaret-Jane; Campbell, Gill; Feldmann, Jörg; Nixon, Graeme F; Mayer, Claus-Dieter; Kwun, In-Sook; Beattie, John H

    2013-09-01

    Mild dietary zinc deprivation in humans and rodents has little effect on blood plasma zinc levels, and yet cellular consequences of zinc depletion can be detected in vascular and other tissues. We proposed that a zinc-regulated humoral factor might mediate the effects of zinc deprivation. Using a novel approach, primary rat vascular smooth muscle cells (VSMCs) were treated with plasma from zinc-deficient (<1 mg Zn/kg) or zinc-adequate (35 mg Zn/kg, pair-fed) adult male rats, and zinc levels were manipulated to distinguish direct and indirect effects of plasma zinc. Gene expression changes were analyzed by microarray and qPCR, and incubation of VSMCs with blood plasma from zinc-deficient rats strongly changed the expression of >2500 genes, compared to incubation of cells with zinc-adequate rat plasma. We demonstrated that this effect was caused by a low-molecular-weight (∼2-kDa) zinc-regulated humoral factor but that changes in gene expression were mostly reversed by adding zinc back to zinc-deficient plasma. Strongly regulated genes were overrepresented in pathways associated with immune function and development. We conclude that zinc deficiency induces the production of a low-molecular-weight humoral factor whose influence on VSMC gene expression is blocked by plasma zinc. This factor is therefore under dual control by zinc.

  12. Study of gene expression alteration in male androgenetic alopecia: evidence of predominant molecular signaling pathways.

    PubMed

    Michel, L; Reygagne, P; Benech, P; Jean-Louis, F; Scalvino, S; Ly Ka So, S; Hamidou, Z; Bianovici, S; Pouch, J; Ducos, B; Bonnet, M; Bensussan, A; Patatian, A; Lati, E; Wdzieczak-Bakala, J; Choulot, J-C; Loing, E; Hocquaux, M

    2017-04-12

    Male androgenetic alopecia (AGA) is the most common form of hair loss in men and is characterized by a distinct pattern of progressive hair loss starting from the frontal area and the vertex of the scalp. Although several genetic risk loci have been identified, relevant genes for AGA remain to be defined. Herein, molecular biomarkers associated with premature AGA were identified through gene expression analysis using cDNA generated from scalp vertex biopsies of hairless/bald men with premature AGA and healthy volunteers. This monocentric study reveals that genes encoding mast cell granule enzymes, inflammatory and immunoglobulin-associated immune mediators were significantly over-expressed in AGA. In contrast, under-expressed genes appear to be associated with the Wnt/β-catenin and BMP/TGF-β signaling pathways. Although involvement of these pathways in hair follicle regeneration is well-described, functional interpretation of the transcriptomic data highlights different events that account for their inhibition. In particular, one of these events depends on the dysregulated expression of proopiomelanocortin (POMC), as confirmed by RT-qPCR and immunohistochemistry. In addition, lower expression of CYP27B1 in AGA subjects supports the notion that changes in vitamin D metabolism contributes to hair loss. This study provides compelling evidence for distinct molecular events contributing to alopecia that may pave way for new therapeutic approaches. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  13. Molecular driver alterations and their clinical relevance in cancer of unknown primary site.

    PubMed

    Löffler, Harald; Pfarr, Nicole; Kriegsmann, Mark; Endris, Volker; Hielscher, Thomas; Lohneis, Philipp; Folprecht, Gunnar; Stenzinger, Albrecht; Dietel, Manfred; Weichert, Wilko; Krämer, Alwin

    2016-07-12

    Cancer of unknown primary (CUP) is defined as metastatic solid malignancy where no primary tumor is detected despite appropriate staging. About 90% of CUP represent adenocarcinoma or undifferentiated carcinoma. Since therapy regimens are only modestly effective, identification of the molecular landscape of these neoplasms might be a promising approach to direct CUP therapy and aid in tumor classification. We screened a cohort of 128 patients with adenocarcinoma or undifferentiated carcinoma meeting the definition of CUP. Massive parallel multigene sequencing of 50 genes, which had been selected due to their relevance as oncogenic drivers or druggable molecular targets could ultimately be performed on samples from 55 patients for whom complete clinical datasets were also available. Overall, 60 tumor-specific mutations and 29 amplifications/deletions, as revealed by coverage analysis, were detected in 46 cases (84%). The most frequently mutated genes were TP53 (30 cases, 55%), KRAS (9 cases, 16%), CDKN2A (5 cases, 9%), and SMAD4 (5 cases, 9%). The most frequently deleted gene was CDKN2A (8 cases, 15%). KRAS and CDKN2A mutations significantly correlated with poor progression-free survival (PFS) and, in case of KRAS, overall survival (OS). WIldtype TP53 and female sex defined a relatively favorable category, with favorable PFS and OS. 8 cases (15%) harbored mutations that may be targetable by currently approved drugs. Taken together, Mutations of relevant driver genes are present in the vast majority of CUP tumors. Some of them impact on prognosis and a subset is putatively druggable.

  14. Altered MCM Protein Levels and Autophagic Flux in Aged and Systemic Sclerosis Dermal Fibroblasts

    PubMed Central

    Dumit, Verónica I.; Küttner, Victoria; Käppler, Jakob; Piera-Velazquez, Sonsoles; Jimenez, Sergio A.; Bruckner-Tuderman, Leena; Uitto, Jouni; Dengjel, Jörn

    2014-01-01

    Aging is a common risk factor of many disorders. With age, the level of insoluble extracellular matrix increases leading to increased stiffness of a number of tissues. Matrix accumulation can also be observed in fibrotic disorders, such as systemic sclerosis (SSc). Although the intrinsic aging process in skin is phenotypically distinct from SSc, here we demonstrate similar behavior of aged and SSc skin fibroblasts in culture. We have used quantitative proteomics to characterize the phenotype of dermal fibroblasts from healthy subjects of various ages and from patients with SSc. Our results demonstrate that proteins involved in DNA and RNA processing decrease with age and in SSc, while those involved in mitochondrial and other metabolic processes behave the opposite. Specifically, mini-chromosome maintenance (MCM) helicase proteins are less abundant with age and SSc, and they exhibit an altered subcellular distribution. We observed that lower levels of MCM7 correlate with reduced cell proliferation, lower autophagic capacity and higher intracellular protein expression phenotypes of aged and SSc cells. Additionally, we show that SSc fibroblasts exhibit higher levels of senescence than their healthy counterparts, suggesting further similarities between the fibrotic disorder and the aging process. Hence, at the molecular level, SSc fibroblasts exhibit intrinsic characteristics of fibroblasts from aged skin. PMID:24496236

  15. Does glimepiride alter the pharmacokinetics of sildenafil citrate in diabetic nephropathy animals: investigating mechanism of interaction by molecular modeling studies.

    PubMed

    Tripathi, Alok Shiomurti; Timiri, Ajay Kumar; Mazumder, Papiya Mitra; Chandewar, Anil

    2015-10-01

    The present study evaluates possible drug interactions between glimepiride (GLIM) and sildenafil citrate (SIL) in streptozotocin (STZ)-induced diabetic nephropathic (DN) animals and also postulates the possible mechanism of interaction based on molecular modeling studies. Diabetic nephropathy was induced by single dose of STZ (60 mg kg(-1), i.p.) and was confirmed by assessing blood and urine biochemical parameters 28 days after induction. Selected DN animals were used to explore the drug interaction between GLIM (0.5 mg kg(-1), p.o.) and SIL (2.5 mg kg(-1), p.o.) on the 29th and 70th day of the protocol. Possible drug interaction was assessed by evaluating the plasma drug concentration using HPLC-UV and changes in biochemical parameters in blood and urine were also determined. The mechanism of the interaction was postulated from the results of a molecular modeling study using the Maestro module of Schrodinger software. DN was confirmed as there was significant alteration in blood and urine biochemical parameters in STZ-treated groups. The concentration of SIL increased significantly (P < 0.001) in rat plasma when co-administered with GLIM on the 70th day of the protocol. Molecular modeling revealed important interactions with rat serum albumin and CYP2C9. GLIM has a strong hydrophobic interaction with binding site residues of rat serum albumin compared to SIL, whereas for CYP2C9, GLIM forms a stronger hydrogen bond than SIL with polar contacts and hydrophobic interactions. The present study concludes that bioavailability of SIL increases when co-administered chronically with GLIM in the management of DN animals, and the mechanism is supported by molecular modeling studies.

  16. 75 FR 5604 - Privacy Act of 1974; Report of an Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-03

    ... HUMAN SERVICES Health Resources and Services Administration Privacy Act of 1974; Report of an Altered... requirements of the Privacy Act of 1974, the Health Resources and Services Administration (HRSA) is proposing... of the system, the system location, categories of individuals covered by the system, categories...

  17. Systemic IL-12 Administration Alters Hepatic Dendritic Cell Stimulation Capabilities

    PubMed Central

    Chan, Tim; Back, Timothy C.; Subleski, Jeffrey J.; Weiss, Jonathan M.; Ortaldo, John R.; Wiltrout, Robert H.

    2012-01-01

    The liver is an immunologically unique organ containing tolerogenic dendritic cells (DC) that maintain an immunosuppressive microenvironment. Although systemic IL-12 administration can improve responses to tumors, the effects of IL-12-based treatments on DC, in particular hepatic DC, remain incompletely understood. In this study, we demonstrate systemic IL-12 administration induces a 2–3 fold increase in conventional, but not plasmacytoid, DC subsets in the liver. Following IL-12 administration, hepatic DC became more phenotypically and functionally mature, resembling the function of splenic DC, but differed as compared to their splenic counterparts in the production of IL-12 following co-stimulation with toll-like receptor (TLR) agonists. Hepatic DCs from IL-12 treated mice acquired enhanced T cell proliferative capabilities similar to levels observed using splenic DCs. Furthermore, IL-12 administration preferentially increased hepatic T cell activation and IFNγ expression in the RENCA mouse model of renal cell carcinoma. Collectively, the data shows systemic IL-12 administration enables hepatic DCs to overcome at least some aspects of the inherently suppressive milieu of the hepatic environment that could have important implications for the design of IL-12-based immunotherapeutic strategies targeting hepatic malignancies and infections. PMID:22428016

  18. Molecular driver alterations and their clinical relevance in cancer of unknown primary site

    PubMed Central

    Endris, Volker; Hielscher, Thomas; Lohneis, Philipp; Folprecht, Gunnar; Stenzinger, Albrecht; Dietel, Manfred

    2016-01-01

    Cancer of unknown primary (CUP) is defined as metastatic solid malignancy where no primary tumor is detected despite appropriate staging. About 90% of CUP represent adenocarcinoma or undifferentiated carcinoma. Since therapy regimens are only modestly effective, identification of the molecular landscape of these neoplasms might be a promising approach to direct CUP therapy and aid in tumor classification. We screened a cohort of 128 patients with adenocarcinoma or undifferentiated carcinoma meeting the definition of CUP. Massive parallel multigene sequencing of 50 genes, which had been selected due to their relevance as oncogenic drivers or druggable molecular targets could ultimately be performed on samples from 55 patients for whom complete clinical datasets were also available. Overall, 60 tumor-specific mutations and 29 amplifications/deletions, as revealed by coverage analysis, were detected in 46 cases (84%). The most frequently mutated genes were TP53 (30 cases, 55%), KRAS (9 cases, 16%), CDKN2A (5 cases, 9%), and SMAD4 (5 cases, 9%). The most frequently deleted gene was CDKN2A (8 cases, 15%). KRAS and CDKN2A mutations significantly correlated with poor progression-free survival (PFS) and, in case of KRAS, overall survival (OS). WIldtype TP53 and female sex defined a relatively favorable category, with favorable PFS and OS. 8 cases (15%) harbored mutations that may be targetable by currently approved drugs. Taken together, Mutations of relevant driver genes are present in the vast majority of CUP tumors. Some of them impact on prognosis and a subset is putatively druggable. PMID:27322425

  19. Sperm of patients with severe asthenozoospermia show biochemical, molecular and genomic alterations.

    PubMed

    Bonanno, Oriana; Romeo, Giulietta; Asero, Paola; Pezzino, Franca Maria; Castiglione, Roberto; Burrello, Nunziatina; Sidoti, Giuseppe; Frajese, Giovanni Vanni; Vicari, Enzo; D'Agata, Rosario

    2016-12-01

    The multifactorial pathological condition, that is, severe low sperm motility is a frequent cause of infertility. However, mechanisms underlying the development of this condition are not completely understood. Single abnormalities have been reported in sperm of patients with asthenozoospermia. In this study, we characterized, in 22 normozoospermic men and in 37 patients with asthenozoospermia, biochemical, molecular and genomic abnormalities that frequently occur in sperm of patients with asthenozoospermia. We evaluated a panel of sperm biomarkers that may affect the motility and fertilizing ability of sperm of patients with severe asthenozoospermia. Since reactive oxygen species (ROS) production is involved in the pathogenesis of such sperm abnormalities, we determined the association between ROS production and sperm abnormalities. High percentage of patients with severe asthenozoospermia showed increased basal and stimulated ROS production. Moreover, these patients showed increased mitochondrial DNA (mtDNA) copy number but decreased mtDNA integrity and they were associated with elevated ROS levels. Furthermore, mitochondrial membrane potential was also significantly decreased and again associated with high ROS production in these patients. However, the rate of nuclear DNA fragmentation was increased only in less than one-fifth of these patients. An important cohort of these patients showed multiple identical biochemical, molecular and genomic abnormalities, which are typical manifestations of oxidative stress. The most frequent association was found in patients with high ROS levels, increased mtDNA copy number and decreased integrity, and low MMP. A smaller cohort of the aforementioned patients also showed nDNA fragmentation. Therefore, patients with asthezoospermia likely present reduced fertilizing potential because of such composed abnormalities.

  20. Molecular and genetic alterations associated with therapy resistance and relapse of acute myeloid leukemia.

    PubMed

    Hackl, Hubert; Astanina, Ksenia; Wieser, Rotraud

    2017-02-20

    The majority of individuals with acute myeloid leukemia (AML) respond to initial chemotherapy and achieve a complete remission, yet only a minority experience long-term survival because a large proportion of patients eventually relapse with therapy-resistant disease. Relapse therefore represents a central problem in the treatment of AML. Despite this, and in contrast to the extensive knowledge about the molecular events underlying the process of leukemogenesis, information about the mechanisms leading to therapy resistance and relapse is still limited. Recently, a number of studies have aimed to fill this gap and provided valuable information about the clonal composition and evolution of leukemic cell populations during the course of disease, and about genetic, epigenetic, and gene expression changes associated with relapse. In this review, these studies are summarized and discussed, and the data reported in them are compiled in order to provide a resource for the identification of molecular aberrations recurrently acquired at, and thus potentially contributing to, disease recurrence and the associated therapy resistance. This survey indeed uncovered genetic aberrations with known associations with therapy resistance that were newly gained at relapse in a subset of patients. Furthermore, the expression of a number of protein coding and microRNA genes was reported to change between diagnosis and relapse in a statistically significant manner. Together, these findings foster the expectation that future studies on larger and more homogeneous patient cohorts will uncover pathways that are robustly associated with relapse, thus representing potential targets for rationally designed therapies that may improve the treatment of patients with relapsed AML, or even facilitate the prevention of relapse in the first place.

  1. Logic circuits based on molecular spider systems.

    PubMed

    Mo, Dandan; Lakin, Matthew R; Stefanovic, Darko

    2016-08-01

    Spatial locality brings the advantages of computation speed-up and sequence reuse to molecular computing. In particular, molecular walkers that undergo localized reactions are of interest for implementing logic computations at the nanoscale. We use molecular spider walkers to implement logic circuits. We develop an extended multi-spider model with a dynamic environment wherein signal transmission is triggered via localized reactions, and use this model to implement three basic gates (AND, OR, NOT) and a cascading mechanism. We develop an algorithm to automatically generate the layout of the circuit. We use a kinetic Monte Carlo algorithm to simulate circuit computations, and we analyze circuit complexity: our design scales linearly with formula size and has a logarithmic time complexity.

  2. Differential behavioral and molecular alterations upon protracted abstinence from cocaine versus morphine, nicotine, THC and alcohol.

    PubMed

    Becker, Jérôme A J; Kieffer, Brigitte L; Le Merrer, Julie

    2016-04-28

    Unified theories of addiction are challenged by differing drug-seeking behaviors and neurobiological adaptations across drug classes, particularly for narcotics and psychostimulants. We previously showed that protracted abstinence to opiates leads to despair behavior and social withdrawal in mice, and we identified a transcriptional signature in the extended amygdala that was also present in animals abstinent from nicotine, Δ9-tetrahydrocannabinol (THC) and alcohol. Here we examined whether protracted abstinence to these four drugs would also share common behavioral features, and eventually differ from abstinence to the prototypic psychostimulant cocaine. We found similar reduced social recognition, increased motor stereotypies and increased anxiety with relevant c-fos response alterations in morphine, nicotine, THC and alcohol abstinent mice. Protracted abstinence to cocaine, however, led to strikingly distinct, mostly opposing adaptations at all levels, including behavioral responses, neuronal activation and gene expression. Together, these data further document the existence of common hallmarks for protracted abstinence to opiates, nicotine, THC and alcohol that develop within motivation/emotion brain circuits. In our model, however, these do not apply to cocaine, supporting the notion of unique mechanisms in psychostimulant abuse.

  3. Altering intra- to inter-molecular hydrogen bonding by dimethylsulfoxide: A TDDFT study of charge transfer for coumarin 343

    NASA Astrophysics Data System (ADS)

    Liu, Xiaochun; Yin, Hang; Li, Hui; Shi, Ying

    2017-04-01

    DFT and TDDFT methods were carried out to investigate the influences of intramolecular and intermolecular hydrogen bonding on excited state charge transfer for coumarin 343 (C343). Intramolecular hydrogen bonding is formed between carboxylic acid group and carbonyl group in C343 monomer. However, in dimethylsulfoxide (DMSO) solution, DMSO 'opens up' the intramolecular hydrogen bonding and forms solute-solvent intermolecular hydrogen bonded C343-DMSO complex. Analysis of frontier molecular orbitals reveals that intramolecular charge transfer (ICT) occurs in the first excited state both for C343 monomer and complex. The results of optimized geometric structures indicate that the intramolecular hydrogen bonding interaction is strengthened while the intermolecular hydrogen bonding is weakened in excited state, which is confirmed again by monitoring the shifts of characteristic peaks of infrared spectra. We demonstrated that DMSO solvent can not only break the intramolecular hydrogen bonding to form intermolecular hydrogen bonding with C343 but also alter the mechanism of excited state hydrogen bonding strengthening.

  4. Hydrothermal alteration in the Reykjanes geothermal system: Insights from Iceland deep drilling program well RN-17

    NASA Astrophysics Data System (ADS)

    Marks, Naomi; Schiffman, Peter; Zierenberg, Robert A.; Franzson, Hjalti; Fridleifsson, Gudmundur Ó.

    2010-01-01

    The Reykjanes geothermal system is a seawater-recharged hydrothermal system that appears to be analogous to seafloor hydrothermal systems in terms of host rock type and low water/rock alteration. The similarities make the Reykjanes system a useful proxy for seafloor vents. At some time during the Pleistocene, the system was dominated by meteoric water recharge, and fluid composition at Reykjanes has evolved through time as a result of changing proportions of meteoric water influx as well as differing pressure and temperature conditions. The purpose of this study is to characterize secondary mineralization, degree of metasomatic alteration, and bulk composition of cuttings from well RN-17 from the Reykjanes geothermal system. The basaltic host rock includes hyaloclastite, breccia, tuff, extrusive basalt, diabase, as well as a marine sedimentary sequence. The progressive hydrothermal alteration sequence observed with increasing depth results from reaction of geothermal fluids with the basaltic host rock. An assemblage of greenschist facies alteration minerals, including actinolite, prehnite, epidote and garnet, occurs at depths as shallow as 350 m; these minerals are commonly found in Icelandic geothermal systems at temperatures above 250 °C (Bird and Spieler, 2004). This requires hydrostatic pressures that exceed the present-day depth to boiling point curve, and therefore must record alteration at higher fluid pressures, perhaps as a result of Pleistocene glaciation. Major, minor, and trace element profiles of the cuttings indicate transitional MORB to OIB composition with limited metasomatic shifts in easily mobilized elements. Changes in MgO, K 2O and loss on ignition indicate that metasomatism is strongly correlated with protolith properties. The textures of alteration minerals reveal alteration style to be strongly dependent on protolith as well. Hyaloclastites are intensely altered with calc-silicate alteration assemblages comprising calcic hydrothermal

  5. Alterations to calling criteria for Between the Flags (an early warning system)

    PubMed Central

    Davis, Tessa; Nogajski, Bec

    2015-01-01

    Early warning systems aim to detect clinical deterioration of patients at an early stage. Between the Flags was introduced in New South Wales Health for this purpose. When patients are transferred from the emergency department to the ward, there are circumstances when the calling criteria need to be altered to take into account the clinical context. It is recognised that confusion exists among junior medical staff about the process of making alterations to the Between the Flags calling criteria. A quality improvement project was implemented by undertaking a baseline survey of junior medical staff, providing education and training (to junior medical staff on the existing guidelines for making alteration to the calling criteria), and conducting a post-implementation survey. A baseline survey demonstrated that 74% of junior medical staff had received no education on making alterations and only 5% knew how long their alterations would last once the patient was transferred to the ward. This has potentially serious consequences for patient safety following transfer. After implementation of training, we found that 63% of junior medical staff were aware of the guidelines on making alterations and 50% knew how long their alterations would last once the patient was transferred to the ward. We conclude that educating junior medical staff improved knowledge on the guidelines for making alterations to calling criteria. PMID:26734326

  6. Charged Particle Alterations of Surfaces in the Solar System

    NASA Technical Reports Server (NTRS)

    Johnson, R. E.

    1995-01-01

    The surfaces of 'airless' bodies in the solar system are exposed to the ambient plasma, micrometeorites, and the solar UV. The effects of these space weathering agents on surfaces in the solar system has been studied in this project. In the last three years work was carried out on volatile depletion at Mars, on sputtering of the lunar surface, on absorption by implanted S in vapor-deposited H2O and its relevance to observations of Europa's surface in the UV, and on the spectral changes produced on irradiating SO2 and its possible relevance to Io. In addition, the role of plasma-induced charging of E-ring grains was evaluated because of its relevance to E-ring particle source and the lifetime of the E-ring. Finally, the detection of sputtered material from Dione by the CAPS instrument on CASSINI was evaluated as a tool for analysis of satellite surface composition, and the role of sputtering on the ambient OH in the vicinity of the ice satellites and the E-ring was evaluated.

  7. Gene Expression in Osteolysis: Review on the Identification of Altered Molecular Pathways in Preclinical and Clinical Studies

    PubMed Central

    Veronesi, Francesca; Tschon, Matilde; Fini, Milena

    2017-01-01

    Aseptic loosening (AL) due to osteolysis is the primary cause of joint prosthesis failure. Currently, a second surgery is still the only available treatment for AL, with its associated drawbacks. The present review aims at identifying genes whose expression is altered in osteolysis, and that could be the target of new pharmacological treatments, with the goal of replacing surgery. This review also aims at identifying the molecular pathways altered by different wear particles. We reviewed preclinical and clinical studies from 2010 to 2016, analyzing gene expression of tissues or cells affected by osteolysis. A total of 32 in vitro, 16 in vivo and six clinical studies were included. These studies revealed that genes belonging to both inflammation and osteoclastogenesis pathways are mainly involved in osteolysis. More precisely, an increase in genes encoding for the following factors were observed: Interleukins 6 and 1β (IL16 and β), Tumor Necrosis Factor α (TNFα), nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1), Cathepsin K (CATK) and Tartrate-resistant acid phosphatase (TRAP). Titanium (Ti) and Polyethylene (PE) were the most studied particles, showing that Ti up-regulated inflammation and osteoclastogenesis related genes, while PE up-regulated primarily osteoclastogenesis related genes. PMID:28245614

  8. Asbestos-Induced Cellular and Molecular Alteration of Immunocompetent Cells and Their Relationship with Chronic Inflammation and Carcinogenesis

    PubMed Central

    Matsuzaki, Hidenori; Maeda, Megumi; Lee, Suni; Nishimura, Yasumitsu; Kumagai-Takei, Naoko; Hayashi, Hiroaki; Yamamoto, Shoko; Hatayama, Tamayo; Kojima, Yoko; Tabata, Rika; Kishimoto, Takumi; Hiratsuka, Junichi; Otsuki, Takemi

    2012-01-01

    Asbestos causes lung fibrosis known as asbestosis as well as cancers such as malignant mesothelioma and lung cancer. Asbestos is a mineral silicate containing iron, magnesium, and calcium with a core of SiO2. The immunological effect of silica, SiO2, involves the dysregulation of autoimmunity because of the complications of autoimmune diseases found in silicosis. Asbestos can therefore cause alteration of immunocompetent cells to result in a decline of tumor immunity. Additionally, due to its physical characteristics, asbestos fibers remain in the lung, regional lymph nodes, and the pleural cavity, particularly at the opening sites of lymphatic vessels. Asbestos can induce chronic inflammation in these areas due to the production of reactive oxygen/nitrogen species. As a consequence, immunocompetent cells can have their cellular and molecular features altered by chronic and recurrent encounters with asbestos fibers, and there may be modification by the surrounding inflammation, all of which eventually lead to decreased tumor immunity. In this paper, the brief results of our investigation regarding reduction of tumor immunity of immunocompetent cells exposed to asbestos in vitro are discussed, as are our findings concerned with an investigation of chronic inflammation and analyses of peripheral blood samples derived from patients with pleural plaque and mesothelioma that have been exposed to asbestos. PMID:22500091

  9. Alteration minerals in impact-generated hydrothermal systems - Exploring host rock variability

    NASA Astrophysics Data System (ADS)

    Schwenzer, Susanne P.; Kring, David A.

    2013-09-01

    Impact-generated hydrothermal systems have been previously linked to the alteration of Mars’ crust and the production of secondary mineral assemblages seen from orbit. The sensitivity of the resultant assemblages has not yet been evaluated as a function of precursor primary rock compositions. In this work, we use thermochemical modeling to explore the variety of minerals that could be produced by altering several known lithologies based on martian meteorite compositions. For a basaltic host rock lithology (Dhofar 378, Humphrey) the main alteration phases are feldspar, zeolite, pyroxene, chlorite, clay (nontronite, kaolinite), and hematite; for a lherzolithic host rock lithology (LEW 88516) the main alteration phases are amphibole, serpentine, chlorite, clay (nontronite, kaolinite), and hematite; and for an ultramafic host rock lithology (Chassigny) the main minerals are secondary olivine, serpentine, magnetite, quartz, and hematite. These assemblages and proportions of phases in each of those cases depend on W/R and temperature. Integrating geologic, hydrologic and alteration mineral evidence, we have developed a model to illustrate the distribution of alteration assemblages that occur in different levels of an impact structure. At the surface, hot, hydrous alteration affects the ejecta and melt sheet producing clay and chlorite. Deeper in the subsurface and depending on the permeability of the rock, a variety of minerals - smectite, chlorite, serpentine, amphiboles and hematite - are produced in a circulating hydrothermal system. These modeled mineral distributions should assist with interpretation of orbital observations and help guide surface exploration by rovers and sample return assets.

  10. Motivation alters impression formation and related neural systems

    PubMed Central

    Zaki, Jamil; Ambady, Nalini

    2017-01-01

    Abstract Observers frequently form impressions of other people based on complex or conflicting information. Rather than being objective, these impressions are often biased by observers’ motives. For instance, observers often downplay negative information they learn about ingroup members. Here, we characterize the neural systems associated with biased impression formation. Participants learned positive and negative information about ingroup and outgroup social targets. Following this information, participants worsened their impressions of outgroup, but not ingroup, targets. This tendency was associated with a failure to engage neural structures including lateral prefrontal cortex, dorsal anterior cingulate cortex, temporoparietal junction, Insula and Precuneus when processing negative information about ingroup (but not outgroup) targets. To the extent that participants engaged these regions while learning negative information about ingroup members, they exhibited less ingroup bias in their impressions. These data are consistent with a model of ‘effortless bias’, under which perceivers fail to process goal-inconsistent information in order to maintain desired conclusions. PMID:27798250

  11. Motivation alters impression formation and related neural systems.

    PubMed

    Hughes, Brent L; Zaki, Jamil; Ambady, Nalini

    2017-01-01

    Observers frequently form impressions of other people based on complex or conflicting information. Rather than being objective, these impressions are often biased by observers' motives. For instance, observers often downplay negative information they learn about ingroup members. Here, we characterize the neural systems associated with biased impression formation. Participants learned positive and negative information about ingroup and outgroup social targets. Following this information, participants worsened their impressions of outgroup, but not ingroup, targets. This tendency was associated with a failure to engage neural structures including lateral prefrontal cortex, dorsal anterior cingulate cortex, temporoparietal junction, Insula and Precuneus when processing negative information about ingroup (but not outgroup) targets. To the extent that participants engaged these regions while learning negative information about ingroup members, they exhibited less ingroup bias in their impressions. These data are consistent with a model of 'effortless bias', under which perceivers fail to process goal-inconsistent information in order to maintain desired conclusions.

  12. Molecular mechanisms of altered bile acid homeostasis in organic solute transporter-alpha knockout mice.

    PubMed

    Lan, Tian; Haywood, Jamie; Rao, Anuradha; Dawson, Paul A

    2011-01-01

    Mutations in the apical sodium-dependent bile acid transporter (SLC10A2) block intestinal bile acid absorption, resulting in a compensatory increase in hepatic bile acid synthesis. Inactivation of the basolateral membrane bile acid transporter (OSTα-OSTβ) also impairs intestinal bile acid absorption, but hepatic bile acid synthesis was paradoxically repressed. We hypothesized that the altered bile acid homeostasis resulted from ileal trapping of bile acids that act via the farnesoid X receptor (FXR) to induce overexpression of FGF15. To test this hypothesis, we investigated whether blocking FXR signaling would reverse the bile acid synthesis phenotype in Ostα null mice. The corresponding null mice were crossbred to generate OstαFxr double-null mice. All experiments compared wild-type, Ostα, Fxr and OstαFxr null littermates. Analysis of the in vivo phenotype included measurements of bile acid fecal excretion, pool size and composition. Hepatic and intestinal gene and protein expression were also examined. OstαFxr null mice exhibited increased bile acid fecal excretion and pool size, and decreased bile acid pool hydrophobicity, as compared with Ostα null mice. Inactivation of FXR reversed the increase in ileal total FGF15 expression, which was associated with a significant increase in hepatic Cyp7a1 expression. Inactivation of FXR largely unmasked the bile acid malabsorption phenotype and corrected the bile acid homeostasis defect in Ostα null mice, suggesting that inappropriate activation of the FXR-FGF15-FGFR4 pathway partially underlies this phenotype. Intestinal morphological changes and reduced apical sodium-dependent bile acid transporter expression were maintained in Ostα(-/-)Fxr(-/-) mice, indicating that FXR is not required for these adaptive responses. Copyright © 2011 S. Karger AG, Basel.

  13. Malaria parasite mutants with altered erythrocyte permeability: a new drug resistance mechanism and important molecular tool

    PubMed Central

    Hill, David A; Desai, Sanjay A

    2010-01-01

    Erythrocytes infected with plasmodia, including those that cause human malaria, have increased permeability to a diverse collection of organic and inorganic solutes. While these increases have been known for decades, their mechanistic basis was unclear until electrophysiological studies revealed flux through one or more ion channels on the infected erythrocyte membrane. Current debates have centered on the number of distinct ion channels, which channels mediate the transport of each solute and whether the channels represent parasite-encoded proteins or human channels activated after infection. This article reviews the identification of the plasmodial surface anion channel and other proposed channels with an emphasis on two distinct channel mutants generated through in vitro selection. These mutants implicate parasite genetic elements in the parasite-induced permeability, reveal an important new antimalarial drug resistance mechanism and provide tools for molecular studies. We also critically examine the technical issues relevant to the detection of ion channels by electrophysiological methods; these technical considerations have general applicability for interpreting studies of various ion channels proposed for the infected erythrocyte membrane. PMID:20020831

  14. Antipsychotics-induced metabolic alterations: focus on adipose tissue and molecular mechanisms.

    PubMed

    Gonçalves, Pedro; Araújo, João Ricardo; Martel, Fátima

    2015-01-01

    The use of antipsychotic drugs for the treatment of mood disorders and psychosis has increased dramatically over the last decade. Despite its consumption being associated with beneficial neuropsychiatric effects in patients, atypical antipsychotics (which are the most frequently prescribed antipsychotics) use is accompanied by some secondary adverse metabolic effects such as weight gain, dyslipidemia and glucose intolerance. The molecular mechanisms underlying these adverse effects are not fully understood but have been suggested to involve a dysregulation of adipose tissue homeostasis. As such, the aim of this paper is to review and discuss the role of adipose tissue in the development of secondary adverse metabolic effects induced by atypical antipsychotics. Data analyzed in this article suggest that atypical antipsychotics may increase adipose tissue (particularly visceral adipose tissue) lipogenesis, differentiation/hyperplasia, pro-inflammatory mediator secretion and insulin resistance and decrease adipose tissue lipolysis. Consequently, patients receiving antipsychotic medication could be at risk of developing obesity, type 2 diabetes and cardiovascular disease. A better knowledge of the impact of these drugs on adipose tissue homeostasis may unveil strategies to develop novel antipsychotic drugs with less adverse metabolic effects and to develop adjuvant therapies (e.g. behavioral and nutritional therapies) to neuropsychiatric patients receiving antipsychotic medication. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

  15. Physiological and molecular alterations promoted by Schizotetranychus oryzae mite infestation in rice leaves

    PubMed Central

    Buffon, Giseli; Blasi, Édina A. R.; Adamski, Janete M.; Ferla, Noeli J.; Berger, Markus; Santi, Lucélia; Lavallée-Adam, Mathieu; Yates, John R.; Beys-da-Silva, Walter O.; Sperotto, Raul A.

    2016-01-01

    Infestation of phytophagous mite Schizotetranychus oryzae in rice causes critical yield losses. To better understand this interaction, we employed Multidimensional Protein Identification Technology (MudPIT) approach to identify differentially expressed proteins. We detected 18 unique proteins in control and 872 in infested leaves, respectively, along with 32 proteins more abundant in control leaves. S. oryzae infestation caused decreased abundance of proteins related to photosynthesis (mostly photosystem II-related), carbon assimilation and energy production, chloroplast detoxification, defense, fatty acid and gibberellin synthesis. On the other hand, infestation caused increased abundance of proteins involved in protein modification and degradation, gene expression at the translation level, protein partitioning to different organelles, lipid metabolism, actin cytoskeleton remodeling, and synthesis of jasmonate, amino acid and molecular chaperones. Our results also suggest that S. oryzae infestation promotes cell wall remodeling and interferes with ethylene biosynthesis in rice leaves. Proteomic data were positively correlated with enzymatic assays and RT-qPCR analysis. Our findings describe the protein expression patterns of infested rice leaves, and suggest that the acceptor side of PSII is probably the major damaged target in the photosynthetic apparatus. These data will be useful in future biotechnological approaches aiming to induce phytophagous mite resistance in rice. PMID:26667653

  16. Molecular and cellular alterations in tobacco smoke-associated larynx cancer.

    PubMed

    Szyfter, K; Szmeja, Z; Szyfter, W; Hemminki, K; Banaszewski, J; Jaskuła-Sztul, R; Louhelainen, J

    1999-09-30

    Tumours of head and neck belong to the most frequent types of cancer world-wide. In Poland, mortality from larynx cancer among males has been continuously increasing during the last decades up to 8.4 deaths per 100,000 men in 1993, which exceeds epidemiological records from other countries. The aetiology of laryngeal cancer is strongly associated with exposure to carcinogens present in tobacco smoke. The review describes a sequence of molecular and cellular events from carcinogenic exposure, DNA adduct formation, detection of mutations in the p53 gene, loss of heterozygosity (LOH) in chromosomal loci encoding the p53 and p16 genes, and loss of control of the cell cycle. The section concerning DNA adducts includes a discussion of the role of such confounders as exogenous exposure, the age and sex of the subject, and disease progression. The significance of genetic factors as individual risk determinants is discussed in relation to bleomycin-induced chromosome instability and in connection with the occurrence of defects in genes encoding detoxifying enzymes. The question concerning the substantial difference between men and women in larynx cancer morbidity and mortality remains open, even when the significantly higher adduct formation in male DNA compared with female material was taken into account. Preliminary experiments suggest a role of the frequently observed loss of the Y-chromosome.

  17. Physiological and Molecular Alterations Promoted by Schizotetranychus oryzae Mite Infestation in Rice Leaves.

    PubMed

    Buffon, Giseli; Blasi, Édina A R; Adamski, Janete M; Ferla, Noeli J; Berger, Markus; Santi, Lucélia; Lavallée-Adam, Mathieu; Yates, John R; Beys-da-Silva, Walter O; Sperotto, Raul A

    2016-02-05

    Infestation of phytophagous mite Schizotetranychus oryzae in rice causes critical yield losses. To better understand this interaction, we employed Multidimensional Protein Identification Technology (MudPIT) approach to identify differentially expressed proteins. We detected 18 and 872 unique proteins in control and infested leaves, respectively, along with 32 proteins more abundant in control leaves. S. oryzae infestation caused decreased abundance of proteins related to photosynthesis (mostly photosystem II-related), carbon assimilation and energy production, chloroplast detoxification, defense, and fatty acid and gibberellin synthesis. On the contrary, infestation caused increased abundance of proteins involved in protein modification and degradation, gene expression at the translation level, protein partitioning to different organelles, lipid metabolism, actin cytoskeleton remodeling, and synthesis of jasmonate, amino acid, and molecular chaperones. Our results also suggest that S. oryzae infestation promotes cell-wall remodeling and interferes with ethylene biosynthesis in rice leaves. Proteomic data were positively correlated with enzymatic assays and RT-qPCR analysis. Our findings describe the protein expression patterns of infested rice leaves and suggest that the acceptor side of PSII is probably the major damaged target in the photosynthetic apparatus. These data will be useful in future biotechnological approaches aiming to induce phytophagous mite resistance in rice.

  18. Systematic Analysis of Sex-Linked Molecular Alterations and Therapies in Cancer.

    PubMed

    Ma, Jonathan; Malladi, Sadhika; Beck, Andrew H

    2016-01-12

    Though patient sex influences response to cancer treatments, little is known of the molecular causes, and cancer therapies are generally given irrespective of patient sex. We assessed transcriptomic differences in tumors from men and women spanning 17 cancer types, and we assessed differential expression between tumor and normal samples stratified by sex across 7 cancers. We used the LincsCloud platform to perform Connectivity Map analyses to link transcriptomic signatures identified in male and female tumors with chemical and genetic perturbagens, and we performed permutation testing to identify perturbagens that showed significantly differential connectivity with male and female tumors. Our analyses predicted that females are sensitive and males are resistant to tamoxifen treatment of lung adenocarcinoma, a finding which is consistent with known male-female differences in lung cancer. We made several novel predictions, including that CDK1 and PTPN1 knockdown would be more effective in males with hepatocellular carcinoma, and SMAD3 and HSPA4 knockdown would be more effective in females with head and neck squamous cell carcinoma. Our results provide a new resource for researchers studying male-female biological and treatment response differences in human cancer. The complete results of our analyses are provided at the website accompanying this manuscript (http://becklab.github.io/SexLinked).

  19. Identification of a Human Airway Epithelial Cell Subpopulation with Altered Biophysical, Molecular, and Metastatic Properties.

    PubMed

    Pagano, Paul C; Tran, Linh M; Bendris, Nawal; O'Byrne, Sean; Tse, Henry T; Sharma, Shivani; Hoech, Jonathan W; Park, Stacy J; Liclican, Elvira L; Jing, Zhe; Li, Rui; Krysan, Kostyantyn; Paul, Manash K; Fontebasso, Yari; Larsen, Jill E; Hakimi, Shaina; Seki, Atsuko; Fishbein, Michael C; Gimzewski, James K; Carlo, Dino Di; Minna, John D; Walser, Tonya C; Dubinett, Steven M

    2017-09-01

    Lung cancers are documented to have remarkable intratumoral genetic heterogeneity. However, little is known about the heterogeneity of biophysical properties, such as cell motility, and its relationship to early disease pathogenesis and micrometastatic dissemination. In this study, we identified and selected a subpopulation of highly migratory premalignant airway epithelial cells that were observed to migrate through microscale constrictions at up to 100-fold the rate of the unselected immortalized epithelial cell lines. This enhanced migratory capacity was found to be Rac1-dependent and heritable, as evidenced by maintenance of the phenotype through multiple cell divisions continuing more than 8 weeks after selection. The morphology of this lung epithelial subpopulation was characterized by increased cell protrusion intensity. In a murine model of micrometastatic seeding and pulmonary colonization, the motility-selected premalignant cells exhibit both enhanced survival in short-term assays and enhanced outgrowth of premalignant lesions in longer-term assays, thus overcoming important aspects of "metastatic inefficiency." Overall, our findings indicate that among immortalized premalignant airway epithelial cell lines, subpopulations with heritable motility-related biophysical properties exist, and these may explain micrometastatic seeding occurring early in the pathogenesis of lung cancer. Understanding, targeting, and preventing these critical biophysical traits and their underlying molecular mechanisms may provide a new approach to prevent metastatic behavior. Cancer Prev Res; 10(9); 514-24. ©2017 AACRSee related editorial by Hynds and Janes, p. 491. ©2017 American Association for Cancer Research.

  20. EVI1-rearranged acute myeloid leukemias are characterized by distinct molecular alterations.

    PubMed

    Lavallée, Vincent-Philippe; Gendron, Patrick; Lemieux, Sébastien; D'Angelo, Giovanni; Hébert, Josée; Sauvageau, Guy

    2015-01-01

    The genetic and transcriptional signature of EVI1 (ecotropic viral integration site 1)-rearranged (EVI1-r) acute myeloid leukemias (AMLs) remains poorly defined. We performed RNA sequencing of 12 EVI1-r AMLs and compared the results with those of other AML subtypes (n = 139) and normal CD34(+) cells (n = 17). Results confirm high frequencies of RAS and other activated signaling mutations (10/12 AMLs) and identify new recurrent mutations in splicing factors (5/12 AMLs in SF3B1 and 2/12 AMLs in U2AF1), IKZF1 (3/12 AMLs), and TP53 (3/12 AMLs). Mutations in IKZF1, a gene located on chromosome 7, and monosomy 7 are mutually exclusive in this disease. Moreover IKZF1 expression is halved in monosomy 7 leukemias. EVI-r AMLs are also characterized by a unique transcriptional signature with high expression levels of MECOM, PREX2, VIP, MYCT1, and PAWR. Our results suggest that EVI1-r AMLs could be molecularly defined by specific transcriptomic anomalies and a hitherto unseen mutational pattern. Larger patient cohorts will better determine the frequency of these events.

  1. EVI1-rearranged acute myeloid leukemias are characterized by distinct molecular alterations

    PubMed Central

    Lavallée, Vincent-Philippe; Gendron, Patrick; Lemieux, Sébastien; D’Angelo, Giovanni; Hébert, Josée

    2015-01-01

    The genetic and transcriptional signature of EVI1 (ecotropic viral integration site 1)-rearranged (EVI1-r) acute myeloid leukemias (AMLs) remains poorly defined. We performed RNA sequencing of 12 EVI1-r AMLs and compared the results with those of other AML subtypes (n = 139) and normal CD34+ cells (n = 17). Results confirm high frequencies of RAS and other activated signaling mutations (10/12 AMLs) and identify new recurrent mutations in splicing factors (5/12 AMLs in SF3B1 and 2/12 AMLs in U2AF1), IKZF1 (3/12 AMLs), and TP53 (3/12 AMLs). Mutations in IKZF1, a gene located on chromosome 7, and monosomy 7 are mutually exclusive in this disease. Moreover IKZF1 expression is halved in monosomy 7 leukemias. EVI-r AMLs are also characterized by a unique transcriptional signature with high expression levels of MECOM, PREX2, VIP, MYCT1, and PAWR. Our results suggest that EVI1-r AMLs could be molecularly defined by specific transcriptomic anomalies and a hitherto unseen mutational pattern. Larger patient cohorts will better determine the frequency of these events. PMID:25331116

  2. Current Management Strategies in Breast Cancer by Targeting Key Altered Molecular Players

    PubMed Central

    Ali, Shazia; Mondal, Neelima; Choudhry, Hani; Rasool, Mahmood; Pushparaj, Peter N.; Khan, Mohammad A.; Mahfooz, Maryam; Sami, Ghufrana A.; Jarullah, Jummanah; Ali, Ashraf; Jamal, Mohammad S.

    2016-01-01

    Breast cancer is the second largest disease affecting women worldwide. It remains the most frequently reported and leading cause of death among women in both developed and developing countries. Tamoxifen and raloxifene are commonly used selective estrogen receptor modulators for treatment of breast cancer in women with high risk, although resistance occurs by tamoxifen after 5 years of therapy and both drugs cause uterine cancer and thromboembolic events. Aromatase inhibitors (AIs) are one of the optional modes used for breast cancer treatment. The combination of AIs along with tamoxifen can also be beneficial. Various therapeutic agents from different sources are being studied, which further need to be improved for potential outcome. For this, clinical trials based on large number of patients with optimal dose and lesser side effects have to be more in practice. Despite the clinical trials going on, there is need of better molecular models, which can identify high risk population, new agents with better benefit having less side effects, and improved biomarkers for treating breast cancer. PMID:26973813

  3. Systematic Analysis of Sex-Linked Molecular Alterations and Therapies in Cancer

    PubMed Central

    Ma, Jonathan; Malladi, Sadhika; Beck, Andrew H

    2016-01-01

    Though patient sex influences response to cancer treatments, little is known of the molecular causes, and cancer therapies are generally given irrespective of patient sex. We assessed transcriptomic differences in tumors from men and women spanning 17 cancer types, and we assessed differential expression between tumor and normal samples stratified by sex across 7 cancers. We used the LincsCloud platform to perform Connectivity Map analyses to link transcriptomic signatures identified in male and female tumors with chemical and genetic perturbagens, and we performed permutation testing to identify perturbagens that showed significantly differential connectivity with male and female tumors. Our analyses predicted that females are sensitive and males are resistant to tamoxifen treatment of lung adenocarcinoma, a finding which is consistent with known male-female differences in lung cancer. We made several novel predictions, including that CDK1 and PTPN1 knockdown would be more effective in males with hepatocellular carcinoma, and SMAD3 and HSPA4 knockdown would be more effective in females with head and neck squamous cell carcinoma. Our results provide a new resource for researchers studying male-female biological and treatment response differences in human cancer. The complete results of our analyses are provided at the website accompanying this manuscript (http://becklab.github.io/SexLinked). PMID:26755347

  4. Cellular and molecular alterations in human epithelial cells transformed by high let radiation

    NASA Astrophysics Data System (ADS)

    Hei, T. K.; Piao, C. Q.; Sutter, T.; Willey, J. C.; Suzuki, K.

    An understanding of the radiobiological effects of high LET radiation is essential for human risk estimation and radiation protection. In the present study, we show that a single, 30 cGy dose of 150 keV/mum ^4He ions can malignantly transform human papillomavirus immortalized human bronchial epithelial [BEP2D] cells. Transformed cells produce progressively growing tumors in nude mice. The transformation frequency by the single dose of alpha particles is estimated to be approximately 4 x 10^-7. Based on the average cross-sectional area of BEP2D cells, it can be calculated that a mean traversal of 1.4 particles per cell is sufficient to induce tumorigenic conversion of these cells 3 to 4 months post-irradiation. Tumorigenic BEP2D cells overexpress mutated p53 tumor suppressor oncoproteins in addition to the cell cycle control gene cyclin D1 and D2. This model provides an opportunity to study the cellular and molecular changes at the various stages in radiation carcinogenesis involving human cells.

  5. Altered Striatocerebellar Metabolism and Systemic Inflammation in Parkinson's Disease

    PubMed Central

    Chen, Hsiu-Ling; Tsai, Nai-Wen

    2016-01-01

    Parkinson's disease (PD) is the most second common neurodegenerative movement disorder. Neuroinflammation due to systemic inflammation and elevated oxidative stress is considered a major factor promoting the pathogenesis of PD, but the relationship of structural brain imaging parameters to clinical inflammatory markers has not been well studied. Our aim was to evaluate the association of magnetic resonance spectroscopy (MRS) measures with inflammatory markers. Blood samples were collected from 33 patients with newly diagnosed PD and 30 healthy volunteers. MRS data including levels of N-acetylaspartate (NAA), creatine (Cre), and choline (Cho) were measured in the bilateral basal ganglia and cerebellum. Inflammatory markers included plasma nuclear DNA, plasma mitochondrial DNA, and apoptotic leukocyte levels. The Cho/Cre ratio in the dominant basal ganglion, the dominant basal ganglia to cerebellum ratios of two MRS parameters NAA/Cre and Cho/Cre, and levels of nuclear DNA, mitochondrial DNA, and apoptotic leukocytes were significantly different between PD patients and normal healthy volunteers. Significant positive correlations were noted between MRS measures and inflammatory marker levels. In conclusion, patients with PD seem to have abnormal levels of inflammatory markers in the peripheral circulation and deficits in MRS measures in the dominant basal ganglion and cerebellum. PMID:27688826

  6. Systemic alterations and their oral manifestations in pregnant women.

    PubMed

    Silva de Araujo Figueiredo, Camilla; Gonçalves Carvalho Rosalem, Cíntia; Costa Cantanhede, Andre Luis; Abreu Fonseca Thomaz, Érika Bárbara; Fontoura Nogueira da Cruz, Maria Carmen

    2017-01-01

    The aims of this literature review are: to depict the main oral diseases that are related to pregnancy; to clarify some of the possible systemic mechanisms that are associated with these changes; and to address issues about oral care during pregnancy. A woman's organs undergo various physiological, neurological, and hormonal changes during pregnancy. Such changes occur gradually and are essential for the development of the fetus, providing what is needed for tissue formation and establishment of reserves for uterine and fetal life. In turn, the oral cavity shows some events during this period. Among the changes most frequently cited in the literature are pyogenic granuloma, gingivitis, and periodontitis. The inflammation of the periodontal tissues due to the formation of the biofilm increases dramatically in size and severity during the course of a normal pregnancy, even without changes in the amount of biofilm present. In addition, a decrease in salivary pH is observed in pregnant women and may lead to an increased incidence of dental caries in this period.

  7. Visualising the molecular alteration of the calcite (104) – water interface by sodium nitrate

    PubMed Central

    Hofmann, Sascha; Voïtchovsky, Kislon; Spijker, Peter; Schmidt, Moritz; Stumpf, Thorsten

    2016-01-01

    The reactivity of calcite, one of the most abundant minerals in the earth’s crust, is determined by the molecular details of its interface with the contacting solution. Recently, it has been found that trace concentrations of NaNO3 severely affect calcite’s (104) surface and its reactivity. Here we combine molecular dynamics (MD) simulations, X-ray reflectivity (XR) and in situ atomic force microscopy (AFM) to probe the calcite (104) – water interface in the presence of NaNO3. Simulations reveal density profiles of different ions near calcite’s surface, with NO3− able to reach closer to the surface than CO32− and in higher concentrations. Reflectivity measurements show a structural destabilisation of the (104) surfaces’ topmost atomic layers in NaNO3 bearing solution, with distorted rotation angles of the carbonate groups and substantial displacement of the lattice ions. Nanoscale AFM results confirm the alteration of crystallographic characteristics, and the ability of dissolved NaNO3 to modify the structure of interfacial water was observed by AFM force spectroscopy. Our experiments and simulations consistently evidence a dramatic deterioration of the crystals’ surface, with potentially important implications for geological and industrial processes. PMID:26877225

  8. Developmental molecular and functional cerebellar alterations induced by PCP4/PEP19 overexpression: implications for Down syndrome.

    PubMed

    Mouton-Liger, François; Sahún, Ignasi; Collin, Thibault; Lopes Pereira, Patricia; Masini, Debora; Thomas, Sophie; Paly, Evelyne; Luilier, Sabrina; Même, Sandra; Jouhault, Quentin; Bennaï, Soumia; Beloeil, Jean-Claude; Bizot, Jean-Charles; Hérault, Yann; Dierssen, Mara; Créau, Nicole

    2014-03-01

    PCP4/PEP19 is a modulator of Ca(2+)-CaM signaling. In the brain, it is expressed in a very specific pattern in postmitotic neurons. In particular, Pcp4 is highly expressed in the Purkinje cell, the sole output neuron of the cerebellum. PCP4, located on human chromosome 21, is present in three copies in individuals with Down syndrome (DS). In a previous study using a transgenic mouse model (TgPCP4) to evaluate the consequences of 3 copies of this gene, we found that PCP4 overexpression induces precocious neuronal differentiation during mouse embryogenesis. Here, we report combined analyses of the cerebellum at postnatal stages (P14 and adult) in which we identified age-related molecular, electrophysiological, and behavioral alterations in the TgPCP4 mouse. While Pcp4 overexpression at P14 induces an earlier neuronal maturation, at adult stage it induces increase in cerebellar CaMK2alpha and in cerebellar LTD, as well as learning impairments. We therefore propose that PCP4 contributes significantly to the development of Down syndrome phenotypes through molecular and functional changes. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Altered Nitric Oxide System in Cardiovascular and Renal Diseases

    PubMed Central

    Bae, Eun Hui; Ma, Seong Kwon; Kim, Soo Wan

    2016-01-01

    Nitric oxide (NO) is synthesized by a family of NO synthases (NOS), including neuronal, inducible, and endothelial NOS (n/i/eNOS). NO-mediated effects can be beneficial or harmful depending on the specific risk factors affecting the disease. In hypertension, the vascular relaxation response to acetylcholine is blunted, and that to direct NO donors is maintained. A reduction in the activity of eNOS is mainly responsible for the elevation of blood pressure, and an abnormal expression of iNOS is likely to be related to the progression of vascular dysfunction. While eNOS/nNOS-derived NO is protective against the development of atherosclerosis, iNOS-derived NO may be proatherogenic. eNOS-derived NO may prevent the progression of myocardial infarction. Myocardial ischemia/reperfusion injury is significantly enhanced in eNOS-deficient animals. An important component of heart failure is the loss of coronary vascular eNOS activity. A pressure-overload may cause severer left ventricular hypertrophy and dysfunction in eNOS null mice than in wild-type mice. iNOS-derived NO has detrimental effects on the myocardium. NO plays an important role in regulating the angiogenesis and slowing the interstitial fibrosis of the obstructed kidney. In unilateral ureteral obstruction, the expression of eNOS was decreased in the affected kidney. In triply n/i/eNOS null mice, nephrogenic diabetes insipidus developed along with reduced aquaporin-2 abundance. In chronic kidney disease model of subtotal-nephrectomized rats, treatment with NOS inhibitors decreased systemic NO production and induced left ventricular systolic dysfunction (renocardiac syndrome). PMID:27231671

  10. Genome-wide gene expression profiling reveals unsuspected molecular alterations in pemphigus foliaceus

    PubMed Central

    Malheiros, Danielle; Panepucci, Rodrigo A; Roselino, Ana M; Araújo, Amélia G; Zago, Marco A; Petzl-Erler, Maria Luiza

    2014-01-01

    Pemphigus foliaceus (PF) is a complex autoimmune disease characterized by bullous skin lesions and the presence of antibodies against desmoglein 1. In this study we sought to contribute to a better understanding of the molecular processes in endemic PF, as the identification of factors that participate in the pathogenesis is a prerequisite for understanding its biological basis and may lead to novel therapeutic interventions. CD4+ T lymphocytes are central to the development of the disease. Therefore, we compared genome-wide gene expression profiles of peripheral CD4+ T cells of various PF patient subgroups with each other and with that of healthy individuals. The patient sample was subdivided into three groups: untreated patients with the generalized form of the disease, patients submitted to immunosuppressive treatment, and patients with the localized form of the disease. Comparisons between different subgroups resulted in 135, 54 and 64 genes differentially expressed. These genes are mainly related to lymphocyte adhesion and migration, apoptosis, cellular proliferation, cytotoxicity and antigen presentation. Several of these genes were differentially expressed when comparing lesional and uninvolved skin from the same patient. The chromosomal regions 19q13 and 12p13 concentrate differentially expressed genes and are candidate regions for PF susceptibility genes and disease markers. Our results reveal genes involved in disease severity, potential therapeutic targets and previously unsuspected processes involved in the pathogenesis. Besides, this study adds original information that will contribute to the understanding of PF's pathogenesis and of the still poorly defined in vivo functions of most of these genes. PMID:24813052

  11. Molecular alterations associated with sulindac-resistant colon tumors in ApcMin/+ mice.

    PubMed

    Greenspan, Emily J; Nichols, Frank C; Rosenberg, Daniel W

    2010-09-01

    Although nonsteroidal anti-inflammatory drugs (NSAID), including sulindac, have been used extensively as chemopreventive agents for colorectal cancer, results are not consistent. NSAIDs, most reportedly sulindac, often do not cause a complete regression of adenomas and some patients develop resistance to NSAID treatment. In this study, we evaluated the effect of sulindac on colon tumorigenesis in the Apc(Min/+) mouse model. Sulindac (180 ppm) given in drinking water for 9 weeks to Apc(Min/+) mice significantly reduced the size of colon tumors, but actually caused an increase in colon tumor multiplicity relative to untreated controls (average of 5.5 versus 1.6 tumors per mouse, respectively; P < 0.0001). This indicated that the drug could inhibit colon tumor progression but not initiation. As expected, in the small intestine, sulindac significantly reduced tumor size and multiplicity relative to untreated controls (average of 2.3 versus 42.0 tumors per mouse, respectively; P < 0.0001). Generation of a panel of prostanoids was comparably suppressed in the small intestine and colon by sulindac treatment. Sulindac is also known to exert its growth inhibitory effects through regulation of many noncyclooxygenase targets, including p21, beta-catenin, E-cadherin, mitochondrial apoptotic proteins, and peroxisome proliferator-activated receptor-gamma. We found that sulindac treatment protected against E-cadherin loss in colon tumors, with associated inhibition of nuclear beta-catenin accumulation. Importantly, p21(WAF1/cip1) and peroxisome proliferator-activated receptor-gamma expression were absent in colon tumors from sulindac-treated mice, suggesting that loss of these proteins is necessary for drug resistance. Together, these observations may be translatable to designing novel clinical therapies using combinations of agents that target multiple molecular pathways to overcome sulindac resistance.

  12. Molecular alterations associated with sulindac resistant colon tumors in ApcMin/+ mice

    PubMed Central

    Greenspan, Emily J.; Nichols, Frank C.; Rosenberg, Daniel W.

    2010-01-01

    Although non-steroidal anti-inflammatory drugs (NSAIDs), including sulindac, have been used extensively as chemopreventive agents for colorectal cancer (CRC), results are not consistent. NSAIDs, most reportedly sulindac, often do not cause a complete regression of adenomas and some patients develop resistance to NSAID treatment. In this study we evaluated the effect of sulindac on colon tumorigenesis in the ApcMin/+ mouse model. Sulindac (180 p.p.m.) given in drinking water for 9 weeks to ApcMin/+ mice significantly reduced the size of colon tumors, but actually caused an increase in colon tumor multiplicity relative to untreated controls (average of 5.5 vs. 1.6 tumors/mouse, respectively; P<0.0001). This indicated that the drug could inhibit colon tumor progression but not initiation. As expected, in the small intestine sulindac significantly reduced tumor size and multiplicity relative to untreated controls (average of 2.3 vs. 42.0 tumors/mouse, respectively; P<0.0001). Generation of a panel of prostanoids was comparably suppressed in the small intestine and colon by sulindac treatment. Sulindac is also known to exert its growth inhibitory effects through regulation of many non-COX targets, including p21, β-catenin, E-cadherin, mitochondrial apoptotic proteins and PPARγ. We found that sulindac treatment protected against E-cadherin loss in colon tumors, with associated inhibition of nuclear β-catenin accumulation. Importantly, p21WAF1/cip1 and PPARγ expression were absent in colon tumors from sulindac-treated mice, suggesting that loss of these proteins is necessary for drug resistance. Together, these observations may be translatable to designing novel clinical therapies utilizing combinations of agents that target multiple molecular pathways to overcome sulindac resistance. PMID:20716632

  13. A New Molecular Surveillance System for Leishmaniasis

    PubMed Central

    Pandey, Kishor; Pandey, Basu Dev; Mallik, Arun Kumar; Acharya, Jyoti; Kato, Kentaro; Kaneko, Osamu; Ferreira, Pedro Eduardo

    2014-01-01

    Abstract. Presently, global efforts are being made to control and eradicate the deadliest tropical diseases through the improvement of adequate interventions. A critical point for programs to succeed is the prompt and accurate diagnosis in endemic regions. Rapid diagnostic tests (RDTs) are being massively deployed and used to improve diagnosis in tropical countries. In the present report, we evaluated the hypothesis of, after use for diagnosis, the reuse of the Leishmania RDT kit as a DNA source, which can be used downstream as a molecular surveillance and/or quality control tool. As a proof of principle, a polymerase chain reaction-based method was used to detect Leishmania spp. minicircle kinetoplast DNA from leishmaniasis RDT kits. Our results show that Leishmania spp. DNA can be extracted from used RDTs and may constitute an important, reliable, and affordable tool to assist in future leishmaniasis molecular surveillance methods. PMID:24752687

  14. Accurate Methods for Large Molecular Systems (Preprint)

    DTIC Science & Technology

    2009-01-06

    Császár, A. G.; Kallay, M.; Gauss, J.; Valeev, E. F.; Flowers , B. A.; Vazquez, J.; Stanton, J. F. J. Chem. Phys. 2004, 121, 11599. (l) Kedziora, G...J. N.; Proc Phys. Soc, 1955, A68, 601. 47. (a) Curtis, L;. Janssen, I.; Nielsen, M. B. Parallel Computing in Quantum Chemistry, CRC press, 2008...A 2006, 110, 10345. 63. Paldus, J., Wilson, S., editor. Handbook of Molecular Physics and Quantum Chemistry, vol. 2. Chichester: Wiley; 2000, p

  15. Competition Effect in Atomic-Molecular System

    NASA Technical Reports Server (NTRS)

    Jia, Suotang; Qin, Lijuan; Qian, Zuliang; Wang, Zugeng; Wang, Gang; Zhou, Guosheng

    1996-01-01

    The competition effects among the processes of atomic ionization, optical pumped stimulated radiation (OPSR), four-wave frequency mixing (FWFM) and molecular stimulated diffuse band radiation at the atomic two-photon resonance of 3S approaches 4D in Na2 - Na mixture were observed. The dip at the two-photon resonance in the excitation spectrum for the diffuse-band radiation was interpreted as suppression of population in 4D state.

  16. 75 FR 13076 - Privacy Act of 1974; Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-18

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF COMMERCE Privacy Act of 1974; Altered System of Records AGENCY: U.S. Census Bureau, Department of Commerce. ACTION: Notice of Amendment, Privacy Act System of Records; COMMERCE/ CENSUS-10 and 5, combining the American...

  17. Altered Placental Tryptophan Metabolism: A Crucial Molecular Pathway for the Fetal Programming of Neurodevelopmental Disorders

    DTIC Science & Technology

    2014-07-01

    First-Strand Synthesis SuperMix for qRT-PCR kit according to manufacturer specifications. qRT-PCR reactions were performed in triplicate using the...Real-Time PCR System. Briefly, for each gene and template 5 combination, 20 µl reactions were set up in triplicate containing 10 µl TaqMan Gene...all reactions were setup in 96-well plates, they were transferred to the StepOnePlus thermocycler, and run using standard cycling conditions of a 2

  18. Accurate Methods for Large Molecular Systems (Postprint)

    DTIC Science & Technology

    2009-01-06

    Tajti, A.; Stanton, J. F. Mol. Phys. 2005, 103, 2159. (k) HEAT: Tajti, A.; Szalay, P. G.; Császár, A. G.; Kallay, M.; Gauss, J.; Valeev, E. F.; Flowers ...Quantum Chemistry; CRC Press: Boca Raton, FL, 2008. (b) Olson, R. M.; Bentz, J. L.; Kendall, R. A.; Schmidt, M. W.; Gordon, M. S. J. Chem. Theory...Eds. Handbook of Molecular Physics and Quantum Chemistry; Wiley: Chichester, U.K., 2000; Vol. 2, pp 272-313. (64) Jeziorski, B.; Moszynski, R

  19. pysimm: A python package for simulation of molecular systems

    NASA Astrophysics Data System (ADS)

    Fortunato, Michael E.; Colina, Coray M.

    In this work, we present pysimm, a python package designed to facilitate structure generation, simulation, and modification of molecular systems. pysimm provides a collection of simulation tools and smooth integration with highly optimized third party software. Abstraction layers enable a standardized methodology to assign various force field models to molecular systems and perform simple simulations. These features have allowed pysimm to aid the rapid development of new applications specifically in the area of amorphous polymer simulations.

  20. Debaryomyces hansenii: A Model System for Marine Molecular Biology

    DTIC Science & Technology

    1991-05-30

    System for Marine Molecular Biology PERIOD OF PERFORMANCE: June 1, 1990 to May 30, 1991 RESEARCH OBJECTIVE: To establish Debaryomyces hansenii as a model...Analysis of 17s rRNA gene from the marine yeast Debaryomyces hansenii . In preparation for Current Genetics. TRAINING ACTIVITIES Two graduate students, one...Institution: University of California, Santa Barbara. Grant Title: Debaryomyces hansenii : A Model System for Marine Molecular Biology. Period of

  1. Systems biology of molecular chaperone networks.

    PubMed

    Csermely, Péter; Korcsmáros, Tamás; Kovács, István A; Szalay, Máté S; Soti, Csaba

    2008-01-01

    Molecular chaperones are not only fascinating molecular machines that help the folding, refolding, activation or assembly of other proteins, but also have a number of functions. These functions can be understood only by considering the emergent properties of cellular networks--and that of chaperones as special network constituents. As a notable example for the network-related roles of chaperones they may act as genetic buffers stabilizing the phenotype of various cells and organisms, and may serve as potential regulators of evolvability. Why are chaperones special in the context of cellular networks? Chaperones: (1) have weak links, i.e. low affinity, transient interactions with most of their partners; (2) connect hubs, i.e. act as 'masterminds' of the cell being close to several centre proteins with a lot of neighbours; and (3) are in the overlaps of network modules, which confers upon them a special regulatory role. Importantly, chaperones may uncouple or even quarantine modules of protein-protein interaction networks, signalling networks, genetic regulatory networks and membrane organelle networks during stress, which gives an additional chaperone-mediated protection for the cell at the network-level. Moreover, chaperones are essential to rebuild inter-modular contacts after stress by their low affinity, 'quasi-random' sampling of the potential interaction partners in different cellular modules. This opens the way to the chaperone-regulated modular evolution of cellular networks, and helps us to design novel therapeutic and anti-ageing strategies.

  2. Molecular systems with open boundaries: Theory and simulation

    NASA Astrophysics Data System (ADS)

    Delle Site, Luigi; Praprotnik, Matej

    2017-06-01

    Typical experimental setups for molecular systems must deal with a certain coupling to the external environment, that is, the system is open and exchanges mass, momentum, and energy with its surroundings. Instead, standard molecular simulations are mostly performed using periodic boundary conditions with a constant number of molecules. In this review, we summarize major development of simulation methodologies, which, contrary to standard techniques, open up the boundaries of a molecular system and allow for exchange of energy and matter with the environment, in and out of equilibrium. In particular, we construct the review around the open boundary simulation approaches based on the Adaptive Resolution Scheme (AdResS), which seamlessly couples different levels of resolution in molecular simulations. Ideas and theoretical concepts used in its development lie at the crossroad of different fields and disciplines and open many different directions for future developments in molecular simulation. We examine progress related to theoretical as well as novel modeling approaches bridging length scales from quantum to the continuum description and report on their application in various molecular systems. The outlook of the review is dedicated to the perspective of how to further incorporate rigorous theoretical approaches such as the Bergmann-Lebowitz and Emch-Sewell models into the molecular simulation algorithms and stimulate further development of open boundary simulation methods and their application.

  3. Molecular Genetic and Gene Therapy Studies of the Musculoskeletal System

    DTIC Science & Technology

    2009-09-01

    Studies of the Musculoskeletal System PRINCIPAL INVESTIGATOR: Subburaman Mohan, Ph.D. CONTRACTING ORGANIZATION: Loma Linda Veterans...2009 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Molecular Genetic and Gene Therapy Studies of the Musculoskeletal System 5b. GRANT NUMBER DAMD17-03...proposed research projects focuses on bone health, including relevance to the musculoskeletal system in battlefield performance and in battlefield

  4. Context-induced reinstatement of methamphetamine seeking is associated with unique molecular alterations in Fos-expressing dorsolateral striatum neurons.

    PubMed

    Rubio, F Javier; Liu, Qing-Rong; Li, Xuan; Cruz, Fabio C; Leão, Rodrigo M; Warren, Brandon L; Kambhampati, Sarita; Babin, Klil R; McPherson, Kylie B; Cimbro, Raffaello; Bossert, Jennifer M; Shaham, Yavin; Hope, Bruce T

    2015-04-08

    Context-induced reinstatement of drug seeking is a well established animal model for assessing the neural mechanisms underlying context-induced drug relapse, a major factor in human drug addiction. Neural activity in striatum has previously been shown to contribute to context-induced reinstatement of heroin, cocaine, and alcohol seeking, but not yet for methamphetamine seeking. In this study, we found that context-induced reinstatement of methamphetamine seeking increased expression of the neural activity marker Fos in dorsal but not ventral striatum. Reversible inactivation of neural activity in dorsolateral but not dorsomedial striatum using the GABA agonists muscimol and baclofen decreased context-induced reinstatement. Based on our previous findings that Fos-expressing neurons play a critical role in conditioned drug effects, we assessed whether context-induced reinstatement was associated with molecular alterations selectively induced within context-activated Fos-expressing neurons. We used fluorescence-activated cell sorting to isolate reinstatement-activated Fos-positive neurons from Fos-negative neurons in dorsal striatum and used quantitative PCR to assess gene expression within these two populations of neurons. Context-induced reinstatement was associated with increased expression of the immediate early genes Fos and FosB and the NMDA receptor subunit gene Grin2a in only Fos-positive neurons. RNAscope in situ hybridization confirmed that Grin2a, as well as Grin2b, expression were increased in only Fos-positive neurons from dorsolateral, but not dorsomedial, striatum. Our results demonstrate an important role of dorsolateral striatum in context-induced reinstatement of methamphetamine seeking and that this reinstatement is associated with unique gene alterations in Fos-expressing neurons.

  5. Context-Induced Reinstatement of Methamphetamine Seeking Is Associated with Unique Molecular Alterations in Fos-Expressing Dorsolateral Striatum Neurons

    PubMed Central

    Rubio, F. Javier; Liu, Qing-Rong; Li, Xuan; Cruz, Fabio C.; Leão, Rodrigo M.; Warren, Brandon L.; Kambhampati, Sarita; Babin, Klil R.; McPherson, Kylie B.; Cimbro, Raffaello; Bossert, Jennifer M.; Shaham, Yavin

    2015-01-01

    Context-induced reinstatement of drug seeking is a well established animal model for assessing the neural mechanisms underlying context-induced drug relapse, a major factor in human drug addiction. Neural activity in striatum has previously been shown to contribute to context-induced reinstatement of heroin, cocaine, and alcohol seeking, but not yet for methamphetamine seeking. In this study, we found that context-induced reinstatement of methamphetamine seeking increased expression of the neural activity marker Fos in dorsal but not ventral striatum. Reversible inactivation of neural activity in dorsolateral but not dorsomedial striatum using the GABA agonists muscimol and baclofen decreased context-induced reinstatement. Based on our previous findings that Fos-expressing neurons play a critical role in conditioned drug effects, we assessed whether context-induced reinstatement was associated with molecular alterations selectively induced within context-activated Fos-expressing neurons. We used fluorescence-activated cell sorting to isolate reinstatement-activated Fos-positive neurons from Fos-negative neurons in dorsal striatum and used quantitative PCR to assess gene expression within these two populations of neurons. Context-induced reinstatement was associated with increased expression of the immediate early genes Fos and FosB and the NMDA receptor subunit gene Grin2a in only Fos-positive neurons. RNAscope in situ hybridization confirmed that Grin2a, as well as Grin2b, expression were increased in only Fos-positive neurons from dorsolateral, but not dorsomedial, striatum. Our results demonstrate an important role of dorsolateral striatum in context-induced reinstatement of methamphetamine seeking and that this reinstatement is associated with unique gene alterations in Fos-expressing neurons. PMID:25855177

  6. Molecular dynamics simulations highlight structural and functional alterations in deafness–related M34T mutation of connexin 26

    PubMed Central

    Zonta, Francesco; Buratto, Damiano; Cassini, Chiara; Bortolozzi, Mario; Mammano, Fabio

    2014-01-01

    Mutations of the GJB2 gene encoding the connexin 26 (Cx26) gap junction protein, which is widely expressed in the inner ear, are the primary cause of hereditary non-syndromic hearing loss in several populations. The deafness–associated single amino acid substitution of methionine 34 (M34) in the first transmembrane helix (TM1) with a threonine (T) ensues in the production of mutant Cx26M34T channels that are correctly synthesized and assembled in the plasma membrane. However, mutant channels overexpressed in HeLa cells retain only 11% of the wild type unitary conductance. Here we extend and rationalize those findings by comparing wild type Cx26 (Cx26WT) and Cx26M34T mutant channels in silico, using molecular dynamics simulations. Our results indicate that the quaternary structure of the Cx26M34T hemichannel is altered at the level of the pore funnel due to the disruption of the hydrophobic interaction between M34 and tryptophan 3 (W3) in the N–terminal helix (NTH). Our simulations also show that external force stimuli applied to the NTHs can detach them from the inner wall of the pore more readily in the mutant than in the wild type hemichannel. These structural alterations significantly increase the free energy barrier encountered by permeating ions, correspondingly decreasing the unitary conductance of the Cx26M34T hemichannel. Our results accord with the proposal that the mutant resides most of the time in a low conductance state. However, the small displacement of the NTHs in our Cx26M34T hemichannel model is not compatible with the formation of a pore plug as in the related Cx26M34A mutant. PMID:24624091

  7. A Molecular Communication System Model for Particulate Drug Delivery Systems.

    PubMed

    Chahibi, Youssef; Pierobon, Massimiliano; Song, Sang Ok; Akyildiz, Ian F

    2013-12-01

    The goal of a drug delivery system (DDS) is to convey a drug where the medication is needed, while, at the same time, preventing the drug from affecting other healthy parts of the body. Drugs composed of micro- or nano-sized particles (particulate DDS) that are able to cross barriers which prevent large particles from escaping the bloodstream are used in the most advanced solutions. Molecular communication (MC) is used as an abstraction of the propagation of drug particles in the body. MC is a new paradigm in communication research where the exchange of information is achieved through the propagation of molecules. Here, the transmitter is the drug injection, the receiver is the drug delivery, and the channel is realized by the transport of drug particles, thus enabling the analysis and design of a particulate DDS using communication tools. This is achieved by modeling the MC channel as two separate contributions, namely, the cardiovascular network model and the drug propagation network. The cardiovascular network model allows to analytically compute the blood velocity profile in every location of the cardiovascular system given the flow input by the heart. The drug propagation network model allows the analytical expression of the drug delivery rate at the targeted site given the drug injection rate. Numerical results are also presented to assess the flexibility and accuracy of the developed model. The study of novel optimization techniques for a more effective and less invasive drug delivery will be aided by this model, while paving the way for novel communication techniques for Intrabody communication networks.

  8. Efficient Molecular Dynamics Simulations of Multiple Radical Center Systems Based on the Fragment Molecular Orbital Method

    SciTech Connect

    Nakata, Hiroya; Schmidt, Michael W; Fedorov, Dmitri G; Kitaura, Kazuo; Nakamura, Shinichiro; Gordon, Mark S

    2014-10-16

    The fully analytic energy gradient has been developed and implemented for the restricted open-shell Hartree–Fock (ROHF) method based on the fragment molecular orbital (FMO) theory for systems that have multiple open-shell molecules. The accuracy of the analytic ROHF energy gradient is compared with the corresponding numerical gradient, illustrating the accuracy of the analytic gradient. The ROHF analytic gradient is used to perform molecular dynamics simulations of an unusual open-shell system, liquid oxygen, and mixtures of oxygen and nitrogen. These molecular dynamics simulations provide some insight about how triplet oxygen molecules interact with each other. Timings reveal that the method can calculate the energy gradient for a system containing 4000 atoms in only 6 h. Therefore, it is concluded that the FMO-ROHF method will be useful for investigating systems with multiple open shells.

  9. Efficient molecular dynamics simulations of multiple radical center systems based on the fragment molecular orbital method.

    PubMed

    Nakata, Hiroya; Schmidt, Michael W; Fedorov, Dmitri G; Kitaura, Kazuo; Nakamura, Shinichiro; Gordon, Mark S

    2014-10-16

    The fully analytic energy gradient has been developed and implemented for the restricted open-shell Hartree-Fock (ROHF) method based on the fragment molecular orbital (FMO) theory for systems that have multiple open-shell molecules. The accuracy of the analytic ROHF energy gradient is compared with the corresponding numerical gradient, illustrating the accuracy of the analytic gradient. The ROHF analytic gradient is used to perform molecular dynamics simulations of an unusual open-shell system, liquid oxygen, and mixtures of oxygen and nitrogen. These molecular dynamics simulations provide some insight about how triplet oxygen molecules interact with each other. Timings reveal that the method can calculate the energy gradient for a system containing 4000 atoms in only 6 h. Therefore, it is concluded that the FMO-ROHF method will be useful for investigating systems with multiple open shells.

  10. ToF-SIMS imaging of molecular-level alteration mechanisms in Le Bonheur de vivre by Henri Matisse

    NASA Astrophysics Data System (ADS)

    Voras, Zachary E.; deGhetaldi, Kristin; Wiggins, Marcie B.; Buckley, Barbara; Baade, Brian; Mass, Jennifer L.; Beebe, Thomas P.

    2015-11-01

    Time-of-flight secondary ion mass spectrometry (ToF-SIMS) has recently been shown to be a valuable tool for cultural heritage studies, especially when used in conjunction with established analytical techniques in the field. The ability of ToF-SIMS to simultaneously image inorganic and organic species within a paint cross section at micrometer-level spatial resolution makes it a uniquely qualified analytical technique to aid in further understanding the processes of pigment and binder alteration, as well as pigment-binder interactions. In this study, ToF-SIMS was used to detect and image both molecular and elemental species related to CdS pigment and binding medium alteration on the painting Le Bonheur de vivre (1905-1906, The Barnes Foundation) by Henri Matisse. Three categories of inorganic and organic components were found throughout Le Bonheur de vivre and co-localized in cross-sectional samples using high spatial resolution ToF-SIMS analysis: (1) species relating to the preparation and photo-induced oxidation of CdS yellow pigments (2) varying amounts of long-chain fatty acids present in both the paint and primary ground layer and (3) specific amino acid fragments, possibly relating to the painting's complex restoration history. ToF-SIMS's ability to discern both organic and inorganic species via cross-sectional imaging was used to compare samples collected from Le Bonheur de vivre to artificially aged reference paints in an effort to gather mechanistic information relating to alteration processes that have been previously explored using μXANES, SR-μXRF, SEM-EDX, and SR-FTIR. The relatively high sensitivity offered by ToF-SIMS imaging coupled to the high spatial resolution allowed for the positive identification of degradation products (such as cadmium oxalate) in specific paint regions that have before been unobserved. The imaging of organic materials has provided an insight into the extent of destruction of the original binding medium, as well as

  11. ToF–SIMS imaging of molecular-level alteration mechanisms in Le Bonheur de vivre by Henri Matisse

    PubMed Central

    deGhetaldi, Kristin; Wiggins, Marcie B.; Buckley, Barbara; Baade, Brian; Mass, Jennifer L.; Beebe, Thomas P.

    2016-01-01

    Time-of-flight secondary ion mass spectrometry (ToF–SIMS) has recently been shown to be a valuable tool for cultural heritage studies, especially when used in conjunction with established analytical techniques in the field. The ability of ToF–SIMS to simultaneously image inorganic and organic species within a paint cross section at micrometer-level spatial resolution makes it a uniquely qualified analytical technique to aid in further understanding the processes of pigment and binder alteration, as well as pigment–binder interactions. In this study, ToF–SIMS was used to detect and image both molecular and elemental species related to CdS pigment and binding medium alteration on the painting Le Bonheur de vivre (1905–1906, The Barnes Foundation) by Henri Matisse. Three categories of inorganic and organic components were found throughout Le Bonheur de vivre and co-localized in cross-sectional samples using high spatial resolution ToF–SIMS analysis: (1) species relating to the preparation and photo-induced oxidation of CdS yellow pigments (2) varying amounts of long-chain fatty acids present in both the paint and primary ground layer and (3) specific amino acid fragments, possibly relating to the painting’s complex restoration history. ToF–SIMS’s ability to discern both organic and inorganic species via cross-sectional imaging was used to compare samples collected from Le Bonheur de vivre to artificially aged reference paints in an effort to gather mechanistic information relating to alteration processes that have been previously explored using μXANES, SR-μXRF, SEM–EDX, and SR-FTIR. The relatively high sensitivity offered by ToF–SIMS imaging coupled to the high spatial resolution allowed for the positive identification of degradation products (such as cadmium oxalate) in specific paint regions that have before been unobserved. The imaging of organic materials has provided an insight into the extent of destruction of the original binding medium

  12. Hydrothermal alteration in the Baca Geothermal System, Redondo Dome, Valles Caldera, New Mexico

    NASA Astrophysics Data System (ADS)

    Hulen, Jeffrey B.; Nielson, Dennis L.

    1986-02-01

    Thermal fluids circulating in the active hydrothermal system of the resurgent Redondo dome of the Valles caldera have interacted with their diverse host rocks to produce well-zoned alteration assemblages, which not only help locate permeable fluid channels but also provide insight into the system's thermal history. The alteration shows that fluid flow has been confined principally to steeply dipping normal faults and subsidiary fractures as well as thin stratigraphic aquifers. Permeability along many of these channels has been reduced or locally eliminated by hydrothermal self-sealing. Alteration from the surface through the base of the Miocene Paliza Canyon Formation is of three distinctive types: argillic, propylitic, and phyllic. Argillic alteration forms a blanket above the deep water table in formerly permeable nonwelded tuffs. Beneath the argillic zone, pervasive propylitic alteration is weakly developed in felsic host rocks but locally intense in deep intermediate composition volcanics. Strong phyllic alteration is commonly but not invariably associated with major active thermal fluid channels. Phyllic zones yielding no fluid were clearly once permeable but now are hydrothermally sealed. High-temperature alteration phases at Baca are presently found at much lower temperatures. We suggest either that isotherms have collapsed due to gradual cooling of the system, that they have retreated without overall heat loss due to uplift of the Redondo dome, that the system has shifted laterally, or that it has contracted due to a drop in the water table. The deepest Well (B-12, 3423 m) in the dome may have penetrated through the base of the active hydrothermal system. Below a depth of 2440 m in this well, hydrothermal veining largely disappears, and the rocks resemble those developed by isochemical thermal metamorphism. The transition is reflected by temperature logs, which show a conductive thermal gradient below 2440 m. This depth may mark the dome's neutral plane

  13. SILAC-based quantitative proteomic analysis reveals widespread molecular alterations in human skin keratinocytes upon chronic arsenic exposure.

    PubMed

    Mir, Sartaj Ahmad; Pinto, Sneha M; Paul, Somnath; Raja, Remya; Nanjappa, Vishalakshi; Syed, Nazia; Advani, Jayshree; Renuse, Santosh; Sahasrabuddhe, Nandini A; Prasad, T S Keshava; Giri, Ashok K; Gowda, Harsha; Chatterjee, Aditi

    2017-03-01

    Chronic exposure to arsenic is associated with dermatological and nondermatological disorders. Consumption of arsenic-contaminated drinking water results in accumulation of arsenic in liver, spleen, kidneys, lungs, and gastrointestinal tract. Although arsenic is cleared from these sites, a substantial amount of residual arsenic is left in keratin-rich tissues including skin. Epidemiological studies suggest the association of skin cancer upon arsenic exposure, however, the mechanism of arsenic-induced carcinogenesis is not completely understood. We developed a cell line based model to understand the molecular mechanisms involved in arsenic-mediated toxicity and carcinogenicity. Human skin keratinocyte cell line, HaCaT, was chronically exposed to 100 nM sodium arsenite over a period of 6 months. We observed an increase in basal ROS levels in arsenic-exposed cells. SILAC-based quantitative proteomics approach resulted in identification of 2111 proteins of which 42 proteins were found to be overexpressed and 54 downregulated (twofold) upon chronic arsenic exposure. Our analysis revealed arsenic-induced overexpression of aldo-keto reductase family 1 member C2 (AKR1C2), aldo-keto reductase family 1 member C3 (AKR1C3), glutamate-cysteine ligase catalytic subunit (GCLC), and NAD(P)H dehydrogenase [quinone] 1 (NQO1) among others. We observed downregulation of several members of the plakin family including periplakin (PPL), envoplakin (EVPL), and involucrin (IVL) that are essential for terminal differentiation of keratinocytes. MRM and Western blot analysis confirmed differential expression of several candidate proteins. Our study provides insights into molecular alterations upon chronic arsenic exposure on skin.

  14. Molecular alterations and expression of succinate dehydrogenase complex in wild-type KIT/PDGFRA/BRAF gastrointestinal stromal tumors.

    PubMed

    Celestino, Ricardo; Lima, Jorge; Faustino, Alexandra; Vinagre, João; Máximo, Valdemar; Gouveia, António; Soares, Paula; Lopes, José Manuel

    2013-05-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, disclosing somatic KIT, PDGFRA and BRAF mutations. Loss of function of succinate dehydrogenase (SDH) complex is an alternative molecular mechanism in GISTs, namely in carriers of germline mutations of the SDH complex that develop Carney-Stratakis dyad characterized by multifocal GISTs and multicentric paragangliomas (PGLs). We studied a series of 25 apparently sporadic primary wild-type (WT) KIT/PDGFRA/BRAF GISTs occurring in patients without personal or familial history of PGLs, re-evaluated clinicopathological features and analyzed molecular alterations and immunohistochemistry expression of SDH complex. As control, we used a series of well characterized 49 KIT/PDGFRA/BRAF-mutated GISTs. SDHB expression was absent in 20% and SDHB germline mutations were detected in 12% of WT GISTs. Germline SDHB mutations were significantly associated to younger age at diagnosis. A significant reduction in SDHB expression in WT GISTs was found when compared with KIT/PDGFRA/BRAF-mutated GISTs. No significant differences were found when comparing DOG-1 and c-KIT expression in WT, SDHB-mutated and KIT/PDGFRA/BRAF-mutated GISTs. Our results confirm the occurrence of germline SDH genes mutations in isolated, apparently sporadic WT GISTs. WT KIT/PDGFRA/BRAF GISTs without SDHB or SDHA/SDHB expression may correspond to Carney-Stratakis dyad or Carney triad. Most importantly, the possibility of PGLs (Carney-Stratakis dyad) and/or pulmonary chondroma (Carney triad) should be addressed in these patients and their kindred.

  15. Molecular alterations and expression of succinate dehydrogenase complex in wild-type KIT/PDGFRA/BRAF gastrointestinal stromal tumors

    PubMed Central

    Celestino, Ricardo; Lima, Jorge; Faustino, Alexandra; Vinagre, João; Máximo, Valdemar; Gouveia, António; Soares, Paula; Manuel Lopes, José

    2013-01-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, disclosing somatic KIT, PDGFRA and BRAF mutations. Loss of function of succinate dehydrogenase (SDH) complex is an alternative molecular mechanism in GISTs, namely in carriers of germline mutations of the SDH complex that develop Carney–Stratakis dyad characterized by multifocal GISTs and multicentric paragangliomas (PGLs). We studied a series of 25 apparently sporadic primary wild-type (WT) KIT/PDGFRA/BRAF GISTs occurring in patients without personal or familial history of PGLs, re-evaluated clinicopathological features and analyzed molecular alterations and immunohistochemistry expression of SDH complex. As control, we used a series of well characterized 49 KIT/PDGFRA/BRAF-mutated GISTs. SDHB expression was absent in 20% and SDHB germline mutations were detected in 12% of WT GISTs. Germline SDHB mutations were significantly associated to younger age at diagnosis. A significant reduction in SDHB expression in WT GISTs was found when compared with KIT/PDGFRA/BRAF-mutated GISTs. No significant differences were found when comparing DOG-1 and c-KIT expression in WT, SDHB-mutated and KIT/PDGFRA/BRAF-mutated GISTs. Our results confirm the occurrence of germline SDH genes mutations in isolated, apparently sporadic WT GISTs. WT KIT/PDGFRA/BRAF GISTs without SDHB or SDHA/SDHB expression may correspond to Carney–Stratakis dyad or Carney triad. Most importantly, the possibility of PGLs (Carney–Stratakis dyad) and/or pulmonary chondroma (Carney triad) should be addressed in these patients and their kindred. PMID:22948025

  16. 77 FR 1073 - Privacy Act of 1974; Report of an Altered System of Records, Including Addition of Routine Uses...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-09

    ...The Food and Drug Administration (FDA) is announcing an alteration to an existing System of Records (System) titled ``Bioresearch Monitoring Information System, HHS/FDA'' (System No. 09- 10-0010). Among other updates, this alteration adds new routine uses for disclosures of certain relevant information to Agencies, authorities, and organizations with responsibilities related to clinical......

  17. A Palaeoproterozoic multi-stage hydrothermal alteration system at Nalunaq gold deposit, South Greenland

    NASA Astrophysics Data System (ADS)

    Bell, Robin-Marie; Kolb, Jochen; Waight, Tod Earle; Bagas, Leon; Thomsen, Tonny B.

    2017-03-01

    Nalunaq is an orogenic, high gold grade deposit situated on the Nanortalik Peninsula, South Greenland. Mineralisation is hosted in shear zone-controlled quartz veins, located in fine- and medium-grained amphibolite. The deposit was the site of Greenland's only operating metalliferous mine until its closure in 2014, having produced 10.67 t of gold. This study uses a combination of field investigation, petrography and U/Pb zircon and titanite geochronology to define a multi-stage hydrothermal alteration system at Nalunaq. A clinopyroxene-plagioclase-garnet(-sulphide) alteration zone (CPGZ) developed in the Nanortalik Peninsula, close to regional peak metamorphism and prior to gold-quartz vein formation. The ca. 1783-1762-Ma gold-quartz veins are hosted in reactivated shear zones with a hydrothermal alteration halo of biotite-arsenopyrite-sericite-actinolite-pyrrhotite(-chlorite-plagioclase-löllingite-tourmaline-titanite), which is best developed in areas of exceptionally high gold grades. Aplite dykes dated to ca. 1762 Ma cross-cut the gold-quartz veins, providing a minimum age for mineralisation. A hydrothermal calcite-titanite alteration assemblage is dated to ca. 1766 Ma; however, this alteration is highly isolated, and as a result, its field relationships are poorly constrained. The hydrothermal alteration and mineralisation is cut by several generations of ca. 1745-Ma biotite granodiorite accompanied by brittle deformation. A ca. 1745-Ma lower greenschist facies hydrothermal epidote-calcite-zoisite alteration assemblage with numerous accessory minerals forms halos surrounding the late-stage fractures. The contrasting hydrothermal alteration styles at Nalunaq indicate a complex history of exhumation from amphibolite facies conditions to lower greenschist facies conditions in an orogenic belt which resembles modern Phanerozoic orogens.

  18. A Palaeoproterozoic multi-stage hydrothermal alteration system at Nalunaq gold deposit, South Greenland

    NASA Astrophysics Data System (ADS)

    Bell, Robin-Marie; Kolb, Jochen; Waight, Tod Earle; Bagas, Leon; Thomsen, Tonny B.

    2016-07-01

    Nalunaq is an orogenic, high gold grade deposit situated on the Nanortalik Peninsula, South Greenland. Mineralisation is hosted in shear zone-controlled quartz veins, located in fine- and medium-grained amphibolite. The deposit was the site of Greenland's only operating metalliferous mine until its closure in 2014, having produced 10.67 t of gold. This study uses a combination of field investigation, petrography and U/Pb zircon and titanite geochronology to define a multi-stage hydrothermal alteration system at Nalunaq. A clinopyroxene-plagioclase-garnet(-sulphide) alteration zone (CPGZ) developed in the Nanortalik Peninsula, close to regional peak metamorphism and prior to gold-quartz vein formation. The ca. 1783-1762-Ma gold-quartz veins are hosted in reactivated shear zones with a hydrothermal alteration halo of biotite-arsenopyrite-sericite-actinolite-pyrrhotite(-chlorite-plagioclase-löllingite-tourmaline-titanite), which is best developed in areas of exceptionally high gold grades. Aplite dykes dated to ca. 1762 Ma cross-cut the gold-quartz veins, providing a minimum age for mineralisation. A hydrothermal calcite-titanite alteration assemblage is dated to ca. 1766 Ma; however, this alteration is highly isolated, and as a result, its field relationships are poorly constrained. The hydrothermal alteration and mineralisation is cut by several generations of ca. 1745-Ma biotite granodiorite accompanied by brittle deformation. A ca. 1745-Ma lower greenschist facies hydrothermal epidote-calcite-zoisite alteration assemblage with numerous accessory minerals forms halos surrounding the late-stage fractures. The contrasting hydrothermal alteration styles at Nalunaq indicate a complex history of exhumation from amphibolite facies conditions to lower greenschist facies conditions in an orogenic belt which resembles modern Phanerozoic orogens.

  19. Study of adaptation to altered gravity through systems analysis of motor control

    NASA Astrophysics Data System (ADS)

    Fox, R. A.; Daunton, N. G.; Corcoran, M. L.

    Maintenance of posture and production of functional, coordinated movement demand integration of sensory feedback with spinal and supra-spinal circuitry to produce adaptive motor control in altered gravity (G). To investigate neuroplastic processes leading to optimal performance in altered G we have studied motor control in adult rats using a battery of motor function tests following chronic exposure to various treatments (hyper-G, hindlimb suspension, chemical distruction of hair cells, space flight). These treatments differentially affect muscle fibers, vestibular receptors, and behavioral compensations and, in consequence, differentially disrupt air righting, swimming, posture and gait. The time-course of recovery from these disruptions varies depending on the function tested and the duration and type of treatment. These studies, with others (e.g., D'Amelio et al. in this volume), indicate that adaptation to altered gravity involves alterations in multiple sensory-motor systems that change at different rates. We propose that the use of parallel studies under different altered G conditions will most efficiently lead to an understanding of the modifications in central (neural) and peripheral (sensory and neuromuscular) systems that underlie sensory-motor adaptation in active, intact individuals.

  20. Increase in 4-Coumaryl Alcohol Units during Lignification in Alfalfa (Medicago sativa) Alters the Extractability and Molecular Weight of Lignin*

    PubMed Central

    Ziebell, Angela; Gracom, Kristen; Katahira, Rui; Chen, Fang; Pu, Yunqiao; Ragauskas, Art; Dixon, Richard A.; Davis, Mark

    2010-01-01

    The lignin content of biomass can impact the ease and cost of biomass processing. Lignin reduction through breeding and genetic modification therefore has potential to reduce costs in biomass-processing industries (e.g. pulp and paper, forage, and lignocellulosic ethanol). We investigated compositional changes in two low-lignin alfalfa (Medicago sativa) lines with antisense down-regulation of p-coumarate 3-hydroxylase (C3H) or hydroxycinnamoyl-CoA:shikimate hydroxycinnamoyltransferase (HCT). We investigated whether the difference in reactivity during lignification of 4-coumaryl alcohol (H) monomers versus the naturally dominant sinapyl alcohol and coniferyl alcohol lignin monomers alters the lignin structure. Sequential base extraction readily reduced the H monomer content of the transgenic lines, leaving a residual lignin greatly enriched in H subunits; the extraction profile highlighted the difference between the control and transgenic lines. Gel permeation chromatography of isolated ball-milled lignin indicated significant changes in the weight average molecular weight distribution of the control versus transgenic lines (CTR1a, 6000; C3H4a, 5500; C3H9a, 4000; and HCT30a, 4000). PMID:20921228

  1. Increase in 4-coumaryl alcohol units during lignification in alfalfa (Medicago sativa) alters the extractability and molecular weight of lignin.

    PubMed

    Ziebell, Angela; Gracom, Kristen; Katahira, Rui; Chen, Fang; Pu, Yunqiao; Ragauskas, Art; Dixon, Richard A; Davis, Mark

    2010-12-10

    The lignin content of biomass can impact the ease and cost of biomass processing. Lignin reduction through breeding and genetic modification therefore has potential to reduce costs in biomass-processing industries (e.g. pulp and paper, forage, and lignocellulosic ethanol). We investigated compositional changes in two low-lignin alfalfa (Medicago sativa) lines with antisense down-regulation of p-coumarate 3-hydroxylase (C3H) or hydroxycinnamoyl-CoA:shikimate hydroxycinnamoyltransferase (HCT). We investigated whether the difference in reactivity during lignification of 4-coumaryl alcohol (H) monomers versus the naturally dominant sinapyl alcohol and coniferyl alcohol lignin monomers alters the lignin structure. Sequential base extraction readily reduced the H monomer content of the transgenic lines, leaving a residual lignin greatly enriched in H subunits; the extraction profile highlighted the difference between the control and transgenic lines. Gel permeation chromatography of isolated ball-milled lignin indicated significant changes in the weight average molecular weight distribution of the control versus transgenic lines (CTR1a, 6000; C3H4a, 5500; C3H9a, 4000; and HCT30a, 4000).

  2. [Molecular identification of cymbidium mosaic Potexvirus and Odontoglossum ringspot Tobamovirus complex infected Phalaenopsis and its pathological ultrastructural alteration].

    PubMed

    Shi, Nong Nong; Xu, Ying; Wang, Hui Zhong; Xie, Li; Hong, Jian

    2007-04-01

    Filamentous and rod-shaped virions, and aggregated crystals were observed in infected leaves of by negative staining and ultramicrotomy. Histologic study synchronously showed typical crystal forms of the two virions: the crystals from filamentous particles congregated in strips, arrayed in multilayer and piled in certain angles or helix between layers; while the crystals from rod-shaped particles arrayed in parallel, angle-layer or helix. The two kinds of crystals both presented in parenchyma cells, plasmodesma, and vascular bundles; as an evidence that indicates the existence of short distance transport of viruses between cells, plasmodesmata were produced through piercing the membrane around the reproducing viral crystals; the chloroplasts in the infected cells were hypoplastic, and the filamentous virion were observed within the chloroplasts; the mitochondrions were over-developed, swelled or even cavitated; the nucleus were also swelled and cavitated. Further multiplex RT-PCR and sequencing that the coat protein genes simultaneously expanded to Cymbidium mosaic potexvirus (CymMV) and Odontoglossum ringspot tobamovirus (ORSV) showed homology with available abstracts from GenBank, and the respective percentages of identity are 98% and 99%-100%. The instant and direct identification evidences of CymMV and ORSV complex infection on phalaenopsis are revealed at both cellular and molecular levels, and the character of its pathological ultrastructural alteration as the gist in cellular pathology for pathogenesis are also presented.

  3. ALTERATIONS IN STATE OF MOLECULAR AGGREGATION OF COLLAGEN INDUCED IN CHICK EMBRYOS BY β-AMINOPROPIONITRILE (LATHYRUS FACTOR)

    PubMed Central

    Levene, Charles I.; Gross, Jerome

    1959-01-01

    The lathyrogenic agents, β-aminopropionitrile and semicarbizide, when applied to the chorio-allantoic membrane of the chick embryo produced a dramatic increase in fragility of the embryo. This alteration was not associated with a change in the concentration of collagen, except in aorta, but was accompanied by a sharp increase in the amount of collagen extractible in cold 1 M NaCl from skin, bone, and aorta. Increase in fragility and extractible collagen began within 3 hours after introduction of the agent and rose steadily for at least 72 hours. Essentially no collagen could be extracted from tissues of normal chick embryos. Both fragility and amount of extractible collagen were dosage- and time-dependent. It is concluded that the extractible collagen in lathyrism consists of a large proportion of dissolved fibers previously insoluble and formed prior to administration of the agent. The data also suggest that the "lathyritic" collagen in vivo is not in molecular dispersion but in an aggregate or fibrillar form. It is dispersed by cooling. The extracted collagen could be reconstituted to typical striated fibrils in vitro and the molecule appeared to be normal in the gross, with regard to asymmetry ratio and intramolecular helical structure. The evidence at hand suggests that at least one of the defects induced by lathyrogenic agents is an interference with the normal intermolecular cross-linking within the collagen fibril. PMID:14416144

  4. Phenotypic and Molecular Alterations in the Mammary Tissue of R-Spondin1 Knock-Out Mice during Pregnancy

    PubMed Central

    Chadi, Sead; Polyte, Jacqueline; Lefevre, Lucas; Castille, Johan; Ehanno, Aude; Laubier, Johann; Jaffrézic, Florence; Le Provost, Fabienne

    2016-01-01

    R-spondin1 (Rspo1) is a member of a secreted protein family which has pleiotropic functions in development and stem cell growth. Rspo1 knock-out mice are sex-reversed, but some remain sub-fertile, so they fail to nurse their pups. A lack of Rspo1 expression in the mammary gland results in an absence of duct side-branching development and defective alveolar formation. The aim of this study was to characterize the phenotypic and molecular alterations of mammary gland due to Rspo1 knock-out. Using the transcriptional profiling of mammary tissues, we identified misregulated genes in the mammary gland of Rspo1 knock-out mice during pregnancy. A stronger expression of mesenchymal markers was observed, without modifications to the structure of mammary epithelial tissue. Mammary epithelial cell immunohistochemical analysis revealed a persistence of virgin markers, which signify a delay in cell differentiation. Moreover, serial transplantation experiments showed that Rspo1 is associated with a regenerative potential of mammary epithelial cell control. Our finding also highlights the negatively regulated expression of Rspo1’s partners, Lgr4 and RNF43, in the mammary gland during pregnancy. Moreover, we offer evidence that Tgf-β signalling is modified in the absence of Rspo1. Taken together, our results show an abrupt halt or delay to mammary development during pregnancy due to the loss of a further differentiated function. PMID:27611670

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

    PubMed

    Lee, Daniel Y; Li, King C P

    2009-08-01

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

  6. Enhanced sampling techniques in molecular dynamics simulations of biological systems.

    PubMed

    Bernardi, Rafael C; Melo, Marcelo C R; Schulten, Klaus

    2015-05-01

    Molecular dynamics has emerged as an important research methodology covering systems to the level of millions of atoms. However, insufficient sampling often limits its application. The limitation is due to rough energy landscapes, with many local minima separated by high-energy barriers, which govern the biomolecular motion. In the past few decades methods have been developed that address the sampling problem, such as replica-exchange molecular dynamics, metadynamics and simulated annealing. Here we present an overview over theses sampling methods in an attempt to shed light on which should be selected depending on the type of system property studied. Enhanced sampling methods have been employed for a broad range of biological systems and the choice of a suitable method is connected to biological and physical characteristics of the system, in particular system size. While metadynamics and replica-exchange molecular dynamics are the most adopted sampling methods to study biomolecular dynamics, simulated annealing is well suited to characterize very flexible systems. The use of annealing methods for a long time was restricted to simulation of small proteins; however, a variant of the method, generalized simulated annealing, can be employed at a relatively low computational cost to large macromolecular complexes. Molecular dynamics trajectories frequently do not reach all relevant conformational substates, for example those connected with biological function, a problem that can be addressed by employing enhanced sampling algorithms. This article is part of a Special Issue entitled Recent developments of molecular dynamics. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. A Molecular atlas of Xenopus respiratory system development.

    PubMed

    Rankin, Scott A; Thi Tran, Hong; Wlizla, Marcin; Mancini, Pamela; Shifley, Emily T; Bloor, Sean D; Han, Lu; Vleminckx, Kris; Wert, Susan E; Zorn, Aaron M

    2015-01-01

    Respiratory system development is regulated by a complex series of endoderm-mesoderm interactions that are not fully understood. Recently Xenopus has emerged as an alternative model to investigate early respiratory system development, but the extent to which the morphogenesis and molecular pathways involved are conserved between Xenopus and mammals has not been systematically documented. In this study, we provide a histological and molecular atlas of Xenopus respiratory system development, focusing on Nkx2.1+ respiratory cell fate specification in the developing foregut. We document the expression patterns of Wnt/β-catenin, fibroblast growth factor (FGF), and bone morphogenetic protein (BMP) signaling components in the foregut and show that the molecular mechanisms of respiratory lineage induction are remarkably conserved between Xenopus and mice. Finally, using several functional experiments we refine the epistatic relationships among FGF, Wnt, and BMP signaling in early Xenopus respiratory system development. We demonstrate that Xenopus trachea and lung development, before metamorphosis, is comparable at the cellular and molecular levels to embryonic stages of mouse respiratory system development between embryonic days 8.5 and 10.5. This molecular atlas provides a fundamental starting point for further studies using Xenopus as a model to define the conserved genetic programs controlling early respiratory system development. © 2014 Wiley Periodicals, Inc.

  8. 76 FR 4462 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ... Altered System of Records AGENCY: Office of Workforce and Career Development (OWCD), Department of Health... maintained by the Office of Workforce and Career Development (OWCD). DATES: Comments must be received on or... Prevention (CDC) Office of Workforce and Career Development (OWCD) Epidemic Intelligence Service...

  9. 32 CFR Appendix F to Part 310 - Format for New or Altered System Report

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 2 2011-07-01 2011-07-01 false Format for New or Altered System Report F Appendix F to Part 310 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) PRIVACY PROGRAM DOD PRIVACY PROGRAM Pt. 310, App. F Appendix F to Part 310—Format...

  10. 76 FR 4440 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ... Altered System of Records AGENCY: Division of Tuberculosis Elimination, National Center for HIV, STD and... for Tuberculosis and other Mycobacterioses, HHS/CDC/NCHSTP.'' HHS is proposing to add the following.... These records will be maintained by the Division of Tuberculosis Elimination, National Center for HIV...

  11. 32 CFR Appendix B to Part 323 - Criteria for New and Altered Record Systems

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 2 2012-07-01 2012-07-01 false Criteria for New and Altered Record Systems B Appendix B to Part 323 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) PRIVACY PROGRAM DEFENSE LOGISTICS AGENCY PRIVACY PROGRAM Pt. 323, App. B Appendix B to...

  12. 76 FR 4480 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ... HUMAN SERVICES Centers for Disease Control and Prevention Privacy Act of 1974; Report of Modified or... Environmental Health and Injury Prevention (CCEHIP), Department of Health and Human Services (DHHS). ACTION: Notification of proposed altered System of Records. SUMMARY: The Department of Health and Human Services...

  13. 75 FR 57806 - Privacy Act of 1974; Report of an Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-22

    ... HUMAN SERVICES Health Resources and Services Administration Privacy Act of 1974; Report of an Altered System of Records AGENCY: Department of Health and Human Services (HHS), Health Resources and Services... requirements of the Privacy Act of 1974, the Health Resources and Services Administration (HRSA) is...

  14. 76 FR 4438 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ... Altered System of Records AGENCY: Divisions of Tuberculosis Elimination, National Center for HIV, STD and... Treatment of Tuberculosis and other Mycobacterioses HHS/CDC/NCHSTP.'' HHS is proposing to add the following.... These records will be maintained by the Division of Tuberculosis Elimination, National Center for...

  15. 75 FR 60468 - Privacy Act of 1974; Report of an Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-30

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES Health Resources and Services Administration Privacy Act of 1974; Report of an Altered System of Records AGENCY: Department of Health and Human Services (HHS), Health Resources and Services...

  16. Charging effects, forces, and conduction in molecular wire systems.

    PubMed

    Emberly, Eldon G; Kirczenow, George

    2002-04-01

    Recently, experiments have shown that effects arising from charging and conformational changes in a molecular wire due to an applied voltage bias can have a significant influence on the transport characteristics of the system. We introduce a tractable theoretical approach based on Landauer theory and total energy methods that treats transport nonlinearities, conformational changes, and charging effects in molecular wires in a unified way. We apply this approach to molecular wires consisting of short chain molecules with different electronic and structural properties bonded to metal contacts. We find that the nonlinear conductance characteristics of these systems are remarkably similar and can be understood in terms of a single physical mechanism. We predict that negative differential resistance should occur at high bias in such molecular wires due to the combined effects of charging and conformational changes on their electronic structure.

  17. A molecular dynamics study of polymer/graphene interfacial systems

    SciTech Connect

    Rissanou, Anastassia N.; Harmandaris, Vagelis

    2014-05-15

    Graphene based polymer nanocomposites are hybrid materials with a very broad range of technological applications. In this work, we study three hybrid polymer/graphene interfacial systems (polystyrene/graphene, poly(methyl methacrylate)/graphene and polyethylene/graphene) through detailed atomistic molecular dynamics (MD) simulations. Density profiles, structural characteristics and mobility aspects are being examined at the molecular level for all model systems. In addition, we compare the properties of the hybrid systems to the properties of the corresponding bulk ones, as well as to theoretical predictions.

  18. Peptide-Based Technologies to Alter Adenoviral Vector Tropism: Ways and Means for Systemic Treatment of Cancer

    PubMed Central

    Reetz, Julia; Herchenröder, Ottmar; Pützer, Brigitte M.

    2014-01-01

    Due to the fundamental progress in elucidating the molecular mechanisms of human diseases and the arrival of the post-genomic era, increasing numbers of therapeutic genes and cellular targets are available for gene therapy. Meanwhile, the most important challenge is to develop gene delivery vectors with high efficiency through target cell selectivity, in particular under in situ conditions. The most widely used vector system to transduce cells is based on adenovirus (Ad). Recent endeavors in the development of selective Ad vectors that target cells or tissues of interest and spare the alteration of all others have focused on the modification of the virus broad natural tropism. A popular way of Ad targeting is achieved by directing the vector towards distinct cellular receptors. Redirecting can be accomplished by linking custom-made peptides with specific affinity to cellular surface proteins via genetic integration, chemical coupling or bridging with dual-specific adapter molecules. Ideally, targeted vectors are incapable of entering cells via their native receptors. Such altered vectors offer new opportunities to delineate functional genomics in a natural environment and may enable efficient systemic therapeutic approaches. This review provides a summary of current state-of-the-art techniques to specifically target adenovirus-based gene delivery vectors. PMID:24699364

  19. STALK : an interactive virtual molecular docking system.

    SciTech Connect

    Levine, D.; Facello, M.; Hallstrom, P.; Reeder, G.; Walenz, B.; Stevens, F.; Univ. of Illinois

    1997-04-01

    Several recent technologies-genetic algorithms, parallel and distributed computing, virtual reality, and high-speed networking-underlie a new approach to the computational study of how biomolecules interact or 'dock' together. With the Stalk system, a user in a virtual reality environment can interact with a genetic algorithm running on a parallel computer to help in the search for likely geometric configurations.

  20. PASS: simple molecular graphics system for personal computers.

    PubMed

    Chelvanayagam, G

    1990-12-01

    An interactive tool for displaying and manipulating molecular structures is presented. The system has a user friendly, menu driven interface and provides good quality graphics for viewing proteins. Full screen stereo viewing and a high degree of flexibility in the investigation of specific sites are among its key attributes. The low cost of the system allows it a diverse range of applicability.

  1. Molecular archeological studies of transmembrane transport systems

    NASA Astrophysics Data System (ADS)

    Saier, Milton H.; Wang, Bin; Sun, Eric I.; Matias, Madeleine; Yen, Ming Ren

    We here review studies concerned with the evolutionary pathways taken for the appearance of complex transport systems. The transmembrane protein constituents of these systems generally arose by (1) intragenic duplications, (2) gene fusions, and (3) the superimposition of enzymes onto carriers. In a few instances, we have documented examples of “reverse” or “retrograde” evolution where complex carriers have apparently lost parts of their polypeptide chains to give rise to simpler channels. Some functional superfamilies of transporters that are energized by adenosine triphosphate (ATP) or phosphoenolpyruvate (PEP) include several independently evolving permease families. The ubiquitous ATP-binding cassette (ABC) superfamily couples transport to ATP hydrolysis where the ATPases are superimposed on at least three distinct, independently evolving families of permeases. The prokaryotic sugar transporting phosphotransferase system (PTS) uses homologous PEP-dependent general energy-coupling phosphoryl transfer enzymes superimposed on at least three independently arising families of permeases to give rise to complex group translocators that modify their sugar substrates during transport, releasing cytoplasmic sugar phosphates. We suggest that simple carriers evolved independently of the energizing enzymes, and that chemical energization of transport resulted from the physical and functional coupling of the enzymes to the carriers.

  2. Systemic alterations induced by a Bothrops alternatus hemorrhagic metalloproteinase (baltergin) in mice.

    PubMed

    Gay, C C; Maruñak, S L; Teibler, P; Ruiz, R; Acosta de Pérez, O C; Leiva, L C

    2009-01-01

    Systemic alterations induced by a Bothrops alternatus hemorrhagin, named baltergin, a 55kDa fibrinogenolytic metalloproteinase isolated from venom of north-eastern Argentina specimens, were studied in mice. It caused macroscopic hemorrhagic spots in lungs which was injected intravenously with a minimum pulmonary hemorrhagic dose of 10microg. Histological observations of lungs showed mainly hemorrhagic areas, evidenced by the presence of erythrocytes in the alveolar spaces, congestion and increase of thickness of alveolar septum due to polymorphonuclear infiltrate and mononuclear cells. Neither macroscopic hemorrhage in other organs nor histological alterations in heart and cerebrum/cerebellum were observed at doses assayed. However, kidney and liver were mildly affected. Kidney examination revealed congestion, subcapsular hemorrhage with local capsule detachment, inflammatory infiltrate and degeneration of tubular cells. Congestion of blood vessels and hydropic degeneration of hepatocytes were observed in liver. Besides, baltergin was able to further hydrolyze type IV collagen. Although the enzyme showed to be less lethal than whole venom, it induced severe pulmonary bleeding and affected kinder and liver in minor grade. In conclusion, baltergin is able to alter the integrity of capillary vessels and simultaneously, to interfere on the hemostatic system. Thus, this metalloproteinase contribute markedly to systemic alterations characteristic of B. alternatus envenomations.

  3. Role of altered intestinal microbiota in systemic inflammation and cardiovascular disease in chronic kidney disease.

    PubMed

    Mafra, Denise; Lobo, Julie C; Barros, Amanda F; Koppe, Laetitia; Vaziri, Nosratola D; Fouque, Denis

    2014-01-01

    The normal intestinal microbiota plays a major role in the maintenance of health and disease prevention. In fact, the alteration of the intestinal microbiota has been shown to contribute to the pathogenesis of several pathological conditions, including obesity and insulin resistance, among others. Recent studies have revealed profound alterations of the gut microbial flora in patients and animals with chronic kidney disease (CKD). Alterations in the composition of the microbiome in CKD may contribute to the systemic inflammation and accumulation of gut-derived uremic toxins, which play a central role in the pathogenesis of accelerated cardiovascular disease and numerous other CKD-associated complications. This review is intended to provide a concise description of the potential role of the CKD-associated changes in the gut microbiome and its potential role the pathogenesis of inflammation and uremic toxicity. In addition, the potential efficacy of pre- and pro-biotics in the restoration of the microbiome is briefly described.

  4. 32 CFR Appendix E to Part 310 - Sample of New or Altered System of Records Notice in Federal Register Format

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Logistics Agency Privacy Act of 1974; Systems of Records AGENCY: Defense Logistics Agency. ACTION: Notice to alter a system of records. SUMMARY: The Defense Logistics Agency proposes to alter a system of records... Logistics Agency, ATTN: DSS-B, 8725 John J. Kingman Road, Suite 2533, Fort Belvoir, VA 22060-6221. FOR...

  5. 32 CFR Appendix C to Part 323 - Instructions for Preparation of Reports to New or Altered Systems

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... or Altered Systems C Appendix C to Part 323 National Defense Department of Defense (Continued) OFFICE.... 323, App. C Appendix C to Part 323—Instructions for Preparation of Reports to New or Altered Systems... activities that are the sources, recipients, or users of the information in the system. C. Supporting...

  6. Phosphorylated S6K1 (Thr389) is a molecular adipose tissue marker of altered glucose tolerance.

    PubMed

    Moreno-Navarrete, José María; Ortega, Francisco; Sánchez-Garrido, Miguel Ángel; Sabater, Mònica; Ricart, Wifredo; Zorzano, Antonio; Tena-Sempere, Manuel; Fernández-Real, José Manuel

    2013-01-01

    Molecular tissue markers of altered glucose metabolism will be useful as potential targets for antidiabetic drugs. S6K1 is a downstream signal of insulin action. We aimed to evaluate (pThr389)S6K1 and total S6K1 levels in human and rat fat depots as candidate markers of altered glucose metabolism. (pThr389)S6K1 and total S6K1 levels were measured using enzyme linked immune sorbent assay (ELISA) in 49 adipose tissue samples from subjects with morbid obesity and in 18 peri-renal white adipose tissue samples from rats. The effects of high glucose and rosiglitazone have been explored in human preadipocytes. (pThr389)S6K1/(total)S6K1 in subcutaneous adipose tissue was significantly increased subjects with Type 2 diabetes (0.78 ± 0.26 vs. 0.55 ± 0.14, P=.02) and associated with fasting glucose (r=0.46, P=.04) and glycated hemoglobin (r=0.63, P=.02) in SAT. Similar associations with fasting glucose (r=0.43, P=.03) and IRS1 (r=-0.41, P=.04) gene expression were found in visceral adipose tissue. In addition, rat experiments confirmed the higher (pThr389)S6K1/totalS6K1 levels in adipose tissue in association with obesity-associated metabolic disturbances. (pThr389)S6K1/totalS6K1 was validated using western blot in rat adipose tissue. Both ELISA and western blot data significantly correlated (r=0.85, P=.005). In human preadipocytes, high glucose medium led to increased (pThr389)S6K1/total S6K1 levels in comparison with normal glucose medium, which was significantly decreased under rosiglitazone administration. In conclusion, in human and rat adipose tissue, phosphorylated S6K1 is a marker for increased glucose levels.

  7. Difference of carboxybetaine and oligo(ethylene glycol) moieties in altering hydrophobic interactions: a molecular simulation study.

    PubMed

    Shao, Qing; White, Andrew D; Jiang, Shaoyi

    2014-01-09

    Polycarboxybetaine and poly(ethylene glycol) materials resist nonspecific protein adsorption but differ in influencing biological functions such as enzymatic activity. To investigate this difference, we studied the influence of carboxybetaine and oligo(ethylene glycol) moieties on hydrophobic interactions using molecular simulations. We employed a model system composed of two non-polar plates and studied the potential of mean force of plate-plate association in carboxybetaine, (ethylene glycol)4, and (ethylene glycol)2 solutions using well-tempered metadynamics simulations. Water, trimethylamine N-oxide, and urea solutions were used as reference systems. We analyzed the variation of the potential of mean force in various solutions to study how carboxybetaine and oligo(ethylene glycol) moieties influence the hydrophobic interactions. To study the origin of their influence, we analyzed the normalized distributions of moieties and water molecules using molecular dynamics simulations. The simulation results showed that oligo(ethylene glycol) moieties repel water molecules away from the non-polar plates and weaken the hydrophobic interactions. Carboxybetaine moieties do not repel water molecules away from the plates and therefore do not influence the hydrophobic interactions.

  8. Effects of chemical alteration on fracture mechanical properties in hydrothermal systems

    NASA Astrophysics Data System (ADS)

    Callahan, O. A.; Eichhubl, P.; Olson, J. E.

    2015-12-01

    Fault and fracture networks often control the distribution of fluids and heat in hydrothermal and epithermal systems, and in related geothermal and mineral resources. Additional chemical influences on conduit evolution are well documented, with dissolution and precipitation of mineral species potentially changing the permeability of fault-facture networks. Less well understood are the impacts of chemical alteration on the mechanical properties governing fracture growth and fracture network geometry. We use double-torsion (DT) load relaxation tests under ambient air conditions to measure the mode-I fracture toughness (KIC) and subcritical fracture growth index (SCI) of variably altered rock samples obtained from outcrop in Dixie Valley, NV. Samples from southern Dixie Valley include 1) weakly altered granite, characterized by minor sericite in plagioclase, albitization and vacuolization of feldspars, and incomplete replacement of biotite with chlorite, and 2) granite from an area of locally intense propylitic alteration with chlorite-calcite-hematite-epidote assemblages. We also evaluated samples of completely silicified gabbro obtained from the Dixie Comstock epithermal gold deposit. In the weakly altered granite KIC and SCI are 1.3 ±0.2 MPam1/2 (n=8) and 59 ±25 (n=29), respectively. In the propylitic assemblage KIC is reduced to 0.6 ±0.1 MPam1/2 (n=11), and the SCI increased to 75 ±36 (n = 33). In both cases, the altered materials have lower fracture toughness and higher SCI than is reported for common geomechanical standards such as Westerly Granite (KIC ~1.7 MPam1/2; SCI ~48). Preliminary analysis of the silicified gabbro shows a significant increase in fracture toughness, 3.6 ±0.4 MPam1/2 (n=2), and SCI, 102 ±45 (n=19), compared to published values for gabbro (2.9 MPam1/2 and SCI = 32). These results suggest that mineralogical and textural changes associated with different alteration assemblages may result in spatially variable rates of fracture

  9. Proton transfer in some periodic molecular systems.

    PubMed

    Chojnacki, Henryk

    2007-07-01

    The electronic structure of representative hydrogen bonded systems: hydrogen cyanide, imidazole and malonic acid have been studied at the non-empirical level. The role of the dimensionality on the potential barrier for the proton transfer has been examined. It was shown that it depends on the crystal structure and only in some cases like hydrogen cyanide or imidazole the relevant crystals may be considered as one-dimensional. However, for more complicated crystallographic structures, e.g. malonic acid, the evaluated barrier is strongly dependent on the dimensionality taken into account in our calculations.

  10. Nondynamical correlation energy in model molecular systems

    NASA Astrophysics Data System (ADS)

    Chojnacki, Henryk

    The hypersurfaces for the deprotonation processes have been studied at the nonempirical level for H3O+, NH+4, PH+4, and H3S+ cations within their correlation consistent basis set. The potential energy curves were calculated and nondynamical correlation energies analyzed. We have found that the restricted Hartree-Fock wavefunction leads to the improper dissociation limit and, in the three latest cases requires multireference description. We conclude that these systems may be treated as a good models for interpretation of the proton transfer mechanism as well as for testing one-determinantal or multireference cases.

  11. Exploring the Photophysical Properties of Molecular Systems Using Excited State Accelerated ab Initio Molecular Dynamics.

    PubMed

    Ortiz-Sánchez, Juan Manuel; Bucher, Denis; Pierce, Levi C T; Markwick, Phineus R L; McCammon, J Andrew

    2012-08-14

    In the present work, we employ excited state accelerated ab initio molecular dynamics (A-AIMD) to efficiently study the excited state energy landscape and photophysical topology of a variety of molecular systems. In particular, we focus on two important challenges for the modeling of excited electronic states: (i) the identification and characterization of conical intersections and crossing seams, in order to predict different and often competing radiationless decay mechanisms, and (ii) the description of the solvent effect on the absorption and emission spectra of chemical species in solution. In particular, using as examples the Schiff bases formaldimine and salicylidenaniline, we show that A-AIMD can be readily employed to explore the conformational space around crossing seams in molecular systems with very different photochemistry. Using acetone in water as an example, we demonstrate that the enhanced configurational space sampling may be used to accurately and efficiently describe both the prominent features and line-shapes of absorption and emission spectra.

  12. Pseudorotational Dynamics of Small Molecular Systems

    NASA Astrophysics Data System (ADS)

    Hagelberg, Frank

    2001-03-01

    A variety of dynamic effects related to the pseudorotation of triatomic singly charged species is explored using the Electron Nuclear Dynamics(END)Theory. The concepts relevant to the motion studied are developed through the analysis of the simplest polyatomic molecule, namely H3+. It is shown that the limiting situation of circular pseudorotation is unattainable for this case. This observation is explained by the anisotropy of the ground state potential energy surface caused by the interaction between the D3h ground state of the molecule and its twofold degenerate first excited state. Further, pseudorotational motion is demonstrated to induce a rotational mode which in turn couples the two shape oscillation modes by action of the Coriolis force. Analogous phenomena are found for Li3+. The Jahn-Teller system C3+ exhibits a range of new motional effects. Particularly, a characteristic frequency shift between the two shape oscillation modes is obtained, resulting from the anisotropy in the curvature of the C2v minimum of C3+. The Jahn-Teller parameters of the system are determined from Electron Nuclear Dynamics simulations.

  13. Continuous-terahertz-wave molecular imaging system for biomedical applications

    NASA Astrophysics Data System (ADS)

    Zhang, Rui; Zhang, Liangliang; Wu, Tong; Wang, Ruixue; Zuo, Shasha; Wu, Dong; Zhang, Cunlin; Zhang, Jue; Fang, Jing

    2016-07-01

    Molecular imaging techniques are becoming increasingly important in biomedical research and potentially in clinical practice. We present a continuous-terahertz (THz)-wave molecular imaging system for biomedical applications, in which an infrared (IR) laser is integrated into a 0.2-THz reflection-mode continuous-THz-wave imaging system to induce surface plasmon polaritons on the nanoparticles and further improve the intensity of the reflected signal from the water around the nanoparticles. A strong and rapid increment of the reflected THz signal in the nanoparticle solution upon the IR laser irradiation is demonstrated, using either gold or silver nanoparticles. This low-cost, simple, and stable continuous-THz-wave molecular imaging system is suitable for miniaturization and practical imaging applications; in particular, it shows great promise for cancer diagnosis and nanoparticle drug-delivery monitoring.

  14. Genetic Ablation of Calcium-independent Phospholipase A2γ Leads to Alterations in Hippocampal Cardiolipin Content and Molecular Species Distribution, Mitochondrial Degeneration, Autophagy, and Cognitive Dysfunction*

    PubMed Central

    Mancuso, David J.; Kotzbauer, Paul; Wozniak, David F.; Sims, Harold F.; Jenkins, Christopher M.; Guan, Shaoping; Han, Xianlin; Yang, Kui; Sun, Gang; Malik, Ibrahim; Conyers, Sara; Green, Karen G.; Schmidt, Robert E.; Gross, Richard W.

    2009-01-01

    Genetic ablation of calcium-independent phospholipase A2γ (iPLA2γ) results in profound alterations in hippocampal phospholipid metabolism and mitochondrial phospholipid homeostasis resulting in enlarged and degenerating mitochondria leading to autophagy and cognitive dysfunction. Shotgun lipidomics demonstrated multiple alterations in hippocampal lipid metabolism in iPLA2γ−/− mice including: 1) a markedly elevated hippocampal cardiolipin content with an altered molecular species composition characterized by a shift to shorter chain length molecular species; 2) alterations in both choline and ethanolamine glycerophospholipids, including a decreased plasmenylethanolamine content; 3) increased oxidized phosphatidylethanolamine molecular species; and 4) an increased content of ceramides. Electron microscopic examination demonstrated the presence of enlarged heteromorphic lamellar structures undergoing degeneration accompanied by the presence of ubiquitin positive spheroid inclusion bodies. Purification of these enlarged heteromorphic lamellar structures by buoyant density centrifugation and subsequent SDS-PAGE and proteomics identified them as degenerating mitochondria. Collectively, these results identify the obligatory role of iPLA2γ in neuronal mitochondrial lipid metabolism and membrane structure demonstrating that iPLA2γ loss of function results in a mitochondrial neurodegenerative disorder characterized by degenerating mitochondria, autophagy, and cognitive dysfunction. PMID:19840936

  15. Primary melanocytic tumors of the central nervous system: a review with focus on molecular aspects.

    PubMed

    Küsters-Vandevelde, Heidi V N; Küsters, Benno; van Engen-van Grunsven, Adriana C H; Groenen, Patricia J T A; Wesseling, Pieter; Blokx, Willeke A M

    2015-03-01

    Primary melanocytic tumors of the central nervous system (CNS) represent a spectrum of rare tumors. They can be benign or malignant and occur in adults as well as in children, the latter often in the context of neurocutaneous melanosis. Until recently, the genetic alterations in these tumors were largely unknown. This is in contrast with cutaneous and uveal melanomas, which are known to harbor distinct oncogenic mutations that can be used as targets for treatment with small-molecule inhibitors in the advanced setting. Recently, novel insights in the molecular alterations underlying primary melanocytic tumors of the CNS were obtained, including different oncogenic mutations in tumors in adult patients (especially GNAQ, GNA11) vs. children (especially NRAS). In this review, the focus is on molecular characteristics of primary melanocytic tumors of the CNS. We summarize what is known about their genetic alterations and discuss implications for pathogenesis and differential diagnosis with other pigmented tumors in or around the CNS. Finally, new therapeutic options with targeted therapy are discussed. © 2014 International Society of Neuropathology.

  16. Different alcohol exposures induce selective alterations on the expression of dynorphin and nociceptin systems related genes in rat brain.

    PubMed

    D'Addario, Claudio; Caputi, Francesca F; Rimondini, Roberto; Gandolfi, Ottavio; Del Borrello, Elia; Candeletti, Sanzio; Romualdi, Patrizia

    2013-05-01

    Molecular mechanisms of adaptive transformations caused by alcohol exposure on opioid dynorphin and nociceptin systems have been investigated in the rat brain. Alcohol was intragastrically administered to rats to resemble human drinking with several hours of exposure: water or alcohol (20% in water) at a dose of 1.5 g/kg three times daily for 1 or 5 days. The development of tolerance and dependence were recorded daily. Brains were dissected 30 minutes (1- and 5-day groups) or 1, 3 or 7 days after the last administration for the three other 5-day groups (groups under withdrawal). Specific alterations in opioid genes expression were ascertained. In the amygdala, an up-regulation of prodynorphin and pronociceptin was observed in the 1-day group; moreover, pronociceptin and the kappa opioid receptor mRNAs in the 5-day group and both peptide precursors in the 1-day withdrawal group were also up-regulated. In the prefrontal cortex, an increase in prodynorhin expression in the 1-day group was detected. These data indicate a relevant role of the dynorphinergic system in the negative hedonic states associated with multiple alcohol exposure. The pattern of alterations observed for the nociceptin system appears to be consistent with its role of functional antagonism towards the actions of ethanol associated with other opioid peptides. Our findings could help to the understanding of how alcohol differentially affects the opioid systems in the brain and also suggest the dynorphin and nociceptin systems as possible targets for the treatment and/or prevention of alcohol dependence.

  17. Impact of DNA mismatch repair system alterations on human fertility and related treatments.

    PubMed

    Hu, Min-hao; Liu, Shu-yuan; Wang, Ning; Wu, Yan; Jin, Fan

    2016-01-01

    DNA mismatch repair (MMR) is one of the biological pathways, which plays a critical role in DNA homeostasis, primarily by repairing base-pair mismatches and insertion/deletion loops that occur during DNA replication. MMR also takes part in other metabolic pathways and regulates cell cycle arrest. Defects in MMR are associated with genomic instability, predisposition to certain types of cancers and resistance to certain therapeutic drugs. Moreover, genetic and epigenetic alterations in the MMR system demonstrate a significant relationship with human fertility and related treatments, which helps us to understand the etiology and susceptibility of human infertility. Alterations in the MMR system may also influence the health of offspring conceived by assisted reproductive technology in humans. However, further studies are needed to explore the specific mechanisms by which the MMR system may affect human infertility. This review addresses the physiological mechanisms of the MMR system and associations between alterations of the MMR system and human fertility and related treatments, and potential effects on the next generation.

  18. Functional alteration in frontolimbic systems relevant to moral judgment in cocaine-dependent subjects.

    PubMed

    Verdejo-Garcia, Antonio; Contreras-Rodríguez, Oren; Fonseca, Francina; Cuenca, Aida; Soriano-Mas, Carles; Rodriguez, Joan; Pardo-Lozano, Ricardo; Blanco-Hinojo, Laura; de Sola Llopis, Susana; Farré, Magí; Torrens, Marta; Pujol, Jesús; de la Torre, Rafael

    2014-03-01

    Cocaine addiction is characterized by persistent decision-making deficits, which are linked to structural and functional abnormalities in frontolimbic systems. Moral judgment is as a special instance of decision making, in which both cognitive and emotional signals must be adequately integrated to decide how to resolve moral dilemmas. Here, we employed a moral dilemmas functional magnetic resonance imaging (fMRI) task to explore possible alterations of frontolimbic systems in cocaine-dependent subjects. We also explored if these alterations relate to more basic deficits in functional connectivity within these systems during spontaneous resting-state activation. Ten cocaine-dependent subjects and 14 non-drug-using controls participated in the study. Cocaine-dependent subjects were carefully selected to discard potentially confounding co-morbidities, and they underwent a uniform supervised abstinence period of 10 days. Both groups were scanned, and fMRI maps were generated to identify (1) brain response to moral dilemmas; and (2) the strength of functional connectivity within frontolimbic systems during resting-state. During the moral dilemmas task, cocaine-dependent subjects showed reduced activation involving frontolimbic structures as the anterior cingulate cortex (ACC), left insula and brain stem. Connectivity analyses showed that cocaine users had less resting-state functional connectivity between ACC, thalamus, insula and brain stem. These results demonstrate that cocaine-dependent subjects have functional alterations in the frontolimbic systems that support moral judgment and social decision making. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.

  19. Impact of DNA mismatch repair system alterations on human fertility and related treatments*

    PubMed Central

    Hu, Min-hao; Liu, Shu-yuan; Wang, Ning; Wu, Yan; Jin, Fan

    2016-01-01

    DNA mismatch repair (MMR) is one of the biological pathways, which plays a critical role in DNA homeostasis, primarily by repairing base-pair mismatches and insertion/deletion loops that occur during DNA replication. MMR also takes part in other metabolic pathways and regulates cell cycle arrest. Defects in MMR are associated with genomic instability, predisposition to certain types of cancers and resistance to certain therapeutic drugs. Moreover, genetic and epigenetic alterations in the MMR system demonstrate a significant relationship with human fertility and related treatments, which helps us to understand the etiology and susceptibility of human infertility. Alterations in the MMR system may also influence the health of offspring conceived by assisted reproductive technology in humans. However, further studies are needed to explore the specific mechanisms by which the MMR system may affect human infertility. This review addresses the physiological mechanisms of the MMR system and associations between alterations of the MMR system and human fertility and related treatments, and potential effects on the next generation. PMID:26739522

  20. 41 CFR 51-9.503 - Effective date of new systems of records or alteration of an existing system of records.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Existing Systems § 51-9.503 Effective date of new systems of records or alteration of an existing system of... 41 Public Contracts and Property Management 1 2014-07-01 2014-07-01 false Effective date of new systems of records or alteration of an existing system of records. 51-9.503 Section 51-9.503 Public...

  1. 41 CFR 51-9.503 - Effective date of new systems of records or alteration of an existing system of records.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Existing Systems § 51-9.503 Effective date of new systems of records or alteration of an existing system of... 41 Public Contracts and Property Management 1 2010-07-01 2010-07-01 true Effective date of new systems of records or alteration of an existing system of records. 51-9.503 Section 51-9.503 Public...

  2. 41 CFR 51-9.503 - Effective date of new systems of records or alteration of an existing system of records.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Existing Systems § 51-9.503 Effective date of new systems of records or alteration of an existing system of... 41 Public Contracts and Property Management 1 2012-07-01 2009-07-01 true Effective date of new systems of records or alteration of an existing system of records. 51-9.503 Section 51-9.503 Public...

  3. 41 CFR 51-9.503 - Effective date of new systems of records or alteration of an existing system of records.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Existing Systems § 51-9.503 Effective date of new systems of records or alteration of an existing system of... 41 Public Contracts and Property Management 1 2011-07-01 2009-07-01 true Effective date of new systems of records or alteration of an existing system of records. 51-9.503 Section 51-9.503 Public...

  4. 41 CFR 51-9.503 - Effective date of new systems of records or alteration of an existing system of records.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Existing Systems § 51-9.503 Effective date of new systems of records or alteration of an existing system of... 41 Public Contracts and Property Management 1 2013-07-01 2013-07-01 false Effective date of new systems of records or alteration of an existing system of records. 51-9.503 Section 51-9.503 Public...

  5. Enhanced Sampling Techniques in Molecular Dynamics Simulations of Biological Systems

    PubMed Central

    Bernardi, Rafael C.; Melo, Marcelo C. R.; Schulten, Klaus

    2014-01-01

    Background Molecular Dynamics has emerged as an important research methodology covering systems to the level of millions of atoms. However, insufficient sampling often limits its application. The limitation is due to rough energy landscapes, with many local minima separated by high-energy barriers, which govern the biomolecular motion. Scope of review In the past few decades methods have been developed that address the sampling problem, such as replica-exchange molecular dynamics, metadynamics and simulated annealing. Here we present an overview over theses sampling methods in an attempt to shed light on which should be selected depending on the type of system property studied. Major Conclusions Enhanced sampling methods have been employed for a broad range of biological systems and the choice of a suitable method is connected to biological and physical characteristics of the system, in particular system size. While metadynamics and replica-exchange molecular dynamics are the most adopted sampling methods to study biomolecular dynamics, simulated annealing is well suited to characterize very flexible systems. The use of annealing methods for a long time was restricted to simulation of small proteins; however, a variant of the method, generalized simulated annealing, can be employed at a relatively low computational cost to large macromolecular complexes. General Significance Molecular dynamics trajectories frequently do not reach all relevant conformational substates, for example those connected with biological function, a problem that can be addressed by employing enhanced sampling algorithms. PMID:25450171

  6. A simplified electrophoretic system for determining molecular weights of proteins.

    PubMed

    Manwell, C

    1977-09-01

    Electrophoresis of 31 different proteins in commercially prepared polyacrylamide gradient gels, Gradipore, yields a linear relationship between a hypothetical limiting pore size (the reciprocal of a limiting gel concentration, GL) and the cube root of the mol.wt., over the range 13 500-9000 000. A regression analysis of these data reveals that 98.6% of all variability in 1/GL is explained by the molecular weight, and this degree of accuracy compares favourably with existing methods for the determination of molecular weight by retardation of mobility in polyacrylamide. This new procedure has the additional advantages that molecular-weight standards can be obtained from readily available body fluids or tissue extracts by localizing enzymes and other proteins by standard histochemical methods, and that the same electrophoretic system can be used in determining molecular weights as is used in routine surveys of populations for individual and species variation in protein heterogeneity.

  7. A priming dose of protons alters the early cardiac cellular and molecular response to 56Fe irradiation

    PubMed Central

    Ramadan, Samy S.; Sridharan, Vijayalakshmi; Koturbash, Igor; Miousse, Isabelle R.; Hauer-Jensen, Martin; Nelson, Gregory A.; Boerma, Marjan

    2015-01-01

    Purpose Recent evidence suggests that the heart may be injured by ionizing radiation at lower doses than was previously thought. This raises concerns about the cardiovascular risks from exposure to radiation during space travel. Since space travel is associated with exposure to both protons from solar particle events and heavy ions from galactic cosmic rays, we here examined the effects of a “priming” dose of protons on the cardiac cellular and molecular response to a “challenge” dose of 56Fe in a mouse model. Methods Male C57BL/6 mice at 10 weeks of age were exposed to sham-irradiation, 0.1 Gy of protons (150 MeV), 0.5 Gy of 56Fe (600 MeV/n), or 0.1 Gy of protons 24 hours prior to 0.5 Gy of 56Fe. Hearts were obtained at 7 days post-irradiation and western-blots were used to determine protein markers of cardiac remodeling, inflammatory infiltration, and cell death. Results Exposure to 56Fe caused an increase in expression of α-smooth muscle cell actin, collagen type III, the inflammatory cell markers mast cell tryptase, CD2 and CD68, the endothelial glycoprotein thrombomodulin, and cleaved caspase 3. Of all proteins investigated, protons at a dose of 0.1 Gy induced a small increase only in cleaved caspase 3 levels. On the other hand, exposure to protons 24 hours before 56Fe prevented all of the responses to 56Fe. Conclusions This study shows that a low dose of protons may prime the heart to respond differently to a subsequent challenge dose of heavy ions. Further investigation is required to identify responses at additional time points, consequences for cardiac function, threshold dose levels, and mechanisms by which a proton priming dose may alter the response to heavy ions. PMID:26948008

  8. A priming dose of protons alters the early cardiac cellular and molecular response to 56Fe irradiation

    NASA Astrophysics Data System (ADS)

    Ramadan, Samy S.; Sridharan, Vijayalakshmi; Koturbash, Igor; Miousse, Isabelle R.; Hauer-Jensen, Martin; Nelson, Gregory A.; Boerma, Marjan

    2016-02-01

    Purpose: Recent evidence suggests that the heart may be injured by ionizing radiation at lower doses than was previously thought. This raises concerns about the cardiovascular risks from exposure to radiation during space travel. Since space travel is associated with exposure to both protons from solar particle events and heavy ions from galactic cosmic rays, we here examined the effects of a ;priming; dose of protons on the cardiac cellular and molecular response to a ;challenge; dose of 56Fe in a mouse model. Methods: Male C57BL/6 mice at 10 weeks of age were exposed to sham-irradiation, 0.1 Gy of protons (150 MeV), 0.5 Gy of 56Fe (600 MeV/n), or 0.1 Gy of protons 24 hours prior to 0.5 Gy of 56Fe. Hearts were obtained at 7 days post-irradiation and western-blots were used to determine protein markers of cardiac remodeling, inflammatory infiltration, and cell death. Results: Exposure to 56Fe caused an increase in expression of α-smooth muscle cell actin, collagen type III, the inflammatory cell markers mast cell tryptase, CD2 and CD68, the endothelial glycoprotein thrombomodulin, and cleaved caspase 3. Of all proteins investigated, protons at a dose of 0.1 Gy induced a small increase only in cleaved caspase 3 levels. On the other hand, exposure to protons 24 hours before 56Fe prevented all of the responses to 56Fe. Conclusions: This study shows that a low dose of protons may prime the heart to respond differently to a subsequent challenge dose of heavy ions. Further investigation is required to identify responses at additional time points, consequences for cardiac function, threshold dose levels, and mechanisms by which a proton priming dose may alter the response to heavy ions.

  9. A priming dose of protons alters the early cardiac cellular and molecular response to (56)Fe irradiation.

    PubMed

    Ramadan, Samy S; Sridharan, Vijayalakshmi; Koturbash, Igor; Miousse, Isabelle R; Hauer-Jensen, Martin; Nelson, Gregory A; Boerma, Marjan

    2016-02-01

    Recent evidence suggests that the heart may be injured by ionizing radiation at lower doses than was previously thought. This raises concerns about the cardiovascular risks from exposure to radiation during space travel. Since space travel is associated with exposure to both protons from solar particle events and heavy ions from galactic cosmic rays, we here examined the effects of a "priming" dose of protons on the cardiac cellular and molecular response to a "challenge" dose of (56)Fe in a mouse model. Male C57BL/6 mice at 10 weeks of age were exposed to sham-irradiation, 0.1 Gy of protons (150 MeV), 0.5 Gy of (56)Fe (600 MeV/n), or 0.1 Gy of protons 24 hours prior to 0.5 Gy of (56)Fe. Hearts were obtained at 7 days post-irradiation and western-blots were used to determine protein markers of cardiac remodeling, inflammatory infiltration, and cell death. Exposure to (56)Fe caused an increase in expression of α-smooth muscle cell actin, collagen type III, the inflammatory cell markers mast cell tryptase, CD2 and CD68, the endothelial glycoprotein thrombomodulin, and cleaved caspase 3. Of all proteins investigated, protons at a dose of 0.1 Gy induced a small increase only in cleaved caspase 3 levels. On the other hand, exposure to protons 24 hours before (56)Fe prevented all of the responses to (56)Fe. This study shows that a low dose of protons may prime the heart to respond differently to a subsequent challenge dose of heavy ions. Further investigation is required to identify responses at additional time points, consequences for cardiac function, threshold dose levels, and mechanisms by which a proton priming dose may alter the response to heavy ions. Copyright © 2015 The Committee on Space Research (COSPAR). Published by Elsevier Ltd. All rights reserved.

  10. Molecular background and physiological consequences of altered peripheral serotonin homeostasis in adult rats perinatally treated with tranylcypromine.

    PubMed

    Blazevic, S; Erjavec, I; Brizic, M; Vukicevic, S; Hranilovic, D

    2015-08-01

    Serotonin (5-hydroxytryptamine, 5-HT) is a biologically active molecule present in mammals in the brain and peripheral tissues where it exerts many physiological functions. Developmental exposure to 5-HT-enhancing agents has been reported to induce long-lasting changes in the brain, but the long-term effects of perinatal 5-HT enhancement on 5-HT balance and function in the peripheral compartment have not been explored. Perinatal treatment of rats with monoamine oxidase (MAO) inhibitor tranylcypromine (TCP), leads to persistent imbalance in central (increased 5-HT degradation and decreased 5-HT concentrations in the brain) and peripheral (increased platelet and decreased plasma 5-HT concentrations) 5-HT homeostasis. In this study, we explored the molecular background of peripheral 5-HT imbalance, and its possible consequences on bone remodeling and hematopoiesis. Jejunum, liver and blood samples were collected from TCP- and saline-treated rats on post-natal day 70. Relative mRNA levels for tryptophan hydroxylase 1 (TPH1) and MAO A were analyzed using quantitative RT-PCR, femoral trabecular bone parameters were measured using microcomputed tomography, while peripheral blood cell number was determined by cell counter. TCP-treated rats displayed significant decrease in expression of Tph1, and significant increase in percentage of bone volume, trabecular number, connectivity density, and leukocyte number. In addition, significant negative correlation was observed between relative concentrations of TPH1 mRNA and trabecular bone parameters. Our results: a) show that perinatal exposure to tranylcypromine leads to long-lasting compensatory decrease in Tph1 expression in the peripheral compartment, accompanied with alterations in bone remodeling and hematopoiesis, b) suggest that peripheral and central 5HT compartment use different strategies to compensate for 5-HT imbalances of the same cause, and c) indicate dominant role of peripheral over central 5-HT in the regulation

  11. Downstream molecular events in the altered profiles of lysophosphatidic acid-induced cAMP in senescent human diploid fibroblasts.

    PubMed

    Jang, Ik Soon; Rhim, Ji Heon; Park, Sang Chul; Yeo, Eui Ju

    2006-04-30

    Lysophosphatidic acid (LPA) is a phospholipid growth factor that acts through G-protein-coupled receptors. Previously, we demonstrated an altered profile of LPA-dependent cAMP content during the aging process of human diploid fibroblasts (HDFs). In attempts to define the molecular events associated with the age-dependent changes in cAMP profiles, we determined the protein kinase A (PKA) activity, phosphorylation of cAMP-response element binding protein (CREB), and the protein expression of CRE-regulatory genes, c-fos and COX-2 in young and senescent HDFs. We observed in senescent cells, an increase in mRNA levels of the catalytic subunit a of PKA and of the major regulatory subunit Ialpha. Senescence-associated increase of cAMP after LPA treatment correlated well with increased CREB phosphorylation accompanying activation of PKA in senescent cells. In senescent cells, after LPA treatment, the expression of c-fos and COX-2 decreased initially, followed by an increase. In young HDFs, CREB phosphorylation decreased following LPA treatment, and both c-fos and COX-2 protein levels increased rapidly. CRE-luciferase assay revealed higher basal CRE-dependent gene expression in young HDFs compared to senescent HDFs. However, LPA-dependent slope of luciferase increased more rapidly in senescent cells than in young cells, presumably due to an increase of LPA-induced CREB phosphorylation. CRE-dependent luciferase activation was abrogated in the presence of inhibitors of PKC, MEK1, p38MAPK, and PKA, in both young and senescent HDFs. We conclude that these kinase are coactivators of the expression of CRE-responsive genes in LPA-induced HDFs and that their changed activities during the aging process contribute to the final expression level of CRE-responsive genes.

  12. COMT val158met polymorphism and molecular alterations in the human dorsolateral prefrontal cortex: Differences in controls and in schizophrenia.

    PubMed

    Shukla, Abhay A; Jha, Manish; Birchfield, Thomas; Mukherjee, Shibani; Gleason, Kelly; Abdisalaam, Salim; Asaithamby, Aroumougame; Adams-Huet, Beverley; Tamminga, Carol A; Ghose, Subroto

    2016-05-01

    The single nucleotide val158met polymorphism in catechol o-methyltransferase (COMT) influences prefrontal cortex function. Working memory, dependent on the dorsolateral prefrontal cortex (DLPFC), has been repeatedly shown to be influenced by this COMT polymorphism. The high activity COMT val isoform is associated with lower synaptic dopamine levels. Altered synaptic dopamine levels are expected to lead to molecular adaptations within the synapse and within DLPFC neural circuitry. In this human post mortem study using high quality DLPFC tissue, we first examined the influence of the COMT val158met polymorphism on markers of dopamine neurotransmission, N-methyl-d-aspartate (NMDA) receptor subunits and glutamatic acid decarboxylase 67 (GAD67), all known to be critical to DLPFC circuitry and function. Next, we compared target gene expression profiles in a cohort of control and schizophrenia cases, each characterized by COMT genotype. We find that the COMT val allele in control subjects is associated with significant upregulation of GluN2A and GAD67 mRNA levels compared to met carriers. Comparisons between control and schizophrenia groups reveal that GluN2A, GAD67 and DRD2 are differentially regulated between diagnostic groups in a genotype specific manner. Chronic antipsychotic treatment in rodents did not explain these differences. These data demonstrate an association between COMTval158met genotype and gene expression profile in the DLPFC of controls, possibly adaptations to maintain DLPFC function. In schizophrenia val homozygotes, these adaptations are not seen and could reflect pathophysiologic mechanisms related to the known poorer performance of these subjects on DLPFC-dependent tasks. Published by Elsevier B.V.

  13. Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease

    PubMed Central

    Ding, Jingzhong; Reynolds, Lindsay M.; Zeller, Tanja; Müller, Christian; Lohman, Kurt; Nicklas, Barbara J.; Kritchevsky, Stephen B.; Huang, Zhiqing; de la Fuente, Alberto; Soranzo, Nicola; Settlage, Robert E.; Chuang, Chia-Chi; Howard, Timothy; Xu, Ning; Goodarzi, Mark O.; Chen, Y.-D. Ida; Rotter, Jerome I.; Siscovick, David S.; Parks, John S.; Murphy, Susan; Jacobs, David R.; Post, Wendy; Tracy, Russell P.; Wild, Philipp S.; Blankenberg, Stefan; Hoeschele, Ina; Herrington, David; McCall, Charles E.

    2015-01-01

    Obesity is linked to type 2 diabetes (T2D) and cardiovascular diseases; however, the underlying molecular mechanisms remain unclear. We aimed to identify obesity-associated molecular features that may contribute to obesity-related diseases. Using circulating monocytes from 1,264 Multi-Ethnic Study of Atherosclerosis (MESA) participants, we quantified the transcriptome and epigenome. We discovered that alterations in a network of coexpressed cholesterol metabolism genes are a signature feature of obesity and inflammatory stress. This network included 11 BMI-associated genes related to sterol uptake (↑LDLR, ↓MYLIP), synthesis (↑SCD, FADS1, HMGCS1, FDFT1, SQLE, CYP51A1, SC4MOL), and efflux (↓ABCA1, ABCG1), producing a molecular profile expected to increase intracellular cholesterol. Importantly, these alterations were associated with T2D and coronary artery calcium (CAC), independent from cardiometabolic factors, including serum lipid profiles. This network mediated the associations between obesity and T2D/CAC. Several genes in the network harbored C-phosphorus-G dinucleotides (e.g., ABCG1/cg06500161), which overlapped Encyclopedia of DNA Elements (ENCODE)-annotated regulatory regions and had methylation profiles that mediated the associations between BMI/inflammation and expression of their cognate genes. Taken together with several lines of previous experimental evidence, these data suggest that alterations of the cholesterol metabolism gene network represent a molecular link between obesity/inflammation and T2D/CAC. PMID:26153245

  14. Design theory and performance of cryogenic molecular adsorption refrigeration systems

    NASA Technical Reports Server (NTRS)

    Hartwig, W. H.; Woltman, A. W.; Masson, J. P.

    1978-01-01

    Closed-cycle operation of molecular adsorption refrigeration systems (MARS) has been demonstrated by using thermally cycled zeolites to adsorb and desorb various gases under pressures of 20-60 atm. This paper develops three aspects of the design theory: the physical theory of molecular adsorption of small molecules such as A, N2, N2O and NH3, the design relations for closed-cycle flow for three or more compressors, and the coefficient of performance. This work is intended to demonstrate nonmechanical gas compression for various cryogenic gases than can compete with mechanical systems with a different mix of advantages and disadvantages.

  15. Silicon isotopes fractionation in meteoric chemical weathering and hydrothermal alteration systems of volcanic rocks (Mayotte)

    NASA Astrophysics Data System (ADS)

    Basile-Doelsch, Isabelle; Puyraveau, Romain-Arnaud; Guihou, Abel; Haurine, Frederic; Deschamps, Pierre; rad, Setareh; Nehlig, Pierre

    2017-04-01

    Low temperature chemical weathering fractionates silicon (Si) isotopes while forming secondary silicates. The Si fractionation ranges of high temperature secondary phyllosilicates formed in hydrothermal alteration environments have not been investigated to date. Several parameters, including temperature, reaction rates, pH, ionic concentrations in solution, precipitation/dissolution series or kinetic versus equilibrium regime are not the same in hydrothermal alteration and surface weathering systems and may lead to different fractionation factors. In this work, we analyzed Si isotopes in these two types of alteration conditions in two profiles sampled on the volcanic island of Mayotte. In both profiles, Si-bearing secondary mineral was kaolinite. Both profiles showed 30Si depletion as a function of the degree of alteration but each with a distinct pattern. In the meteoric weathering profile, from the bottom to the top, a gradual decrease of the δ30Si from parent rock (-0.29 ± 0.13 ‰) towards the most weathered product (-2.05 ± 0.13 ‰) was observed. In the hydrothermal alteration profile, in which meteoric weathering was also superimposed at the top of the profile, an abrupt transition of the δ30Si was measured at the interface between parent-rock (-0.21 ± 0.11 ‰) and the altered products, with a minimum value of -3.06 ± 0.16 ‰˙ At the scale of Si-bearing secondary minerals, in the chemical weathering system, a Δ30Sikaol-parentrock of -1.9 ‰ was observed, in agreement with results in the literature. A low temperature kinetic fractionation 30ɛ of -2.29 ‰ was calculated using a simple steady state model. However, an unexpected Δ30Sikaol-parentrock of -2.85 ‰ was measured in the hydrothermal alteration site, pointing to possible mechanisms linked to dissolution/precipitation series and/or to ionic composition of the solution as the main controlling factors of fractionation in hydrothermal conditions. At the scale of the profiles, both δ30Si

  16. Petrology of Philippine geothermal systems and the application of alteration mineralogy to their assessment

    NASA Astrophysics Data System (ADS)

    Reyes, Agnes G.

    1990-10-01

    Philippine geothermal systems occur in the vicinity of large Holocene calc-alkaline volcanic complexes. Wells drilled in these areas encountered multiple intrusions; the latest dikes are the subsurface manifestations of the youngest heat source. Commonly, at least two hydrothermal regimes are juxtaposed in a single area, with the latest being in equilibrium with the present temperature and chemical regime. Alteration by neutral-pH water is pervasive and abundant. A contact-metamorphic aureole also occurs near intrusives. Alteration due to acid-sulfate fluids is generally confined to permeable structures. Neutral-pH alteration is divided into four zones on the basis of key clay minerals, and two subzones are defined by calc-silicates. These are the smectite (ambient to 180°C), transition (180-230°C), illite (230-320°C) and biotite (270-340°C) zones. Subzones are defined by epidote (250-340°C) and amphibole (280-340°C). The four main zones of acid alteration are: kaolinite (ambient to 120°C), dickite ± kaolinite (120-200°C), dickite ± pyrophyllite (200-250°C), and pyrophyllite ± illite (230-320°C). Where relict high-temperature alteration reaches the surface, the area being drilled is usually the outflow zone of the present system. These hydrothermal mineral assemblages are used: (1) as geothermometers; (2) to assist in determining the depth at which the production casing will be set during drilling; (3) to estimate fluid pH and other chemical parameters; (4) to predict possible corrosion and scaling tendencies of the fluids; (5) as a measure of permeability and possible cold water influx into wells; (6) as a guide to field hydrology; and (7) to estimate roughly the thickness of the eroded overburden.

  17. Local and systemic biochemical alterations induced by Bothrops atrox snake venom in mice

    PubMed Central

    de Souza, Carlos AT; Kayano, Anderson M; Setúbal, Sulamita S; Pontes, Adriana S; Furtado, Juliana L; Kwasniewski, Fábio H; Zaqueo, Kayena D; Soares, Andreimar M; Stábeli, Rodrigo G; Zuliani, Juliana P

    2012-01-01

    The local and systemic alterations induced by Bothrops atrox snake venom (BaV) injection in mice were studied. BaV induced superoxide production by migrated neutrophils, mast cell degranulation and phagocytosis by macrophages. Moreover, BaV caused hemorrhage in dorsum of mice after 2hr post- injection. Three hours post-injection in gastrocnemius muscle, we also observed myonecrosis, which was assessed by the determination of serum and tissue CK besides the release of urea, but not creatinine and uric acid, indicating kidney alterations. BaV also induced the release of LDH and transaminases (ALT and AST) indicating tissue and liver abnormalities. In conclusion, the data indicate that BaV induces events of local and systemic importance. PMID:23487552

  18. Local and systemic biochemical alterations induced by Bothrops atrox snake venom in mice.

    PubMed

    de Souza, Carlos At; Kayano, Anderson M; Setúbal, Sulamita S; Pontes, Adriana S; Furtado, Juliana L; Kwasniewski, Fábio H; Zaqueo, Kayena D; Soares, Andreimar M; Stábeli, Rodrigo G; Zuliani, Juliana P

    2012-01-01

    The local and systemic alterations induced by Bothrops atrox snake venom (BaV) injection in mice were studied. BaV induced superoxide production by migrated neutrophils, mast cell degranulation and phagocytosis by macrophages. Moreover, BaV caused hemorrhage in dorsum of mice after 2hr post- injection. Three hours post-injection in gastrocnemius muscle, we also observed myonecrosis, which was assessed by the determination of serum and tissue CK besides the release of urea, but not creatinine and uric acid, indicating kidney alterations. BaV also induced the release of LDH and transaminases (ALT and AST) indicating tissue and liver abnormalities. In conclusion, the data indicate that BaV induces events of local and systemic importance.

  19. Ab initio centroid path integral molecular dynamics: Application to vibrational dynamics of diatomic molecular systems

    NASA Astrophysics Data System (ADS)

    Ohta, Yasuhito; Ohta, Koji; Kinugawa, Kenichi

    2004-01-01

    An ab initio centroid molecular dynamics (CMD) method is developed by combining the CMD method with the ab initio molecular orbital method. The ab initio CMD method is applied to vibrational dynamics of diatomic molecules, H2 and HF. For the H2 molecule, the temperature dependence of the peak frequency of the vibrational spectral density is investigated. The results are compared with those obtained by the ab initio classical molecular dynamics method and exact quantum mechanical treatment. It is shown that the vibrational frequency obtained from the ab initio CMD approaches the exact first excitation frequency as the temperature lowers. For the HF molecule, the position autocorrelation function is also analyzed in detail. The present CMD method is shown to well reproduce the exact quantum result for the information on the vibrational properties of the system.

  20. Volatiles on solar system objects: Carbon dioxide on Iapetus and aqueous alteration in CM chondrites

    NASA Astrophysics Data System (ADS)

    Palmer, Eric Edward

    2009-12-01

    Volatiles are critical in understanding the history of the solar system. We conducted two case studies intended to further this understanding. First, we analyzed the presence of CO2 on Iapetus. Second, we evaluated aqueous alteration in CM chondrites. We studied the distribution, stability and production of CO2 on Saturn's moon Iapetus. We determined that CO2 is concentrated exclusively on Iapetus' dark material with an effective thickness of 31 nm. The total CO2 on Iapetus' surface is 2.3x108 kg. However, CO2 should not be present because it has a limited residence time on the surface of Iapetus. Our thermal calculations and modeling show that CO2 in the form of frost will not remain on Iapetus' surface beyond a few hundred years. Thus, it must be complexed with dark material. However, photodissociation will destroy the observed inventory in ˜1/2 an Earth year. The lack of thermal and radiolytic stability requires an active source. We conducted experiments showing UV radiation generates CO2 under Iapetus-like conditions. We created a simulated regolith by mixing crushed water ice with isotopically labeled carbon. We then irradiated it with UV light at low temperature and pressure, producing 1.1x1015 parts m-2 s-1. Extrapolating to Iapetus, photolysis could generate 8.4x107 kg y-1, which makes photolytic production a good candidate for the source of the CO2 detected on Iapetus. We also studied the aqueous alteration of metal-bearing assemblages in CM chondrites. We examined Murchison, Cold Bokkeveld, Nogoya, and Murray using microscopy, electron microprobe analysis and scanning electron microscopy. Alteration on CM meteorites occurred within at least three microchemical environments: S-rich water, Si-rich water and water without substantial reactive components. Kamacite alters into tochilinite, cronstedtite, or magnetite. Sulfur associated alteration can form accessory minerals: P-rich sulfides, eskolaite and schreibersite. Additionally, we determined that there

  1. Development of a screening system for the detection of chemically induced DNA methylation alterations in a zebrafish liver cell line.

    PubMed

    Farmen, Eivind; Hultman, Maria Therese; Anglès d'Auriac, Marc; Tollefsen, Knut Erik

    2014-01-01

    Early molecular events with correlation to disease, such as aberrant DNA methylation, emphasize the importance of DNA methylation as a potential environmental biomarker. Currently, little is known regarding how various environmental contaminants and mixtures alter DNA methylation in aquatic organisms, and testing is both time- and labor-consuming. Therefore, the potential of an in vitro screening method was evaluated by exposing zebrafish liver cells (ZF-L) for 96 h to the nonmutagenic model substance 5'-azacytidine (AZA), as well as a selection of environmental pollutants such as sodium arsenite (NAS), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 17α-ethinylestradiol (EE2), and diethylstilbestrol (DES). Six single genes with reported and anticipated importance in cancer were selected for analysis. Methylation of gene promoter areas was monitored by bisulfite conversion and high-resolution melt (HRM) analysis after exposure to sublethal concentrations of the test compounds. Subsequently, results were validated with direct bisulfite sequencing. Exposure of ZF-L cells to 0.5 μM AZA for 96 h led to hypomethylation of genes with both low and high basal methylation indicating similarity to mechanism of action in mammals. Further, NAS, EE2, and DES were shown to induce significant alterations in methylation, whereas TCDD did not. It was concluded that cell line exposure in combination with HRM may provide an initial contaminant screening assay by quantifying DNA methylation alterations with high throughput capacity. In addition, the rapid determination of effects following contaminant exposure with this in vitro system points to the possibility for new in vivo applications to be useful for environmental monitoring.

  2. System and method for altering the tack of materials using an electrohydraulic discharge

    SciTech Connect

    Banerjee, Sujit; Corcoran, Howard

    2007-11-13

    A system and method for altering the tack of a material, namely a polymer used as an adhesive, also known as stickies, or pitch. The present invention reduces the tack of the stickies and pitch by exposing the materials for a short duration to low-energy pulsed electrical discharges between a pair of electrodes that are submerged in a liquid medium, such as a fiber stream, water, a pulp slurry, or whitewater.

  3. System and method for altering the tack of materials using an electrohydraulic discharge

    DOEpatents

    Banerjee, Sujit; Corcoran, Howard

    2003-01-01

    A system and method for altering the tack of a material, namely a polymer used as an adhesive, also known as stickies, or pitch. The present invention reduces the tack of the stickies and pitch by exposing the materials for a short duration to low-energy pulsed electrical discharges between a pair of electrodes that are submerged in a liquid medium, such as a fiber stream, water, a pulp slurry, or whitewater.

  4. Proceedings: Second international conference on intelligent systems for molecular biology

    SciTech Connect

    Altman, R.; Brutlag, D.; Karp, P.; Lathrop, R.; Searls, D.

    1994-12-31

    This volume provided full papers for presentations at the Second International Conference on Intelligent Systems for Molecular Biology held August 14-17, 1994 at Stanford University, Stanford, California. Each individual paper has been separately abstracted and indexed for the database.

  5. Multi-Scale Molecular Deconstruction of the Serotonin Neuron System.

    PubMed

    Okaty, Benjamin W; Freret, Morgan E; Rood, Benjamin D; Brust, Rachael D; Hennessy, Morgan L; deBairos, Danielle; Kim, Jun Chul; Cook, Melloni N; Dymecki, Susan M

    2015-11-18

    Serotonergic (5HT) neurons modulate diverse behaviors and physiology and are implicated in distinct clinical disorders. Corresponding diversity in 5HT neuronal phenotypes is becoming apparent and is likely rooted in molecular differences, yet a comprehensive approach characterizing molecular variation across the 5HT system is lacking, as is concomitant linkage to cellular phenotypes. Here we combine intersectional fate mapping, neuron sorting, and genome-wide RNA-seq to deconstruct the mouse 5HT system at multiple levels of granularity-from anatomy, to genetic sublineages, to single neurons. Our unbiased analyses reveal principles underlying system organization, 5HT neuron subtypes, constellations of differentially expressed genes distinguishing subtypes, and predictions of subtype-specific functions. Using electrophysiology, subtype-specific neuron silencing, and conditional gene knockout, we show that these molecularly defined 5HT neuron subtypes are functionally distinct. Collectively, this resource classifies molecular diversity across the 5HT system and discovers sertonergic subtypes, markers, organizing principles, and subtype-specific functions with potential disease relevance.

  6. Multi-Scale Molecular Deconstruction of the Serotonin Neuron System

    PubMed Central

    Okaty, Benjamin W.; Freret, Morgan E.; Rood, Benjamin D.; Brust, Rachael D.; Hennessy, Morgan L.; deBairos, Danielle; Kim, Jun Chul; Cook, Melloni N.; Dymecki, Susan M.

    2016-01-01

    Summary Serotonergic (5HT) neurons modulate diverse behaviors and physiology and are implicated in distinct clinical disorders. Corresponding diversity in 5HT neuronal phenotypes is becoming apparent and is likely rooted in molecular differences, yet a comprehensive approach characterizing molecular variation across the 5HT system is lacking, as is concomitant linkage to cellular phenotypes. Here we combine intersectional fate mapping, neuron sorting, and genome-wide RNA-Seq to deconstruct the mouse 5HT system at multiple levels of granularity—from anatomy, to genetic sublineages, to single neurons. Our unbiased analyses reveal: principles underlying system organization, novel 5HT neuron subtypes, constellations of differentially expressed genes distinguishing subtypes, and predictions of subtype-specific functions. Using electrophysiology, subtype-specific neuron silencing, and conditional gene knockout, we show that these molecularly defined 5HT neuron subtypes are functionally distinct. Collectively, this resource classifies molecular diversity across the 5HT system and discovers new subtypes, markers, organizing principles, and subtype-specific functions with potential disease relevance. PMID:26549332

  7. Short-term sleep deprivation leads to decreased systemic redox metabolites and altered epigenetic status.

    PubMed

    Trivedi, Malav S; Holger, Dana; Bui, Anh Tuyet; Craddock, Travis J A; Tartar, Jaime L

    2017-01-01

    Sleep is critical for repair as well as the rejuvenation processes in the body and many of these functions are regulated via underlying cellular metabolic homeostasis. Changes in sleep pattern are reported to alter such metabolic function resulting in altered disease susceptibility or behavior. Here, we measured the extent to which overnight total sleep deprivation (SD) in young adult humans can influence systemic (plasma-derived) redox-metabolism including the major antioxidant, glutathione as well as DNA methylation levels. Nineteen participants (n = 19, μ age = 21, SD = 3.09) underwent morning testing before and after overnight total SD. Biochemical measures before and after SD revealed that glutathione, ATP, cysteine, and homocysteine levels were significantly reduced following one night of sleep deprivation (all p's < 0.01). Parallel to the well-recognized fact that sleep deprivation (maintaining wakefulness) uses up metabolic reserves, we observed that morning cortisol levels were blunted after sleep deprivation. There were no significant correlations between self-reported or actigraphy-measured sleep and the biochemical measurements, strongly indicating that prior sleep behavior did not have any direct influence on the biochemical measures taken at baseline or after sleep deprivation. Results from the current investigation supports the previous literature implicating the induction of oxidative stress and ATP depletion with sleep deprivation. Furthermore, such altered antioxidant status can also induce downstream epigenetic changes. Although we did not measure the specific genes that were altered under the influence of such sleep deprivation, such epigenetic changes could potentially contribute towards disease predisposition.

  8. Molecular clocks and the early evolution of metazoan nervous systems.

    PubMed

    Wray, Gregory A

    2015-12-19

    The timing of early animal evolution remains poorly resolved, yet remains critical for understanding nervous system evolution. Methods for estimating divergence times from sequence data have improved considerably, providing a more refined understanding of key divergences. The best molecular estimates point to the origin of metazoans and bilaterians tens to hundreds of millions of years earlier than their first appearances in the fossil record. Both the molecular and fossil records are compatible, however, with the possibility of tiny, unskeletonized, low energy budget animals during the Proterozoic that had planktonic, benthic, or meiofaunal lifestyles. Such animals would likely have had relatively simple nervous systems equipped primarily to detect food, avoid inhospitable environments and locate mates. The appearance of the first macropredators during the Cambrian would have changed the selective landscape dramatically, likely driving the evolution of complex sense organs, sophisticated sensory processing systems, and diverse effector systems involved in capturing prey and avoiding predation.

  9. Molecular clocks and the early evolution of metazoan nervous systems

    PubMed Central

    Wray, Gregory A.

    2015-01-01

    The timing of early animal evolution remains poorly resolved, yet remains critical for understanding nervous system evolution. Methods for estimating divergence times from sequence data have improved considerably, providing a more refined understanding of key divergences. The best molecular estimates point to the origin of metazoans and bilaterians tens to hundreds of millions of years earlier than their first appearances in the fossil record. Both the molecular and fossil records are compatible, however, with the possibility of tiny, unskeletonized, low energy budget animals during the Proterozoic that had planktonic, benthic, or meiofaunal lifestyles. Such animals would likely have had relatively simple nervous systems equipped primarily to detect food, avoid inhospitable environments and locate mates. The appearance of the first macropredators during the Cambrian would have changed the selective landscape dramatically, likely driving the evolution of complex sense organs, sophisticated sensory processing systems, and diverse effector systems involved in capturing prey and avoiding predation. PMID:26554040

  10. Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease.

    PubMed

    Ding, Jingzhong; Reynolds, Lindsay M; Zeller, Tanja; Müller, Christian; Lohman, Kurt; Nicklas, Barbara J; Kritchevsky, Stephen B; Huang, Zhiqing; de la Fuente, Alberto; Soranzo, Nicola; Settlage, Robert E; Chuang, Chia-Chi; Howard, Timothy; Xu, Ning; Goodarzi, Mark O; Chen, Y-D Ida; Rotter, Jerome I; Siscovick, David S; Parks, John S; Murphy, Susan; Jacobs, David R; Post, Wendy; Tracy, Russell P; Wild, Philipp S; Blankenberg, Stefan; Hoeschele, Ina; Herrington, David; McCall, Charles E; Liu, Yongmei

    2015-10-01

    Obesity is linked to type 2 diabetes (T2D) and cardiovascular diseases; however, the underlying molecular mechanisms remain unclear. We aimed to identify obesity-associated molecular features that may contribute to obesity-related diseases. Using circulating monocytes from 1,264 Multi-Ethnic Study of Atherosclerosis (MESA) participants, we quantified the transcriptome and epigenome. We discovered that alterations in a network of coexpressed cholesterol metabolism genes are a signature feature of obesity and inflammatory stress. This network included 11 BMI-associated genes related to sterol uptake (↑LDLR, ↓MYLIP), synthesis (↑SCD, FADS1, HMGCS1, FDFT1, SQLE, CYP51A1, SC4MOL), and efflux (↓ABCA1, ABCG1), producing a molecular profile expected to increase intracellular cholesterol. Importantly, these alterations were associated with T2D and coronary artery calcium (CAC), independent from cardiometabolic factors, including serum lipid profiles. This network mediated the associations between obesity and T2D/CAC. Several genes in the network harbored C-phosphorus-G dinucleotides (e.g., ABCG1/cg06500161), which overlapped Encyclopedia of DNA Elements (ENCODE)-annotated regulatory regions and had methylation profiles that mediated the associations between BMI/inflammation and expression of their cognate genes. Taken together with several lines of previous experimental evidence, these data suggest that alterations of the cholesterol metabolism gene network represent a molecular link between obesity/inflammation and T2D/CAC. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  11. Prenatal arsenic exposure alters the programming of the glucocorticoid signaling system during embryonic development.

    PubMed

    Caldwell, Katharine E; Labrecque, Matthew T; Solomon, Benjamin R; Ali, Abdulmehdi; Allan, Andrea M

    2015-01-01

    The glucocorticoid system, which plays a critical role in a host of cellular functions including mood disorders and learning and memory, has been reported to be disrupted by arsenic. In previous work we have developed and characterized a prenatal moderate arsenic exposure (50ppb) model and identified several deficits in learning and memory and mood disorders, as well as alterations within the glucocorticoid receptor signaling system in the adolescent mouse. In these present studies we assessed the effects of arsenic on the glucocorticoid receptor (GR) pathway in both the placenta and the fetal brain in response at two critical periods, embryonic days 14 and 18. The focus of these studies was on the 11β-hydroxysteroid dehydrogenase enzymes (11β-HSD1 and 11β-HSD2) which play a key role in glucorticoid synthesis, as well as the expression and set point of the GR negative feedback regulation. Negative feedback regulation is established early in development. At E14 we found arsenic exposure significantly decreased expression of both protein and message in brain of GR and the 11β-HSD1, while 11β-HSD2 enzyme protein levels were increased but mRNA levels were decreased in the brain. These changes in brain protein continued into the E18 time point, but mRNA levels were no longer significantly altered. Placental HSD11B2 mRNA was not altered by arsenic treatment but protein levels were elevated at E14. GR placental protein levels were decreased at E18 in the arsenic exposed condition. This suggests that arsenic exposure may alter GR expression levels as a consequence of a prolonged developmental imbalance between 11β-HSD1 and 11β-HSD2 protein expression despite decreased 11HSDB2 mRNA. The suppression of GR and the failure to turn down 11β-HSD2 protein expression during fetal development may lead to an altered set point for GR signaling throughout adulthood. To our knowledge, these studies are the first to demonstrate that gestational exposure to moderate levels of

  12. Prenatal arsenic exposure alters the programming of the glucocorticoid signaling system during embryonic development

    PubMed Central

    Caldwell, Katharine E.; Labrecque, Matthew T.; Solomon, Benjamin R.; Ali, Abdulmehdi; Allan, Andrea M.

    2015-01-01

    The glucocorticoid system, which plays a critical role in a host of cellular functions including mood disorders and learning and memory, has been reported to be disrupted by arsenic. In previous work we have developed and characterized a prenatal moderate arsenic exposure (50 ppb) model and identified several deficits in learning and memory and mood disorders, as well as alterations within the glucocorticoid receptor signaling system in the adolescent mouse. In these present studies we assessed the effects of arsenic on the glucocorticoid receptor (GR) pathway in both the placenta and the fetal brain in response at two critical periods, embryonic days 14 and 18. The focus of these studies was on the 11β-hydroxysteroid dehydrogenase enzymes (11β-HSD1 and 11β-HSD2) which play a key role in glucorticoid synthesis, as well as the expression and set point of the GR negative feedback regulation. Negative feedback regulation is established early in development. At E14 we found arsenic exposure significantly decreased expression of both protein and message in brain of GR and the 11β-HSD1, while 11β-HSD2 enzyme protein levels were increased but mRNA levels were decreased in the brain. These changes in brain protein continued into the E18 time point, but mRNA levels were no longer significantly altered. Placental HSD11B2 mRNA was not altered by arsenic treatment but protein levels were elevated at E14. GR placental protein levels were decreased at E18 in the arsenic exposed condition. This suggests that arsenic exposure may alter GR expression levels as a consequence of a prolonged developmental imbalance between 11β-HSD1 and 11β-HSD2 protein expression despite decreased 11HSDB2 mRNA. The suppression of GR and the failure to turn down 11β-HSD2 protein expression during fetal development may lead to an altered set point for GR signaling throughout adulthood. To our knowledge, these studies are the first to demonstrate that gestational exposure to moderate levels of

  13. Parallel molecular dynamics on a multi signalprocessor system

    NASA Astrophysics Data System (ADS)

    Scott, W.; Gunzinger, A.; Bäumle, B.; Kohler, P.; Müller, U. A.; Mühll, H.-R. Vonder; Eichenberger, A.; Guggenbühl, W.; Ironmonger, N.; Müller-Plathe, F.; van Gunsteren, W. F.

    1993-04-01

    This paper gives an overview of a parallel computer architecture called MUSIC (Multi Signalprocessor System with Intelligent Communication), which has been developed at the Swiss Federal Institute of Technology. The current version achieves a peak performance of 3.8 GFlops. We discuss the system software and tools used to program the system and then present our implementation of a molecular dynamics simulation program which uses the architecture of MUSIC in an efficient way. We demonstrate the correctness of our implementation and give measurements of the performance of the system. To the best of our knowledge, MUSIC outperforms the most powerful present-day vector supercomputers.

  14. Molecular absorption cryogenic cooler for liquid hydrogen propulsion systems

    NASA Technical Reports Server (NTRS)

    Klein, G. A.; Jones, J. A.

    1982-01-01

    A light weight, long life molecular absorption cryogenic cooler (MACC) system is described which can use low temperature waste heat to provide cooling for liquid hydrogen propellant tanks for interplanetary spacecraft. Detailed tradeoff studies were made to evaluate the refrigeration system component interactions in order to minimize the mass of the spacecraft cooler system. Based on this analysis a refrigerator system mass of 31 kg is required to provide the .48 watts of cooling required by a 2.3 meter diameter liquid hydrogen tank.

  15. Alterations in the Ubiquitin Proteasome System in Persistent but Not Reversible Proteinuric Diseases

    PubMed Central

    Beeken, Maire; Lindenmeyer, Maja T.; Blattner, Simone M.; Radón, Victoria; Oh, Jun; Meyer, Tobias N.; Hildebrand, Diana; Schlüter, Hartmut; Reinicke, Anna T.; Knop, Jan-Hendrik; Vivekanandan-Giri, Anuradha; Münster, Silvia; Sachs, Marlies; Wiech, Thorsten; Pennathur, Subramaniam; Cohen, Clemens D.; Kretzler, Matthias; Stahl, Rolf A.K.

    2014-01-01

    Podocytes are the key cells affected in nephrotic glomerular kidney diseases, and they respond uniformly to injury with cytoskeletal rearrangement. In nephrotic diseases, such as membranous nephropathy and FSGS, persistent injury often leads to irreversible structural damage, whereas in minimal change disease, structural alterations are mostly transient. The factors leading to persistent podocyte injury are currently unknown. Proteolysis is an irreversible process and could trigger persistent podocyte injury through degradation of podocyte-specific proteins. We, therefore, analyzed the expression and functional consequence of the two most prominent proteolytic systems, the ubiquitin proteasome system (UPS) and the autophagosomal/lysosomal system, in persistent and transient podocyte injuries. We show that differential upregulation of both proteolytic systems occurs in persistent human and rodent podocyte injury. The expression of specific UPS proteins in podocytes differentiated children with minimal change disease from children with FSGS and correlated with poor clinical outcome. Degradation of the podocyte-specific protein α-actinin-4 by the UPS depended on oxidative modification in membranous nephropathy. Notably, the UPS was overwhelmed in podocytes during experimental glomerular disease, resulting in abnormal protein accumulation and compensatory upregulation of the autophagosomal/lysosomal system. Accordingly, inhibition of both proteolytic systems enhanced proteinuria in persistent nephrotic disease. This study identifies altered proteolysis as a feature of persistent podocyte injury. In the future, specific UPS proteins may serve as new biomarkers or therapeutic targets in persistent nephrotic syndrome. PMID:24722446

  16. Detection of molecular alterations in methamphetamine-activated Fos-expressing neurons from a single rat dorsal striatum using fluorescence-activated cell sorting (FACS)

    PubMed Central

    Liu, Qing-Rong; Rubio, Francisco J.; Bossert, Jennifer M.; Marchant, Nathan J.; Fanous, Sanya; Hou, Xingyu; Shaham, Yavin; Hope, Bruce T.

    2013-01-01

    Methamphetamine and other drugs activate a small proportion of all neurons in the brain. We previously developed a FACS-based method to characterize molecular alterations induced selectively in activated neurons that express the neural activity marker Fos. However, this method requires pooling samples from many rats. We now describe a modified FACS-based method to characterize molecular alterations in Fos-expressing dorsal striatal neurons from a single rat using a multiplex pre-amplification strategy. Fos and NeuN (a neuronal marker) immunohistochemistry indicate that 6–7% of dorsal striatum neurons were activated 90 min after acute methamphetamine injections (5 mg/kg, i.p) while less than 1% of neurons were activated by saline injections. We used FACS to separate NeuN-labeled neurons into Fos-positive and Fos-negative neurons and assessed mRNA expression using RT-qPCR from as little as 5 Fos-positive neurons. Methamphetamine induced 3–20-fold increases of immediate early genes arc, homer-2, c-fos, fosB and its isoforms (ΔfosB and a novel isoform ΔfosB-2) in Fos-positive but not Fos-negative neurons. IEG mRNA induction was 10-fold lower or absent when assessed in unsorted samples from single dorsal striatum homogenates. Our modified method makes it feasible to study unique molecular alterations in neurons activated by drugs or drug-associated cues in complex addiction models. PMID:23895375

  17. A Novel Ex Ovo Banding Technique to Alter Intracardiac Hemodynamics in an Embryonic Chicken System.

    PubMed

    Menon, Vinal; Junor, Lorain; Balhaj, Marwa; Eberth, John F; Potts, Jay D

    2016-05-13

    The new model presented here can be used to understand the influence of hemodynamics on specific cardiac developmental processes, at the cellular and molecular level. To alter intracardiac hemodynamics, fertilized chicken eggs are incubated in a humidified chamber to obtain embryos of the desired stage (HH17). Once this developmental stage is achieved, the embryo is maintained ex ovo and hemodynamics in the embryonic heart are altered by partially constricting the outflow tract (OFT) with a surgical suture at the junction of the OFT and ventricle (OVJ). Control embryos are also cultured ex ovo but are not subjected to the surgical intervention. Banded and control embryos are then incubated in a humidified incubator for the desired period of time, after which 2D ultrasound is employed to analyze the change in blood flow velocity at the OVJ as a result of OFT banding. Once embryos are maintained ex ovo, it is important to ensure adequate hydration in the incubation chamber so as to prevent drying and eventually embryo death. Using this new banded model, it is now possible to perform analyses of changes in the expression of key players involved in valve development and to understand the role of hemodynamics on cellular responses in vivo, which could not be achieved previously.

  18. 5-HT systems: emergent targets for memory formation and memory alterations.

    PubMed

    Meneses, Alfredo

    2013-01-01

    Drugs acting through 5-hydroxytryptamine (serotonin or 5-HT) systems modulate memory and its alterations, although the mechanisms involved are poorly understood. 5-HT drugs may present promnesic and/or antiamnesic (or even being amnesic) effects. Key questions regarding 5-HT markers include whether receptors directly or indirectly participate and/or contribute to the physiological and pharmacological basis of memory and its pathogenesis; hence, the major aim of this article was to examine recent advances in emergent targets of the 5-HT systems for memory formation and memory alterations. Recent reviews and findings are summarized, mainly in the context of the growing notion of memory deficits in brain disorders (e.g., posttraumatic stress disorder, mild cognitive impairment, consumption of drugs, poststroke cognitive dysfunctions, schizophrenia, Parkinson disease, and infection-induced memory impairments). Mainly, mammalian and (some) human data were the focus. At least agonists and antagonists for 5-HT1A/1B, 5-HT2A/2B/2C, 5-HT3, 5-HT4, 5-HT6, and 5-HT7 receptors as well as serotonin uptake inhibitors seem to have a promnesic and/or antiamnesic effect in different conditions and 5-HT markers seem to be associated to neural changes. Available evidence offers clues about the possibilities, but the exact mechanisms remain unclear. For instance, 5-HT transporter expression seems to be a reliable neural marker related to memory mechanisms and its alterations.

  19. Alteration of cortico-limbic-striatal neural system in major depressive disorder and bipolar disorder.

    PubMed

    Jiang, Xiaowei; Dai, Xu; Kale Edmiston, Elliot; Zhou, Qian; Xu, Ke; Zhou, Yifang; Wu, Feng; Kong, Lingtao; Wei, Shengnan; Zhou, Yuning; Chang, Miao; Geng, Haiyang; Wang, Dahai; Wang, Ye; Cui, Wenhui; Wang, Fei; Tang, Yanqing

    2017-10-15

    It is often difficult to differentiate major depressive disorder (MDD) and bipolar disorder (BD) merely according to clinical symptoms. Similarities and differences in neural activity between the two disorders remain unclear. In current study, we use amplitude of low-frequency fluctuations (ALFF) to compare neural activation changes between MDD and BD patients. One hundred and eighty-three adolescents and young adults (57 MDD, 46 BD and 80 healthy controls, HC) were scanned during resting state. The ALFF for each participant was calculated, and were then compared among all groups using voxel-based analysis. There was a significant effect of diagnosis in the core regions of cortico-limbic-striatal neural system. Furthermore, MDD showed left-sided abnormal neural activity while BD showed a bilateral abnormality in this neural system. This study was underpowered to consider medications, mood states and neural developmental effects on the neural activation. Differences in lateralization of ALFF alterations were found. Alterations predominated in the left hemisphere for MDD, whereas alterations were bilateral for BD. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Bringing light into the dark triplet space of molecular systems.

    PubMed

    Ge, Jing; Zhang, Qun; Jiang, Jun; Geng, Zhigang; Jiang, Shenlong; Fan, Kaili; Guo, Zhenkun; Hu, Jiahua; Chen, Zongwei; Chen, Yang; Wang, Xiaoping; Luo, Yi

    2015-05-21

    A molecule or a molecular system always consists of excited states of different spin multiplicities. With conventional optical excitations, only the (bright) states with the same spin multiplicity of the ground state could be directly reached. How to reveal the dynamics of excited (dark) states remains the grand challenge in the topical fields of photochemistry, photophysics, and photobiology. For a singlet-triplet coupled molecular system, the (bright) singlet dynamics can be routinely examined by conventional femtosecond pump-probe spectroscopy. However, owing to the involvement of intrinsically fast decay channels such as intramolecular vibrational redistribution and internal conversion, it is very difficult, if not impossible, to single out the (dark) triplet dynamics. Herein, we develop a novel strategy that uses an ultrafast broadband white-light continuum as a excitation light source to enhance the probability of intersystem crossing, thus facilitating the population flow from the singlet space to the triplet space. With a set of femtosecond time-reversed pump-probe experiments, we report on a proof-of-concept molecular system (i.e., the malachite green molecule) that the pure triplet dynamics can be mapped out in real time through monitoring the modulated emission that occurs solely in the triplet space. Significant differences in excited-state dynamics between the singlet and triplet spaces have been observed. This newly developed approach may provide a useful tool for examining the elusive dark-state dynamics of molecular systems and also for exploring the mechanisms underlying molecular luminescence/photonics and solar light harvesting.

  1. Genome-wide analysis uncovers novel recurrent alterations in primary central nervous system lymphomas

    PubMed Central

    Braggio, Esteban; Van Wier, Scott; Ojha, Juhi; McPhail, Ellen; Asmann, Yan W.; Egan, Jan; da Silva, Jackline Ayres; Schiff, David; Lopes, M Beatriz; Decker, Paul A; Valdez, Riccardo; Tibes, Raoul; Eckloff, Bruce; Witzig, Thomas E.; Stewart, A Keith; Fonseca, Rafael; O’Neill, Brian Patrick

    2015-01-01

    Purpose Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin lymphoma confined to the CNS. Whether there is a PCNSL-specific genomic signature and, if so, how it differs from systemic diffuse large B-cell lymphoma (DLBCL) is uncertain. Experimental design We performed a comprehensive genomic study of tumor samples from 19 immunocompetent PCNSL patients. Testing comprised array-comparative genomic hybridization and whole exome sequencing. Results Biallelic inactivation of TOX and PRKCD were recurrently found in PCNSL but not in systemic DLBCL, suggesting a specific role in PCNSL pathogenesis. Additionally, we found a high prevalence of MYD88 mutations (79%) and CDKN2A biallelic loss (60%). Several genes recurrently affected in PCNSL were common with systemic DLBCL, including loss of TNFAIP3, PRDM1, GNA13, TMEM30A, TBL1XR1, B2M, CD58, activating mutations of CD79B, CARD11 and translocations IgH-BCL6. Overall, BCR/TLR/NF-κB pathways were altered in >90% of PNCSL, highlighting its value for targeted therapeutic approaches. Furthermore, integrated analysis showed enrichment of pathways associated with immune response, proliferation, apoptosis, and lymphocyte differentiation. Conclusions In summary, genome-wide analysis uncovered novel recurrent alterations, including TOX and PRKCD, helping to differentiate PCNSL from systemic DLBCL and related lymphomas. PMID:25991819

  2. Alterations of the emotional processing system may underlie preserved rapid reaction time in tinnitus.

    PubMed

    Carpenter-Thompson, Jake R; Akrofi, Kwaku; Schmidt, Sara A; Dolcos, Florin; Husain, Fatima T

    2014-06-03

    Although alterations of the limbic system have been linked to tinnitus persistence, the neural networks underlying such alteration are unclear. The present study investigated the effect of tinnitus on emotional processing in middle-aged adults using functional magnetic resonance imaging and stimuli from the International Affective Digital Sounds database. There were three groups of participants: bilateral hearing loss with tinnitus (TIN), age- and gender-matched controls with bilateral hearing loss without tinnitus (HL) and matched normal hearing controls without tinnitus (NH). In the scanner, subjects rated sounds as pleasant, unpleasant, or neutral. The TIN and NH groups, but not the HL group, responded faster to affective sounds compared to neutral sounds. The TIN group had elevated response in bilateral parahippocampus and right insula compared to the NH group, and left parahippocampus compared to HL controls for pleasant relative to neutral sounds. A region-of-interest analysis detected increased activation for NH controls in the right amygdala when responding to affective stimuli, but failed to find a similar heightened response in the TIN and HL groups. All three groups showed increased response in auditory cortices for the affective relative to neutral sounds comparisons. Our results suggest that the emotional processing network is altered in tinnitus to rely on the parahippocampus and insula, rather than the amygdala, and this alteration may maintain a select advantage for the rapid processing of affective stimuli despite the hearing loss. The complex interaction of tinnitus and the limbic system should be accounted for in development of new tinnitus management strategies. Copyright © 2014. Published by Elsevier B.V.

  3. Preparation of Low Molecular Weight Gelatin Using Microwave Discharge Electrodeless Lamp/TiO2 Photocatalyst Hybrid System.

    PubMed

    Lee, Do-Jin; Kim, Hangun; Park, Young-Kwon; Kim, Byung Hoon; Lee, Heon; Jungf, Sana-Chul

    2016-02-01

    In this study, an MDEL/TiO2 photocatalyst hybrid system was applied to the production of low molecular weight gelatin. The molecular weight of produed gelatin decreased with increasing microwave intensity and increasing treatment time. The abscission of the chemical bonds between the con- stituents of gelatin by photocatalytic reaction did not alter the characteristics of gelatin. Formation of any by-products due to side reaction was not observed. It is suggested that gelatin was depolymerized by hydroxyl radicals produced during the MDEL/TiO2 photochemical reaction.

  4. From molecular classification to targeted therapeutics: the changing face of systemic therapy in metastatic gastroesophageal cancer.

    PubMed

    Murphy, Adrian; Kelly, Ronan J

    2015-01-01

    Histological classification of adenocarcinoma or squamous cell carcinoma for esophageal cancer or using the Lauren classification for intestinal and diffuse type gastric cancer has limited clinical utility in the management of advanced disease. Germline mutations in E-cadherin (CDH1) or mismatch repair genes (Lynch syndrome) were identified many years ago but given their rarity, the identification of these molecular alterations does not substantially impact treatment in the advanced setting. Recent molecular profiling studies of upper GI tumors have added to our knowledge of the underlying biology but have not led to an alternative classification system which can guide clinician's therapeutic decisions. Recently the Cancer Genome Atlas Research Network has proposed four subtypes of gastric cancer dividing tumors into those positive for Epstein-Barr virus, microsatellite unstable tumors, genomically stable tumors, and tumors with chromosomal instability. Unfortunately to date, many phase III clinical trials involving molecularly targeted agents have failed to meet their survival endpoints due to their use in unselected populations. Future clinical trials should utilize molecular profiling of individual tumors in order to determine the optimal use of targeted therapies in preselected patients.

  5. Detection of molecular alterations in methamphetamine-activated Fos-expressing neurons from a single rat dorsal striatum using fluorescence-activated cell sorting (FACS).

    PubMed

    Liu, Qing-Rong; Rubio, Francisco J; Bossert, Jennifer M; Marchant, Nathan J; Fanous, Sanya; Hou, Xingyu; Shaham, Yavin; Hope, Bruce T

    2014-01-01

    Methamphetamine and other drugs activate a small proportion of all neurons in the brain. We previously developed a fluorescence-activated cell sorting (FACS)-based method to characterize molecular alterations induced selectively in activated neurons that express the neural activity marker Fos. However, this method requires pooling samples from many rats. We now describe a modified FACS-based method to characterize molecular alterations in Fos-expressing dorsal striatal neurons from a single rat using a multiplex pre-amplification strategy. Fos and NeuN (a neuronal marker) immunohistochemistry indicate that 5-6% of dorsal striatum neurons were activated 90 min after acute methamphetamine injections (5 mg/kg, i.p.) while less than 0.5% of neurons were activated by saline injections. We used FACS to separate NeuN-labeled neurons into Fos-positive and Fos-negative neurons and assessed mRNA expression using RT-qPCR from as little as five Fos-positive neurons. Methamphetamine induced 3-20-fold increases of immediate early genes arc, homer-2, c-fos, fosB, and its isoforms (ΔfosB and a novel isoform ΔfosB-2) in Fos-positive but not Fos-negative neurons. Immediate early gene mRNA induction was 10-fold lower or absent when assessed in unsorted samples from single dorsal striatum homogenates. Our modified method makes it feasible to study unique molecular alterations in neurons activated by drugs or drug-associated cues in complex addiction models. Methamphetamine and other drugs activate a small proportion of all neurons in the brain. We here report an improved method to characterize molecular alterations induced selectively in activated neurons that express the neural activity marker Fos. We used FACS along with targeted PCR pre-amplification to assess acute methamphetamine-induced gene expression from as few as 5 Fos-expressing neurons from a single rat dorsal striatum. Methamphetamine induced 3-20-fold increases of immediate early genes (IEGs) in Fos-positive but not

  6. Molecular and structural basis of inner core lipopolysaccharide alterations in Escherichia coli: incorporation of glucuronic acid and phosphoethanolamine in the heptose region.

    PubMed

    Klein, Gracjana; Müller-Loennies, Sven; Lindner, Buko; Kobylak, Natalia; Brade, Helmut; Raina, Satish

    2013-03-22

    It is well established that lipopolysaccharide (LPS) often carries nonstoichiometric substitutions in lipid A and in the inner core. In this work, the molecular basis of inner core alterations and their physiological significance are addressed. A new inner core modification of LPS is described, which arises due to the addition of glucuronic acid on the third heptose with a concomitant loss of phosphate on the second heptose. This was shown by chemical and structural analyses. Furthermore, the gene whose product is responsible for the addition of this sugar was identified in all Escherichia coli core types and in Salmonella and was designated waaH. Its deduced amino acid sequence exhibits homology to glycosyltransferase family 2. The transcription of the waaH gene is positively regulated by the PhoB/R two-component system in a growth phase-dependent manner, which is coordinated with the transcription of the ugd gene explaining the genetic basis of this modification. Glucuronic acid modification was observed in E. coli B, K12, R2, and R4 core types and in Salmonella. We also show that the phosphoethanolamine (P-EtN) addition on heptose I in E. coli K12 requires the product of the ORF yijP, a new gene designated as eptC. Incorporation of P-EtN is also positively regulated by PhoB/R, although it can occur at a basal level without a requirement for any regulatory inducible systems. This P-EtN modification is essential for resistance to a variety of factors, which destabilize the outer membrane like the addition of SDS or challenge to sublethal concentrations of Zn(2+).

  7. [CRISPR-Cas system as molecular scissors for gene therapy].

    PubMed

    Heinz, G A; Mashreghi, M-F

    2017-02-01

    Since the discovery of the CRISPR-Cas system as the adaptive immune system of prokaryotes, the underlying mechanism has proven to be a precise molecular tool for the targeted editing of genetic information in various cell types. By using the CRISPR-Cas9 system DNA sequences can be cut out at any site in the genome and changed in a sequence-specific manner. In the long term this provides the opportunity to cure diseases caused by gene mutations.

  8. Easy creation of polymeric systems for molecular dynamics with Assemble!

    NASA Astrophysics Data System (ADS)

    Degiacomi, Matteo T.; Erastova, Valentina; Wilson, Mark R.

    2016-05-01

    We present Assemble!, a program greatly simplifying the preparation of molecular dynamics simulations of polymeric systems. The program is controlled either via command line or an intuitive Graphical User Interface, and runs on all major operating systems. Assemble! allows the creation of a desired system of polymer chains from constituent monomers, packs the chains into a box according to the required concentration and returns all the files needed for simulation with Gromacs. We illustrate the capabilities of Assemble! by demonstrating the easy preparation of a 300 monomers-long polyisoprene in hexane, and a heterogeneous mixture of polybutadiene.

  9. FINE AMBIENT AIR PARTICULAR MATTER EXPOSURE INDUCES MOLECULAR ALTERATIONS INDICATIVE OF CARDIOVASCULAR DISEASE PROGRESSION IN ATHEROSCLEROTIC SUSCEPTIBLE MICE

    EPA Science Inventory

    Epidemiological, clinical, and toxicological studies have demonstrated that exposure to ambient air particulate matter (PM) can alter cardiovascular function and may influence cardiovascular disease (CVD). It has been shown that exposure to concentrated ambient air particles (CA...

  10. FINE AMBIENT AIR PARTICULAR MATTER EXPOSURE INDUCES MOLECULAR ALTERATIONS INDICATIVE OF CARDIOVASCULAR DISEASE PROGRESSION IN ATHEROSCLEROTIC SUSCEPTIBLE MICE

    EPA Science Inventory

    Epidemiological, clinical, and toxicological studies have demonstrated that exposure to ambient air particulate matter (PM) can alter cardiovascular function and may influence cardiovascular disease (CVD). It has been shown that exposure to concentrated ambient air particles (CA...

  11. Molecular marker systems in insects: current trends and future avenues.

    PubMed

    Behura, Susanta K

    2006-10-01

    Insects comprise the largest species composition in the entire animal kingdom and possess a vast undiscovered genetic diversity and gene pool that can be better explored using molecular marker techniques. Current trends of application of DNA marker techniques in diverse domains of insect ecological studies show that mitochondrial DNA (mtDNA), microsatellites, random amplified polymorphic DNA (RAPD), expressed sequence tags (EST) and amplified fragment length polymorphism (AFLP) markers have contributed significantly for progresses towards understanding genetic basis of insect diversity and for mapping medically and agriculturally important genes and quantitative trait loci in insect pests. Apart from these popular marker systems, other novel approaches including transposon display, sequence-specific amplification polymorphism (S-SAP), repeat-associated polymerase chain reaction (PCR) markers have been identified as alternate marker systems in insect studies. Besides, whole genome microarray and single nucleotide polymorphism (SNP) assays are becoming more popular to screen genome-wide polymorphisms in fast and cost effective manner. However, use of such methodologies has not gained widespread popularity in entomological studies. The current study highlights the recent trends of applications of molecular markers in insect studies and explores the technological advancements in molecular marker tools and modern high throughput genotyping methodologies that may be applied in entomological researches for better understanding of insect ecology at molecular level.

  12. ANN expert system screening for illicit amphetamines using molecular descriptors

    NASA Astrophysics Data System (ADS)

    Gosav, S.; Praisler, M.; Dorohoi, D. O.

    2007-05-01

    The goal of this study was to develop and an artificial neural network (ANN) based on computed descriptors, which would be able to classify the molecular structures of potential illicit amphetamines and to derive their biological activity according to the similarity of their molecular structure with amphetamines of known toxicity. The system is necessary for testing new molecular structures for epidemiological, clinical, and forensic purposes. It was built using a database formed by 146 compounds representing drugs of abuse (mainly central stimulants, hallucinogens, sympathomimetic amines, narcotics and other potent analgesics), precursors, or derivatized counterparts. Their molecular structures were characterized by computing three types of descriptors: 38 constitutional descriptors (CDs), 69 topological descriptors (TDs) and 160 3D-MoRSE descriptors (3DDs). An ANN system was built for each category of variables. All three networks (CD-NN, TD-NN and 3DD-NN) were trained to distinguish between stimulant amphetamines, hallucinogenic amphetamines, and nonamphetamines. A selection of variables was performed when necessary. The efficiency with which each network identifies the class identity of an unknown sample was evaluated by calculating several figures of merit. The results of the comparative analysis are presented.

  13. System Concept for Remote Measurement of Asteroid Molecular Composition

    NASA Astrophysics Data System (ADS)

    Hughes, G. B.; Lubin, P. M.; Zhang, Q.; Brashears, T.; Cohen, A. N.; Madajian, J.

    2016-12-01

    We propose a method for probing the molecular composition of cold solar system targets (asteroids, comets, planets, moons) from a distant vantage, such as from a spacecraft orbiting the object. A directed energy beam is focused on the target. With sufficient flux, the spot temperature rises rapidly, and evaporation of surface materials occurs. The melted spot creates a high-temperature blackbody source, and ejected material creates a plume of surface materials in front of the spot. Molecular and atomic absorption of the blackbody radiation occurs within the ejected plume. Bulk composition of the surface material is investigated by using a spectrometer to view the heated spot through the ejected material. Our proposed method differs from technologies such as Laser-Induced Breakdown Spectroscopy (LIBS), which atomizes and ionizes materials in the target; scattered ions emit characteristic radiation, and the LIBS detector performs atomic composition analysis by observing emission spectra. Standoff distance for LIBS is limited by the strength of characteristic emission, and distances greater than 10 m are problematic. Our proposed method detects atomic and molecular absorption spectra in the plume; standoff distance is limited by the size of heated spot, and the plume opacity; distances on the order of tens of kilometers are immediately feasible. Simulations have been developed for laser heating of a rocky target, with concomitant evaporation. Evaporation rates lead to determination of plume density and opacity. Absorption profiles for selected materials are estimated from plume properties. Initial simulations of absorption profiles with laser heating show great promise for molecular composition analysis from tens of kilometers distance. This paper explores the feasibility a hypothetical mission that seeks to perform surface molecular composition analysis of a near-earth asteroid while the craft orbits the asteroid. Such a system has compelling potential benefit for

  14. Security Policies for Mitigating the Risk of Load Altering Attacks on Smart Grid Systems

    SciTech Connect

    Ryutov, Tatyana; AlMajali, Anas; Neuman, Clifford

    2015-04-01

    While demand response programs implement energy efficiency and power quality objectives, they bring potential security threats to the Smart Grid. The ability to influence load in a system enables attackers to cause system failures and impacts the quality and integrity of power delivered to customers. This paper presents a security mechanism to monitor and control load according to a set of security policies during normal system operation. The mechanism monitors, detects, and responds to load altering attacks. We examined the security requirements of Smart Grid stakeholders and constructed a set of load control policies enforced by the mechanism. We implemented a proof of concept prototype and tested it using the simulation environment. By enforcing the proposed policies in this prototype, the system is maintained in a safe state in the presence of load drop attacks.

  15. Molecular Mechanisms of Aging and Immune System Regulation in Drosophila

    PubMed Central

    Eleftherianos, Ioannis; Castillo, Julio Cesar

    2012-01-01

    Aging is a complex process that involves the accumulation of deleterious changes resulting in overall decline in several vital functions, leading to the progressive deterioration in physiological condition of the organism and eventually causing disease and death. The immune system is the most important host-defense mechanism in humans and is also highly conserved in insects. Extensive research in vertebrates has concluded that aging of the immune function results in increased susceptibility to infectious disease and chronic inflammation. Over the years, interest has grown in studying the molecular interaction between aging and the immune response to pathogenic infections. The fruit fly Drosophila melanogaster is an excellent model system for dissecting the genetic and genomic basis of important biological processes, such as aging and the innate immune system, and deciphering parallel mechanisms in vertebrate animals. Here, we review the recent advances in the identification of key players modulating the relationship between molecular aging networks and immune signal transduction pathways in the fly. Understanding the details of the molecular events involved in aging and immune system regulation will potentially lead to the development of strategies for decreasing the impact of age-related diseases, thus improving human health and life span. PMID:22949833

  16. Cryogenic molecular separation system for radioactive (11)C ion acceleration.

    PubMed

    Katagiri, K; Noda, A; Suzuki, K; Nagatsu, K; Boytsov, A Yu; Donets, D E; Donets, E D; Donets, E E; Ramzdorf, A Yu; Nakao, M; Hojo, S; Wakui, T; Noda, K

    2015-12-01

    A (11)C molecular production/separation system (CMPS) has been developed as part of an isotope separation on line system for simultaneous positron emission tomography imaging and heavy-ion cancer therapy using radioactive (11)C ion beams. In the ISOL system, (11)CH4 molecules will be produced by proton irradiation and separated from residual air impurities and impurities produced during the irradiation. The CMPS includes two cryogenic traps to separate specific molecules selectively from impurities by using vapor pressure differences among the molecular species. To investigate the fundamental performance of the CMPS, we performed separation experiments with non-radioactive (12)CH4 gases, which can simulate the chemical characteristics of (11)CH4 gases. We investigated the separation of CH4 molecules from impurities, which will be present as residual gases and are expected to be difficult to separate because the vapor pressure of air molecules is close to that of CH4. We determined the collection/separation efficiencies of the CMPS for various amounts of air impurities and found desirable operating conditions for the CMPS to be used as a molecular separation device in our ISOL system.

  17. Cross linking molecular systems to form ultrathin dielectric layers

    NASA Astrophysics Data System (ADS)

    Feng, Danqin

    Dehydrogenation leads to cross linking of polymer or polymer like formation in very different systems: self-assembled monolayers and in closo -carboranes leading to the formation of semiconducting and dielectric boron carbide. We find evidence of intermolecular interactions for a self-assembled monolayer (SAM) formed from a large molecular adsorbate, [1,1';4',1"-terphenyl]-4,4"-dimethanethiol, from the dispersion of the molecular orbitals with changing the wave vector k and from the changes with temperature. With the formation self assembled molecular (SAM) layer, the molecular orbitals hybridize to electronic bands, with indications of significant band dispersion of the unoccupied molecular orbitals. Although organic adsorbates and thin films are generally regarded as "soft" materials, the effective Debye temperature, indicative of the dynamic motion of the lattice normal to the surface, can be very high, e.g. in the multilayer film formed from [1,1'-biphenyl]-4,4'-dimethanethiol (BPDMT). Depending on molecular orientation, the effective Debye temperature can be comparable to that of graphite due to the 'stiffness' of the benzene rings, but follows the expected Debye-Waller behavior for the core level photoemission intensities with temperature. This is not always the case. We find that a monomolecular film formed from [1,1';4',1"-terphenyl]-4,4"-dimethanethiol deviates from Debye-Waller temperature behavior and is likely caused by temperature dependent changes in molecular orientation. We also find evidence for the increase in dielectric character with polymerization (cross-linking) in spite of the decrease in the HOMO-LUMO gap upon irradiation of TPDMT. The changes in the HOMO-LUMO gap, with cross-linking, are roughly consistent with the band dispersion. The decomposition and cross-linking processes are also accompanied by changes in molecular orientation. The energetics of the three isomeric carborane cage compounds [ closo-1,2-orthocarborane, closo-1

  18. Effect of Heating Method on Alteration of Protein Molecular Structure in Flaxseed: Relationship with Changes in Protein Subfraction Profile and Digestion in Dairy Cows.

    PubMed

    Ahmad Khan, Nazir; Booker, Helen; Yu, Peiqiang

    2015-01-21

    This study evaluated the effect of heating methods on alteration of protein molecular structure in flaxseed (Linum usitatissimum L.) in relation to changes in protein subfraction profile and digestion in dairy cows. Seeds from two flaxseed varieties, sampled from two replicate plots at two locations, were evaluated. The seeds were either maintained in their raw state or heated in an air-draft oven (dry heating) or autoclave (moist heating) for 60 min at 120 °C or by microwave irradiation (MIR) for 5 min. Compared to raw seeds, moist heating decreased (P < 0.05) soluble protein (SP) content [56.5 ± 5.55 to 25.9 ± 6.16% crude protein (CP)] and increased (P < 0.05) rumen undegraded protein (RUP) content (36.0 ± 5.19 to 46.9 ± 2.72% CP) and intestinal digestibility of RUP (61.0 ± 2.28 to 63.8 ± 2.67% RUP). Dry heating did not alter (P > 0.05) the protein subfraction profile and rumen degradation kinetics, whereas MIR increased (P < 0.05) the RUP content from 36.0 ± 5.19 to 40.4 ± 4.67% CP. The MIR and dry heating did not alter (P > 0.05) the amide I to amide II ratio, but moist heating decreased (P < 0.05) both the amide I to amide II ratio and α-helix-to-β-sheet ratio. Regression equations based on protein molecular spectral intensities provided high prediction power for estimation of heat-induced changes in SP (R(2) = 0.62), RUP (R(2) = 0.71), and intestinal digestibility of RUP (R(2) = 0.72). Overall, heat-induced changes in protein nutritive value and digestion were strongly associated with heat-induced alteration in protein molecular structures.

  19. Interactive display of molecular models using a microcomputer system

    NASA Technical Reports Server (NTRS)

    Egan, J. T.; Macelroy, R. D.

    1980-01-01

    A simple, microcomputer-based, interactive graphics display system has been developed for the presentation of perspective views of wire frame molecular models. The display system is based on a TERAK 8510a graphics computer system with a display unit consisting of microprocessor, television display and keyboard subsystems. The operating system includes a screen editor, file manager, PASCAL and BASIC compilers and command options for linking and executing programs. The graphics program, written in USCD PASCAL, involves the centering of the coordinate system, the transformation of centered model coordinates into homogeneous coordinates, the construction of a viewing transformation matrix to operate on the coordinates, clipping invisible points, perspective transformation and scaling to screen coordinates; commands available include ZOOM, ROTATE, RESET, and CHANGEVIEW. Data file structure was chosen to minimize the amount of disk storage space. Despite the inherent slowness of the system, its low cost and flexibility suggests general applicability.

  20. Inflammation and schizophrenia: alterations in cytokine levels and perturbation in antioxidative defense systems.

    PubMed

    Al-Asmari, A K; Khan, Md W

    2014-02-01

    Although several theories have been proposed including developmental/neurodegenerative processes, neurotransmitter abnormalities, viral infection, and immune dysfunction, the exact causative factor of schizophrenia is unclear. A relationship between inflammation and schizophrenia has been supported by abnormal cytokine production and altered antioxidant status. This study was aimed to examine the alterations in serum oxidative-antioxidative status and cytokine levels of schizophrenic patients. A total of 91 schizophrenic patients from Saudi Arabia and 50 age- and sex-matched healthy controls were enrolled in the present study. Fresh blood samples were collected to measure the levels of cytokines and markers of oxidative stress by spectrophotometric assays simultaneously. We observed that there was a significant increase in the levels of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 and a decrease in the levels of interferon-γ. Lipid peroxides are elevated in serum, while total-sulfhydryl levels were decreased. Also, the activities of superoxide dismutase and glutathione peroxidase were decreased, while the activities of catalase, glutathione reductase, and myeloperoxidase were found to be elevated in serum. We conclude that inflammation resulting from dysregulation of cytokines and altered antioxidant systems may play a critical role in the etiology of schizophrenia.

  1. Systemic inflammatory response syndrome (SIRS): molecular pathophysiology and gene therapy.

    PubMed

    Matsuda, Naoyuki; Hattori, Yuichi

    2006-07-01

    In recent years, extensive basic science research has led to a clear understanding of the molecular mechanisms contributing to the pathophysiology of sepsis. Sepsis is now defined as a systemic inflammatory response syndrome (SIRS) in which there is an identifiable focus of infection. SIRS can be also precipitated by non-infective events such as trauma, pancreatitis, and surgery. As a consequence of an overactive SIRS response, the function of various organ systems may be compromised, resulting in multiple organ dysfunction syndrome (MODS) and death. Production and activation of multiple proinflammatory genes are likely to play a key role in the pathogenesis of MODS development. This review article focuses on the molecular mechanisms and components involved in the pathogenesis of severe sepsis. This includes cellular targets of sepsis-inducing bacterial products and their signaling pathways with a major emphasis on transcription factors and new therapeutic approaches to severe sepsis.

  2. Extending Molecular Theory to Steady-State Diffusing Systems

    SciTech Connect

    FRINK,LAURA J. D.; SALINGER,ANDREW G.; THOMPSON,AIDAN P.

    1999-10-22

    Predicting the properties of nonequilibrium systems from molecular simulations is a growing area of interest. One important class of problems involves steady state diffusion. To study these cases, a grand canonical molecular dynamics approach has been developed by Heffelfinger and van Swol [J. Chem. Phys., 101, 5274 (1994)]. With this method, the flux of particles, the chemical potential gradients, and density gradients can all be measured in the simulation. In this paper, we present a complementary approach that couples a nonlocal density functional theory (DFT) with a transport equation describing steady-state flux of the particles. We compare transport-DFT predictions to GCMD results for a variety of ideal (color diffusion), and nonideal (uphill diffusion and convective transport) systems. In all cases excellent agreement between transport-DFT and GCMD calculations is obtained with diffusion coefficients that are invariant with respect to density and external fields.

  3. Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice.

    PubMed

    Bercik, Premysl; Verdu, Elena F; Foster, Jane A; Macri, Joseph; Potter, Murray; Huang, Xiaxing; Malinowski, Paul; Jackson, Wendy; Blennerhassett, Patricia; Neufeld, Karen A; Lu, Jun; Khan, Waliul I; Corthesy-Theulaz, Irene; Cherbut, Christine; Bergonzelli, Gabriela E; Collins, Stephen M

    2010-12-01

    Clinical and preclinical studies have associated gastrointestinal inflammation and infection with altered behavior. We investigated whether chronic gut inflammation alters behavior and brain biochemistry and examined underlying mechanisms. AKR mice were infected with the noninvasive parasite Trichuris muris and given etanercept, budesonide, or specific probiotics. Subdiaphragmatic vagotomy was performed in a subgroup of mice before infection. Gastrointestinal inflammation was assessed by histology and quantification of myeloperoxidase activity. Serum proteins were measured by proteomic analysis, circulating cytokines were measured by fluorescence activated cell sorting array, and serum tryptophan and kynurenine were measured by liquid chromatography. Behavior was assessed using light/dark preference and step-down tests. In situ hybridization was used to assess brain-derived neurotrophic factor (BDNF) expression in the brain. T muris caused mild to moderate colonic inflammation and anxiety-like behavior that was associated with decreased hippocampal BDNF messenger RNA (mRNA). Circulating tumor necrosis factor-α and interferon-γ, as well as the kynurenine and kynurenine/tryptophan ratio, were increased. Proteomic analysis showed altered levels of several proteins related to inflammation and neural function. Administration of etanercept, and to a lesser degree of budesonide, normalized behavior, reduced cytokine and kynurenine levels, but did not influence BDNF expression. The probiotic Bifidobacterium longum normalized behavior and BDNF mRNA but did not affect cytokine or kynurenine levels. Anxiety-like behavior was present in infected mice after vagotomy. Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry, which can be normalized by inflammation-dependent and -independent mechanisms, neither of which requires the integrity of the vagus nerve. Copyright © 2010 AGA Institute. Published by Elsevier Inc

  4. Subtle alterations in memory systems and normal visual attention in the GAERS model of absence epilepsy.

    PubMed

    Marques-Carneiro, J E; Faure, J-B; Barbelivien, A; Nehlig, A; Cassel, J-C

    2016-03-01

    Even if considered benign, absence epilepsy may alter memory and attention, sometimes subtly. Very little is known on behavior and cognitive functions in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model of absence epilepsy. We focused on different memory systems and sustained visual attention, using Non Epileptic Controls (NECs) and Wistars as controls. A battery of cognitive/behavioral tests was used. The functionality of reference, working, and procedural memory was assessed in the Morris water maze (MWM), 8-arm radial maze, T-maze and/or double-H maze. Sustained visual attention was evaluated in the 5-choice serial reaction time task. In the MWM, GAERS showed delayed learning and less efficient working memory. In the 8-arm radial maze and T-maze tests, working memory performance was normal in GAERS, although most GAERS preferred an egocentric strategy (based on proprioceptive/kinesthetic information) to solve the task, but could efficiently shift to an allocentric strategy (based on spatial cues) after protocol alteration. Procedural memory and visual attention were mostly unimpaired. Absence epilepsy has been associated with some learning problems in children. In GAERS, the differences in water maze performance (slower learning of the reference memory task and weak impairment of working memory) and in radial arm maze strategies suggest that cognitive alterations may be subtle, task-specific, and that normal performance can be a matter of strategy adaptation. Altogether, these results strengthen the "face validity" of the GAERS model: in humans with absence epilepsy, cognitive alterations are not easily detectable, which is compatible with subtle deficits. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  5. Prenatal stress-induced alterations in major physiological systems correlate with gut microbiota composition in adulthood.

    PubMed

    Golubeva, Anna V; Crampton, Sean; Desbonnet, Lieve; Edge, Deirdre; O'Sullivan, Orla; Lomasney, Kevin W; Zhdanov, Alexander V; Crispie, Fiona; Moloney, Rachel D; Borre, Yuliya E; Cotter, Paul D; Hyland, Niall P; O'Halloran, Ken D; Dinan, Timothy G; O'Keeffe, Gerard W; Cryan, John F

    2015-10-01

    Early-life adverse experiences, including prenatal stress (PNS), are associated with a higher prevalence of neurodevelopmental, cardiovascular and metabolic disorders in affected offspring. Here, in a rat model of chronic PNS, we investigate the impact of late gestational stress on physiological outcomes in adulthood. Sprague-Dawley pregnant dams were subjected to repeated restraint stress from embryonic day 14 to day 20, and their male offspring were assessed at 4 months of age. PNS induced an exaggeration of the hypothalamic-pituitary-adrenal (HPA) axis response to stress, as well as an elevation of blood pressure and impairment of cognitive function. Altered respiratory control was also observed, as demonstrated by increased variability in basal respiratory frequency and abnormal frequency responses to both hypoxic and hypercapnic challenges. PNS also affected gastrointestinal neurodevelopment and function, as measured by a decrease in the innervation density of distal colon and an increase in the colonic secretory response to catecholaminergic stimulation. Finally, PNS induced long lasting alterations in the intestinal microbiota composition. 16S rRNA gene 454 pyrosequencing revealed a strong trend towards decreased numbers of bacteria in the Lactobacillus genus, accompanied by elevated abundance of the Oscillibacter, Anaerotruncus and Peptococcus genera in PNS animals. Strikingly, relative abundance of distinct bacteria genera significantly correlated with certain respiratory parameters and the responsiveness of the HPA axis to stress. Together, these findings provide novel evidence that PNS induces long-term maladaptive alterations in the gastrointestinal and respiratory systems, accompanied by hyper-responsiveness to stress and alterations in the gut microbiota. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. The Auditory Corticocollicular System: Molecular and Circuit-Level Considerations

    PubMed Central

    Stebbings, Kevin A.; Lesicko, Alexandria M.H.; Llano, Daniel A.

    2014-01-01

    We live in a world imbued with a rich mixture of complex sounds. Successful acoustic communication requires the ability to extract meaning from those sounds, even when degraded. One strategy used by the auditory system is to harness high-level contextual cues to modulate the perception of incoming sounds. An ideal substrate for this process is the massive set of top-down projections emanating from virtually every level of the auditory system. In this review, we provide a molecular and circuit-level description of one of the largest of these pathways: the auditory corticocollicular pathway. While its functional role remains to be fully elucidated, activation of this projection system can rapidly and profoundly change the tuning of neurons in the inferior colliculus. Several specific issues are reviewed. First, we describe the complex heterogeneous anatomical organization of the corticocollicular pathway, with particular emphasis on the topography of the pathway. We also review the laminar origin of the corticocollicular projection and discuss known physiological and morphological differences between subsets of corticocollicular cells. Finally, we discuss recent findings about the molecular micro-organization of the inferior colliculus and how it interfaces with corticocollicular termination patterns. Given the assortment of molecular tools now available to the investigator, it is hoped that his review will help guide future research on the role of this pathway in normal hearing. PMID:24911237

  7. System and method for altering characteristics of materials using an electrohydraulic discharge

    DOEpatents

    Banerjee, Sujit

    2003-06-03

    System and method for oxidizing contaminants to alter specific properties, such as tack, of contaminants. The present invention reduces the tack of the stickies and pitch by exposing the materials for a short duration to low-energy pulsed electrical discharges between a pair of electrodes that are submerged in a liquid medium, such as a fiber stream, water, a pulp slurry, or whitewater. An electrical discharge in the liquid medium oxidizes materials, which may be dissolved or suspended therein, such as stickies, pitch, sulfide, ink, toner, and other substances, thereby reducing tack, odor, and/or zeta potential, as well as producing other desirable effect.

  8. Tank waste remediation system optimized processing strategy with an altered treatment scheme

    SciTech Connect

    Slaathaug, E.J.

    1996-03-01

    This report provides an alternative strategy evolved from the current Hanford Site Tank Waste Remediation System (TWRS) programmatic baseline for accomplishing the treatment and disposal of the Hanford Site tank wastes. This optimized processing strategy with an altered treatment scheme performs the major elements of the TWRS Program, but modifies the deployment of selected treatment technologies to reduce the program cost. The present program for development of waste retrieval, pretreatment, and vitrification technologies continues, but the optimized processing strategy reuses a single facility to accomplish the separations/low-activity waste (LAW) vitrification and the high-level waste (HLW) vitrification processes sequentially, thereby eliminating the need for a separate HLW vitrification facility.

  9. Investigations of the Effects of Altered Vestibular System Function on Hindlimb Anti-Gravity Muscles

    NASA Technical Reports Server (NTRS)

    Lowery, Mary Sue

    1998-01-01

    Exposure to different gravitational environments, both the microgravity of spaceflight and the hypergravity of centrifugation, result in altered vestibulo-spinal function which can be reversed by reacclimation to earth gravity (2). Control of orientation, posture, and locomotion are functions of the vestibular system which are altered by changes in gravitational environment. Not only is the vestibular system involved with coordination and proprioception, but the gravity sensing portion of the vestibular system also plays a major role in maintaining muscle tone through projections to spinal cord motoneurons that control anti-gravity muscles. I have been involved with investigations of several aspects of the link between vestibular inputs and muscle morphology and function during my work with Dr. Nancy Daunton this summer and the previous summer. We have prepared a manuscript for submission (4) to Aviation, Space, and Environmental Medicine based on work that I performed last summer in Dr. Daunton's lab. Techniques developed for that project will be utilized in subsequent experiments begun in the summer of 1998. I have been involved with the development of a pilot project to test the effects of vestibular galvanic stimulation (VGS) on anti-gravity muscles and in another project testing the effects of the ototoxic drug streptomycin on the otolith-spinal reflex and anti-gravity muscle morphology.

  10. Investigations of the Effects of Altered Vestibular System Function on Hindlimb Anti-Gravity Muscles

    NASA Technical Reports Server (NTRS)

    Lowery, Mary Sue

    1998-01-01

    Exposure to different gravitational environments, both the microgravity of spaceflight and the hypergravity of centrifugation, result in altered vestibulo-spinal function which can be reversed by reacclimation to earth gravity (2). Control of orientation, posture, and locomotion are functions of the vestibular system which are altered by changes in gravitational environment. Not only is the vestibular system involved with coordination and proprioception, but the gravity sensing portion of the vestibular system also plays a major role in maintaining muscle tone through projections to spinal cord motoneurons that control anti-gravity muscles. I have been involved with investigations of several aspects of the link between vestibular inputs and muscle morphology and function during my work with Dr. Nancy Daunton this summer and the previous summer. We have prepared a manuscript for submission (4) to Aviation, Space, and Environmental Medicine based on work that I performed last summer in Dr. Daunton's lab. Techniques developed for that project will be utilized in subsequent experiments begun in the summer of 1998. I have been involved with the development of a pilot project to test the effects of vestibular galvanic stimulation (VGS) on anti-gravity muscles and in another project testing the effects of the ototoxic drug streptomycin on the otolith-spinal reflex and anti-gravity muscle morphology.

  11. Dilated cardiomyopathy-induced disruption of basement membrane alters the lever systems acting on the heart.

    PubMed

    Mohamed, Iman A; El-Badri, Nagwa; Zaher, Amr

    2017-06-01

    Dilated cardiomyopathy (DCM) is considered the most common form of non-ischemic heart diseases. DCM, occurs in response to both non-genetic and genetic factors, and has been associated with cytoskeletal protein mutations, impairing the contractile apparatus of cardiac myocytes. However, the pathology underlying the marked left ventricular dilatation remains unclear. Moreover, patients with end-stage DCM show alterations in the composition of the extracellular matrix (ECM), and myocardial fibrosis even when the cardiac myocytes are intact. Therefore we hypothesize that DCM is a disease of basement membrane, which functions to support sarcomeric interactions with the ECM, and not only impaired cardiac contractility. We propose that under physiological conditions, the heart could be considered a second-class lever system. Disruption of the basement membrane in DCM would cause disarray in the alignment of cardiac myocytes and alteration in the second-class lever system of the heart. Thus, current inotropic agents show minimal or no effect on therapy as they target cardiac contractility rather than cardiac architecture and the lever systems of the heart. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. The altered gravity effect on proliferative system of two-day pea germs

    NASA Astrophysics Data System (ADS)

    Artemenko, O. A.

    The study of clinorotation effect on proliferative system sensibility of plants is very important for understanding and future investigations of their development characteristics and for examination of cell cycle regulation molecular mechanisms. Determination of two-day pea germ mitotic activity of cells, correlation of mitosis phase and DNA content point to decrease of these parameters under clinorotation during the first 12 hours of the factor influence. Cell cycle stabilization after 12 hours of the experiment show high adaptation capacity of plant proliferative system.

  13. Plasma proteomic profiles from disease-discordant monozygotic twins suggest that molecular pathways are shared in multiple systemic autoimmune diseases*

    PubMed Central

    2011-01-01

    Introduction Although systemic autoimmune diseases (SAID) share many clinical and laboratory features, whether they also share some common features of pathogenesis remains unclear. We assessed plasma proteomic profiles among different SAID for evidence of common molecular pathways that could provide insights into pathogenic mechanisms shared by these diseases. Methods Differential quantitative proteomic analyses (one-dimensional reverse-phase liquid chromatography-mass spectrometry) were performed to assess patterns of plasma protein expression. Monozygotic twins (four pairs discordant for systemic lupus erythematosus, four pairs discordant for juvenile idiopathic arthritis and two pairs discordant for juvenile dermatomyositis) were studied to minimize polymorphic gene effects. Comparisons were also made to 10 unrelated, matched controls. Results Multiple plasma proteins, including acute phase reactants, structural proteins, immune response proteins, coagulation and transcriptional factors, were differentially expressed similarly among the different SAID studied. Multivariate Random Forest modeling identified seven proteins whose combined altered expression levels effectively segregated affected vs. unaffected twins. Among these seven proteins, four were also identified in univariate analyses of proteomic data (syntaxin 17, α-glucosidase, paraoxonase 1, and the sixth component of complement). Molecular pathway modeling indicated that these factors may be integrated through interactions with a candidate plasma biomarker, PON1 and the pro-inflammatory cytokine IL-6. Conclusions Together, these data suggest that different SAID may share common alterations of plasma protein expression and molecular pathways. An understanding of the mechanisms leading to the altered plasma proteomes common among these SAID may provide useful insights into their pathogeneses. PMID:22044644

  14. Ethanol modulation of mammalian BK channels in excitable tissues: molecular targets and their possible contribution to alcohol-induced altered behavior

    PubMed Central

    Dopico, Alex M.; Bukiya, Anna N.; Martin, Gilles E.

    2014-01-01

    In most tissues, the function of Ca2+- and voltage-gated K+ (BK) channels is modified in response to ethanol concentrations reached in human blood during alcohol intoxication. In general, modification of BK current from ethanol-naïve preparations in response to brief ethanol exposure results from changes in channel open probability without modification of unitary conductance or change in BK protein levels in the membrane. Protracted and/or repeated ethanol exposure, however, may evoke changes in BK expression. The final ethanol effect on BK open probability leading to either BK current potentiation or BK current reduction is determined by an orchestration of molecular factors, including levels of activating ligand (Ca2+i), BK subunit composition and post-translational modifications, and the channel's lipid microenvironment. These factors seem to allosterically regulate a direct interaction between ethanol and a recognition pocket of discrete dimensions recently mapped to the channel-forming (slo1) subunit. Type of ethanol exposure also plays a role in the final BK response to the drug: in several central nervous system regions (e.g., striatum, primary sensory neurons, and supraoptic nucleus), acute exposure to ethanol reduces neuronal excitability by enhancing BK activity. In contrast, protracted or repetitive ethanol administration may alter BK subunit composition and membrane expression, rendering the BK complex insensitive to further ethanol exposure. In neurohypophyseal axon terminals, ethanol potentiation of BK channel activity leads to a reduction in neuropeptide release. In vascular smooth muscle, however, ethanol inhibition of BK current leads to cell contraction and vascular constriction. PMID:25538625

  15. Ethanol modulation of mammalian BK channels in excitable tissues: molecular targets and their possible contribution to alcohol-induced altered behavior.

    PubMed

    Dopico, Alex M; Bukiya, Anna N; Martin, Gilles E

    2014-01-01

    In most tissues, the function of Ca(2+)- and voltage-gated K(+) (BK) channels is modified in response to ethanol concentrations reached in human blood during alcohol intoxication. In general, modification of BK current from ethanol-naïve preparations in response to brief ethanol exposure results from changes in channel open probability without modification of unitary conductance or change in BK protein levels in the membrane. Protracted and/or repeated ethanol exposure, however, may evoke changes in BK expression. The final ethanol effect on BK open probability leading to either BK current potentiation or BK current reduction is determined by an orchestration of molecular factors, including levels of activating ligand (Ca(2+) i), BK subunit composition and post-translational modifications, and the channel's lipid microenvironment. These factors seem to allosterically regulate a direct interaction between ethanol and a recognition pocket of discrete dimensions recently mapped to the channel-forming (slo1) subunit. Type of ethanol exposure also plays a role in the final BK response to the drug: in several central nervous system regions (e.g., striatum, primary sensory neurons, and supraoptic nucleus), acute exposure to ethanol reduces neuronal excitability by enhancing BK activity. In contrast, protracted or repetitive ethanol administration may alter BK subunit composition and membrane expression, rendering the BK complex insensitive to further ethanol exposure. In neurohypophyseal axon terminals, ethanol potentiation of BK channel activity leads to a reduction in neuropeptide release. In vascular smooth muscle, however, ethanol inhibition of BK current leads to cell contraction and vascular constriction.

  16. Use of the MLPA assay in the molecular diagnosis of gene copy number alterations in human genetic diseases.

    PubMed

    Stuppia, Liborio; Antonucci, Ivana; Palka, Giandomenico; Gatta, Valentina

    2012-01-01

    Multiplex Ligation-dependent Probe Amplification (MLPA) assay is a recently developed technique able to evidence variations in the copy number of several human genes. Due to this ability, MLPA can be used in the molecular diagnosis of several genetic diseases whose pathogenesis is related to the presence of deletions or duplications of specific genes. Moreover, MLPA assay can also be used in the molecular diagnosis of genetic diseases characterized by the presence of abnormal DNA methylation. Due to the large number of genes that can be analyzed by a single technique, MLPA assay represents the gold standard for molecular analysis of all pathologies derived from the presence of gene copy number variation. In this review, the main applications of the MLPA technique for the molecular diagnosis of human diseases are described.

  17. The reflex effects of alterations in lung volume on systemic vascular resistance in the dog

    PubMed Central

    Daly, M. de Burgh; Hazzledine, Julie L.; Ungar, A.

    1967-01-01

    1. The reflex effects of alterations in lung volume on systemic vascular resistance have been studied in anaesthetized dogs under conditions in which the systemic circulation was perfused at constant blood flow. The pressures in the isolated perfused carotid sinuses and aortic arch, and the arterial blood PO2 and PCO2 were maintained constant. 2. A maintained inflation of the lungs produced by injection of air into the trachea caused a fall in systemic arterial perfusion pressure, indicating vasodilatation. The size of the systemic vasodilator response varied directly with the pressure and volume of gas used to inflate the lungs. A similar effect was observed when the tidal volume of lungs ventilated by an intermittent positive pressure was increased. 3. Collapse of the lungs by creating a pneumothorax in closed-chest spontaneously breathing animals evoked a systemic vasoconstrictor response which was reversed when the lungs were re-expanded. 4. These vasodilator responses were abolished by dividing the pulmonary branches of the thoracic vagosympathetic nerves. Evidence is presented that the afferent fibres run in the cervical vagosympathetic nerves and through the stellate ganglia. 5. The responses were unaffected by atropine, but were abolished by hexamethonium, guanethidine and by bretylium tosylate, indicating that they are mediated via the sympathetic nervous system. 6. Evidence is presented that the lungs are a constant course of afferent impulses inhibiting the `vasomotor centre', and that the lung inflation—systemic vasodilator reflex is a potential mechanism operating in eupnoeic breathing. PMID:6032204

  18. High-order-harmonic generation in atomic and molecular systems

    NASA Astrophysics Data System (ADS)

    Suárez, Noslen; Chacón, Alexis; Pérez-Hernández, Jose A.; Biegert, Jens; Lewenstein, Maciej; Ciappina, Marcelo F.

    2017-03-01

    High-order-harmonic generation (HHG) results from the interaction of ultrashort laser pulses with matter. It configures an invaluable tool to produce attosecond pulses, moreover, to extract electron structural and dynamical information of the target, i.e., atoms, molecules, and solids. In this contribution, we introduce an analytical description of atomic and molecular HHG, that extends the well-established theoretical strong-field approximation (SFA). Our approach involves two innovative aspects: (i) First, the bound-continuum and rescattering matrix elements can be analytically computed for both atomic and multicenter molecular systems, using a nonlocal short range model, but separable, potential. When compared with the standard models, these analytical derivations make possible to directly examine how the HHG spectra depend on the driven media and laser-pulse features. Furthermore, we can turn on and off contributions having distinct physical origins or corresponding to different mechanisms. This allows us to quantify their importance in the various regions of the HHG spectra. (ii) Second, as reported recently [N. Suárez et al., Phys. Rev. A 94, 043423 (2016), 10.1103/PhysRevA.94.043423], the multicenter matrix elements in our theory are free from nonphysical gauge- and coordinate-system-dependent terms; this is accomplished by adapting the coordinate system to the center from which the corresponding time-dependent wave function originates. Our SFA results are contrasted, when possible, with the direct numerical integration of the time-dependent Schrödinger equation in reduced and full dimensionality. Very good agreement is found for single and multielectronic atomic systems, modeled under the single active electron approximation, and for simple diatomic molecular systems. Interference features, ubiquitously present in every strong-field phenomenon involving a multicenter target, are also captured by our model.

  19. Oral Drug Delivery Systems Comprising Altered Geometric Configurations for Controlled Drug Delivery

    PubMed Central

    Moodley, Kovanya; Pillay, Viness; Choonara, Yahya E.; du Toit, Lisa C.; Ndesendo, Valence M. K.; Kumar, Pradeep; Cooppan, Shivaan; Bawa, Priya

    2012-01-01

    Recent pharmaceutical research has focused on controlled drug delivery having an advantage over conventional methods. Adequate controlled plasma drug levels, reduced side effects as well as improved patient compliance are some of the benefits that these systems may offer. Controlled delivery systems that can provide zero-order drug delivery have the potential for maximizing efficacy while minimizing dose frequency and toxicity. Thus, zero-order drug release is ideal in a large area of drug delivery which has therefore led to the development of various technologies with such drug release patterns. Systems such as multilayered tablets and other geometrically altered devices have been created to perform this function. One of the principles of multilayered tablets involves creating a constant surface area for release. Polymeric materials play an important role in the functioning of these systems. Technologies developed to date include among others: Geomatrix® multilayered tablets, which utilizes specific polymers that may act as barriers to control drug release; Procise®, which has a core with an aperture that can be modified to achieve various types of drug release; core-in-cup tablets, where the core matrix is coated on one surface while the circumference forms a cup around it; donut-shaped devices, which possess a centrally-placed aperture hole and Dome Matrix® as well as “release modules assemblage”, which can offer alternating drug release patterns. This review discusses the novel altered geometric system technologies that have been developed to provide controlled drug release, also focusing on polymers that have been employed in such developments. PMID:22312236

  20. Oral drug delivery systems comprising altered geometric configurations for controlled drug delivery.

    PubMed

    Moodley, Kovanya; Pillay, Viness; Choonara, Yahya E; du Toit, Lisa C; Ndesendo, Valence M K; Kumar, Pradeep; Cooppan, Shivaan; Bawa, Priya

    2012-01-01

    Recent pharmaceutical research has focused on controlled drug delivery having an advantage over conventional methods. Adequate controlled plasma drug levels, reduced side effects as well as improved patient compliance are some of the benefits that these systems may offer. Controlled delivery systems that can provide zero-order drug delivery have the potential for maximizing efficacy while minimizing dose frequency and toxicity. Thus, zero-order drug release is ideal in a large area of drug delivery which has therefore led to the development of various technologies with such drug release patterns. Systems such as multilayered tablets and other geometrically altered devices have been created to perform this function. One of the principles of multilayered tablets involves creating a constant surface area for release. Polymeric materials play an important role in the functioning of these systems. Technologies developed to date include among others: Geomatrix(®) multilayered tablets, which utilizes specific polymers that may act as barriers to control drug release; Procise(®), which has a core with an aperture that can be modified to achieve various types of drug release; core-in-cup tablets, where the core matrix is coated on one surface while the circumference forms a cup around it; donut-shaped devices, which possess a centrally-placed aperture hole and Dome Matrix(®) as well as "release modules assemblage", which can offer alternating drug release patterns. This review discusses the novel altered geometric system technologies that have been developed to provide controlled drug release, also focusing on polymers that have been employed in such developments.

  1. Pressure-oxidation autoclave as an analogue for acid-sulphate alteration in epithermal systems

    NASA Astrophysics Data System (ADS)

    Craw, D.

    2006-07-01

    Gold extraction at the Macraes gold mine in New Zealand involves concentration of pyrite and arsenopyrite, oxidation of those sulphides, then cyanidation. The ore concentrate is predominantly Otago Schist host rock (andesitic composition) with up to 15% sulphides. The oxidation step is conducted on ore concentrate slurry in an autoclave at 225°C and 3,800 kPa oxygen gas pressure with continuous feed. The slurry takes ca. 1 h to pass through the autoclave, during which time the sulphides are almost completely oxidised. Sulphide oxidation causes strong acidification of the slurry, which is maintained at pH of 1-2 by addition of CaCO3. Scales form on walls in the autoclave, with minerals reflecting progressive oxidation and alteration of the ore through the system. The schist in the ore feed has mineralogy similar to propylitically altered andesite: quartz, albite, muscovite, chlorite, and pyrite. Muscovite undergoes almost complete dissolution, with associated precipitation of quartz and alunite (KAl3(SO4)2(OH)6). Other principal minerals deposited and discharged include anhydrite (and/or gypsum), jarosite (KFe3(SO4)2(OH)6), hematite (and/or amorphous iron oxyhydroxide), and amorphous arsenates. Dissolved ferrous iron passes right through the autoclave, and variably hydrated Fe2+and Fe3+sulphate minerals, including rozenite and szomolnokite (both FeSO4.hydrate) and ferricopiapite (Fe5(SO4)6O(OH).hydrate), are formed along the way. The autoclave chemical system resembles acid-sulphate hydrothermal activity in geothermal systems and high-sulphidation epithermal mineral deposits formed in arc environments. These natural acid-sulphate systems are pervaded by volcanic vapours in the near-surface environment, where widespread dissolution of host rocks occurs and deposition of quartz, alunite, and anhydrite is common. Some of the volume loss associated with these natural systems may be due to dissolution of soluble sulphate minerals by later-stage groundwater incursion.

  2. Molecular genetic system for regenerative studies using newts.

    PubMed

    Hayashi, Toshinori; Yokotani, Naoki; Tane, Shoji; Matsumoto, Akira; Myouga, Ayumi; Okamoto, Mitsumasa; Takeuchi, Takashi

    2013-02-01

    Urodele newts have the remarkable capability of organ regeneration, and have been used as a unique experimental model for more than a century. However, the mechanisms underlying regulation of the regeneration are not well understood, and gene functions in particular remain largely unknown. To elucidate gene function in regeneration, molecular genetic analyses are very powerful. In particular, it is important to establish transgenic or knockout (mutant) lines, and systematically cross these lines to study the functions of the genes. In fact, such systems have been developed for other vertebrate models. However, there is currently no experimental model system using molecular genetics for newt regenerative research due to difficulties with respect to breeding newts in the laboratory. Here, we show that the Iberian ribbed newt (Pleurodeles waltl) has outstanding properties as a laboratory newt. We developed conditions under which we can obtain a sufficient number and quality of eggs throughout the year, and shortened the period required for sexual maturation from 18 months to 6 months. In addition, P. waltl newts are known for their ability, like other newts, to regenerate various tissues. We revealed that their ability to regenerate various organs is equivalent to that of Japanese common newts. We also developed a method for efficient transgenesis. These studies demonstrate that P. waltl newts are a suitable model animal for analysis of regeneration using molecular genetics. Establishment of this experimental model will enable us to perform comparable studies using these newts and other vertebrate models.

  3. Review and application of group theory to molecular systems biology

    PubMed Central

    2011-01-01

    In this paper we provide a review of selected mathematical ideas that can help us better understand the boundary between living and non-living systems. We focus on group theory and abstract algebra applied to molecular systems biology. Throughout this paper we briefly describe possible open problems. In connection with the genetic code we propose that it may be possible to use perturbation theory to explore the adjacent possibilities in the 64-dimensional space-time manifold of the evolving genome. With regards to algebraic graph theory, there are several minor open problems we discuss. In relation to network dynamics and groupoid formalism we suggest that the network graph might not be the main focus for understanding the phenotype but rather the phase space of the network dynamics. We show a simple case of a C6 network and its phase space network. We envision that the molecular network of a cell is actually a complex network of hypercycles and feedback circuits that could be better represented in a higher-dimensional space. We conjecture that targeting nodes in the molecular network that have key roles in the phase space, as revealed by analysis of the automorphism decomposition, might be a better way to drug discovery and treatment of cancer. PMID:21696623

  4. Review and application of group theory to molecular systems biology.

    PubMed

    Rietman, Edward A; Karp, Robert L; Tuszynski, Jack A

    2011-06-22

    In this paper we provide a review of selected mathematical ideas that can help us better understand the boundary between living and non-living systems. We focus on group theory and abstract algebra applied to molecular systems biology. Throughout this paper we briefly describe possible open problems. In connection with the genetic code we propose that it may be possible to use perturbation theory to explore the adjacent possibilities in the 64-dimensional space-time manifold of the evolving genome. With regards to algebraic graph theory, there are several minor open problems we discuss. In relation to network dynamics and groupoid formalism we suggest that the network graph might not be the main focus for understanding the phenotype but rather the phase space of the network dynamics. We show a simple case of a C6 network and its phase space network. We envision that the molecular network of a cell is actually a complex network of hypercycles and feedback circuits that could be better represented in a higher-dimensional space. We conjecture that targeting nodes in the molecular network that have key roles in the phase space, as revealed by analysis of the automorphism decomposition, might be a better way to drug discovery and treatment of cancer.

  5. Effects of altered auditory feedback across effector systems: production of melodies by keyboard and singing.

    PubMed

    Pfordresher, Peter Q; Mantell, James T

    2012-01-01

    We report an experiment that tested whether effects of altered auditory feedback (AAF) during piano performance differ from its effects during singing. These effector systems differ with respect to the mapping between motor gestures and pitch content of auditory feedback. Whereas this action-effect mapping is highly reliable during phonation in any vocal motor task (singing or speaking), mapping between finger movements and pitch occurs only in limited situations, such as piano playing. Effects of AAF in both tasks replicated results previously found for keyboard performance (Pfordresher, 2003), in that asynchronous (delayed) feedback slowed timing whereas alterations to feedback pitch increased error rates, and the effect of asynchronous feedback was similar in magnitude across tasks. However, manipulations of feedback pitch had larger effects on singing than on keyboard production, suggesting effector-specific differences in sensitivity to action-effect mapping with respect to feedback content. These results support the view that disruption from AAF is based on abstract, effector independent, response-effect associations but that the strength of associations differs across effector systems.

  6. Early Antipsychotic Treatment in Juvenile Rats Elicits Long-Term Alterations to the Dopamine Neurotransmitter System.

    PubMed

    De Santis, Michael; Lian, Jiamei; Huang, Xu-Feng; Deng, Chao

    2016-11-22

    Prescription of antipsychotic drugs (APDs) to children has substantially increased in recent years. Whilst current investigations into potential long-term effects have uncovered some alterations to adult behaviours, further investigations into potential changes to neurotransmitter systems are required. The current study investigated potential long-term changes to the adult dopamine (DA) system following aripiprazole, olanzapine and risperidone treatment in female and male juvenile rats. Levels of tyrosine hydroxylase (TH), phosphorylated-TH (p-TH), dopamine active transporter (DAT), and D₁ and D₂ receptors were measured via Western blot and/or receptor autoradiography. Aripiprazole decreased TH and D₁ receptor levels in the ventral tegmental area (VTA) and p-TH levels in the prefrontal cortex (PFC) of females, whilst TH levels decreased in the PFC of males. Olanzapine decreased PFC p-TH levels and increased D₂ receptor expression in the PFC and nucleus accumbens (NAc) in females only. Additionally, risperidone treatment increased D₁ receptor levels in the hippocampus of females, whilst, in males, p-TH levels increased in the PFC and hippocampus, D₁ receptor expression decreased in the NAc, and DAT levels decreased in the caudate putamen (CPu), and elevated in the VTA. These results suggest that early treatment with various APDs can cause different long-term alterations in the adult brain, across both treatment groups and genders.

  7. Early Antipsychotic Treatment in Juvenile Rats Elicits Long-Term Alterations to the Dopamine Neurotransmitter System

    PubMed Central

    De Santis, Michael; Lian, Jiamei; Huang, Xu-Feng; Deng, Chao

    2016-01-01

    Prescription of antipsychotic drugs (APDs) to children has substantially increased in recent years. Whilst current investigations into potential long-term effects have uncovered some alterations to adult behaviours, further investigations into potential changes to neurotransmitter systems are required. The current study investigated potential long-term changes to the adult dopamine (DA) system following aripiprazole, olanzapine and risperidone treatment in female and male juvenile rats. Levels of tyrosine hydroxylase (TH), phosphorylated-TH (p-TH), dopamine active transporter (DAT), and D1 and D2 receptors were measured via Western blot and/or receptor autoradiography. Aripiprazole decreased TH and D1 receptor levels in the ventral tegmental area (VTA) and p-TH levels in the prefrontal cortex (PFC) of females, whilst TH levels decreased in the PFC of males. Olanzapine decreased PFC p-TH levels and increased D2 receptor expression in the PFC and nucleus accumbens (NAc) in females only. Additionally, risperidone treatment increased D1 receptor levels in the hippocampus of females, whilst, in males, p-TH levels increased in the PFC and hippocampus, D1 receptor expression decreased in the NAc, and DAT levels decreased in the caudate putamen (CPu), and elevated in the VTA. These results suggest that early treatment with various APDs can cause different long-term alterations in the adult brain, across both treatment groups and genders. PMID:27879654

  8. Association between Oro-Facial Defects and Systemic Alterations in Children Affected by Marfan Syndrome

    PubMed Central

    Docimo, Raffaella; Maturo, Paolo; D’Auria, Francesca; Grego, Susanna; Costacurta, Micaela; Perugia, Cesare; Chiariello, Luigi

    2013-01-01

    Background: It is important to establish an early diagnosis of the Marfan Syndrome (MFS) for providing an adequate pharmacological or surgical therapy. Nevertheless, this diagnosis may be complex, given the multi-organic involvement of this disease. Aims: In this work, we evaluated the oral phenotype in a group of paediatric patients with a clinical diagnosis of MFS, to quantify the association of the oro-facial defects with other systemic alterations. Settings and Design: Paediatric subjects who were aged, with a clinical diagnosis of MFS, were selected from our regional Marfan monitoring unit. Methods and Material: All the patients were subjected to Paediatric Dentistry examinations and a radiological screening with Panoramic and Cephalometric X-Rays. The aortic dilation (Aortic Z-score value), the hyperlaxity of the ligaments and scoliosis were evaluated by cardio-surgical and orthopaedics specialists. Statistical Analysis: The correlations between the oral and systemic alterations were analyzed by using the chi square test for the nominal variables. Results and Conclusions: We found a significant correlation of the Aortic Z – score with multiple oral defects which included retrognathia, malar hypoplasia, cross bite, oral respiration and an ogival palate. An association of the oral defects with hyperlaxity of the ligaments and scoliosis was also found. Thus, the data suggested that dentists should be more involved in a multidisciplinary approach, to provide an early MFS diagnosis in paediatric patients. PMID:23730650

  9. Morphologic alterations in rat brain following systemic and intraventricular methotrexate injection: light and electron microscopic studies.

    PubMed

    Gregorios, J B; Gregorios, A B; Mora, J; Marcillo, A; Fojaco, R M; Green, B

    1989-01-01

    To determine the morphological substrate of acute methotrexate (MTX) encephalopathy, light and electron microscopic studies were performed on rat brains after short-term intraperitoneal (IP) and intraventricular (IV) injections of MTX. In both models, Alzheimer type II astrocytosis was the initial and major pathologic alteration seen by light microscopy. The neurons, oligodendrocytes, myelin and endothelial cells were relatively spared. Ultrastructural studies showed pleomorphism and condensation of mitochondria, membrane-bound vacuoles, prominent stacks of sparsely granular, rough endoplasmic reticulum and progressive hydropic swelling of astrocytic perikarya and their processes. The astroglial alterations were reversible after cessation of the drug but persisted for a longer time with repeated IP administration. Gastrointestinal complications and overall mortality were also greater with higher doses and increasing frequency of IP MTX injection. White matter necrosis was noted only after IV injection of high-dose MTX. The neuropathologic changes of MTX leukoencephalopathy can be replicated in an animal model by IV injection of the drug. The reversibility of the changes that were seen following IP administration correlates with the transient neurologic deficits observed in some patients after high-dose systemic MTX therapy. The initially selective astroglial effect suggests that astrocytes might be a target for MTX toxicity, although other central nervous system components may also be adversely affected by the drug.

  10. Molecular dynamics evaluation of self-diffusion in Yukawa systems

    NASA Astrophysics Data System (ADS)

    Ohta, H.; Hamaguchi, S.

    2000-11-01

    Self-diffusion coefficients of Yukawa systems in the fluid phase are obtained from molecular dynamics simulations in a wide range of the thermodynamical parameters. The Yukawa system is a collection of particles interacting through Yukawa (i.e., screened Coulomb) potentials, which may serve as a model for charged dust particles in a plasma or colloidal particles in electrolytes. The self-diffusion coefficients are found to follow a simple scaling law with respect to the system temperature, which is consistent with the universal scaling (i.e., temperature scaling independent of the ratio of interparticle distance to screening length) observed by Robbins et al. [J. Chem. Phys. 88, 3286 (1988)] if the fluid system is near solidification. Also discussed is the velocity autocorrelation function, which is in part used to determine the self-diffusion coefficients through the Green-Kubo formula.

  11. Molecular physiology of vesicular glutamate transporters in the digestive system.

    PubMed

    Li, Tao; Ghishan, Fayez-K; Bai, Liqun

    2005-03-28

    Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Packaging and storage of glutamate into glutamatergic neuronal vesicles require ATP-dependent vesicular glutamate uptake systems, which utilize the electrochemical proton gradient as a driving force. Three vesicular glutamate transporters (VGLUT1-3) have been recently identified from neuronal tissue where they play a key role to maintain the vesicular glutamate level. Recently, it has been demonstrated that glutamate signaling is also functional in peripheral neuronal and non-neuronal tissues, and occurs in sites of pituitary, adrenal, pineal glands, bone, GI tract, pancreas, skin, and testis. The glutamate receptors and VGLUTs in digestive system have been found in both neuronal and endocrinal cells. The glutamate signaling in the digestive system may have significant relevance to diabetes and GI tract motility disorders. This review will focus on the most recent update of molecular physiology of digestive VGLUTs.

  12. Analysis of lidar systems for profiling aurorally excited molecular species.

    PubMed

    Collins, R L; Lummerzheim, D; Smith, R W

    1997-08-20

    We report a detailed analysis of lidar systems that profile aurorally excited molecular species in the upper mesosphere and lower thermosphere ( ~80 -300 km). Current profiling of this region is performed with incoherent scatter radars that determine the total electron and ion concentrations but not the individual species. Studies of the aeronomy of the thermosphere requires knowledge of the species present and their relative populations in the different vibrational and rotational states. We review the spectroscopy of nitrogen to determine an optimized lidar system. We combine these results with current auroral observations and models to determine the performance of an actual lidar system. The study shows that such systems can provide high-resolution (1 km, 100 s) measurements of these species with current laser technology.

  13. Olfactory memory formation in Drosophila: from molecular to systems neuroscience.

    PubMed

    Davis, Ronald L

    2005-01-01

    The olfactory nervous system of insects and mammals exhibits many similarities, which suggests that the mechanisms for olfactory learning may be shared. Molecular genetic investigations of Drosophila learning have uncovered numerous genes whose gene products are essential for olfactory memory formation. Recent studies of the products of these genes have continued to expand the range of molecular processes known to underlie memory formation. Recent research has also broadened the neuroanatomical areas thought to mediate olfactory learning to include the antennal lobes in addition to a previously accepted and central role for the mushroom bodies. The roles for neurons extrinsic to the mushroom body neurons are becoming better defined. Finally, the genes identified to participate in Drosophila olfactory learning have conserved roles in mammalian organisms, highlighting the value of Drosophila for gene discovery.

  14. Amorphous drug delivery systems: molecular aspects, design, and performance.

    PubMed

    Kaushal, Aditya Mohan; Gupta, Piyush; Bansal, Arvind Kumar

    2004-01-01

    The biopharmaceutical properties-especially the solubility and permeability-of a molecule contribute to its overall therapeutic efficacy. The newer tools of drug discovery have caused a shift in the properties of drug-like compounds, resulting in drugs with poor aqueous solubility and permeability, which offer delivery challenges, thus requiring considerable pharmaceutical manning. The modulation of solubility is a more viable option for enhancing bioavailability than permeability, because of the lack of "safe" approaches to enhance the latter. Solid-state manipulation in general, and amorphization in particular, are preferred ways of enhancing solubility and optimizing delivery of poorly soluble drugs. This review attempts to address the diverse issues pertaining to amorphous drug delivery systems. We discuss the various thermodynamic phenomenon such as glass transition, fragility, molecular mobility, devitrification kinetics, and molecular-level chemical interactions that contribute to the ease of formation, the solubility advantage, and the stability of amorphous drugs. The engineering of pharmaceutical alloys by solubilizing and stabilizing carriers, commonly termed solid dispersions, provide avenues for exploiting the benefits of amorphous systems. Carrier properties, mechanisms of drug release, and study of release kinetics help to improve the predictability of performance. The review also addresses the various barriers in the design of amorphous delivery systems, use of amorphous form in controlled release delivery systems, and their in vivo performance.

  15. Thermal variability alters the impact of climate warming on consumer-resource systems.

    PubMed

    Fey, Samuel B; Vasseur, David A

    2016-07-01

    Thermal variation through space and time are prominent features of ecosystems that influence processes at multiple levels of biological organization. Yet, it remains unclear how populations embedded within biological communities will respond to climate warming in thermally variable environments, particularly as climate change alters existing patterns of thermal spatial and temporal variability. As environmental temperatures increase above historical ranges, organisms may increasingly rely on extreme habitats to effectively thermoregulate. Such locations desirable in their thermal attributes (e.g., thermal refugia) are often suboptimal for resource acquisition (e.g., underground tunnels). Thus, via the expected increase in both mean temperatures and diel thermal variation, climate warming may heighten the trade-off for consumers between behaviors maximizing thermal performance and those maximizing resource acquisition. Here, we integrate behavioral, physiological, and trophic ecology to provide a general framework for understanding how temporal thermal variation, mediated by access to a thermal refugium, alters the response of consumer-resource systems to warming. We use this framework to predict how temporal variation and access to thermal refugia affect the persistence of consumers and resources during climate warming, how the quality of thermal refugia impact consumer-resource systems, and how consumer-resource systems with fast vs. slow ecological dynamics respond to warming. Our results show that the spatial thermal variability provided by refugia can elevate consumer biomass at warmer temperatures despite reducing the fraction of time consumers spend foraging, that temporal variability detrimentally impacts consumers at high environmental temperatures, and that consumer-resource systems with fast ecological dynamics are most vulnerable to climate warming. Thus, incorporating both estimates of thermal variability and species interactions may be necessary to

  16. Trypanosoma cruzi Disrupts Thymic Homeostasis by Altering Intrathymic and Systemic Stress-Related Endocrine Circuitries

    PubMed Central

    Lepletier, Ailin; de Carvalho, Vinicius Frias; e Silva, Patricia Machado Rodrigues; Villar, Silvina; Pérez, Ana Rosa; Savino, Wilson; Morrot, Alexandre

    2013-01-01

    We have previously shown that experimental infection caused by Trypanosoma cruzi is associated with changes in the hypothalamus-pituitary-adrenal axis. Increased glucocorticoid (GC) levels are believed to be protective against the effects of acute stress during infection but result in depletion of CD4+CD8+ thymocytes by apoptosis, driving to thymic atrophy. However, very few data are available concerning prolactin (PRL), another stress-related hormone, which seems to be decreased during T. cruzi infection. Considering the immunomodulatory role of PRL upon the effects caused by GC, we investigated if intrathymic cross-talk between GC and PRL receptors (GR and PRLR, respectively) might influence T. cruzi-induced thymic atrophy. Using an acute experimental model, we observed changes in GR/PRLR cross-activation related with the survival of CD4+CD8+ thymocytes during infection. These alterations were closely related with systemic changes, characterized by a stress hormone imbalance, with progressive GC augmentation simultaneously to PRL reduction. The intrathymic hormone circuitry exhibited an inverse modulation that seemed to counteract the GC-related systemic deleterious effects. During infection, adrenalectomy protected the thymus from the increase in apoptosis ratio without changing PRL levels, whereas an additional inhibition of circulating PRL accelerated the thymic atrophy and led to an increase in corticosterone systemic levels. These results demonstrate that the PRL impairment during infection is not caused by the increase of corticosterone levels, but the opposite seems to occur. Accordingly, metoclopramide (MET)-induced enhancement of PRL secretion protected thymic atrophy in acutely infected animals as well as the abnormal export of immature and potentially autoreactive CD4+CD8+ thymocytes to the periphery. In conclusion, our findings clearly show that Trypanosoma cruzi subverts mouse thymus homeostasis by altering intrathymic and systemic stress

  17. Alterations in the hippocampal endocannabinoid system in diet-induced obese mice.

    PubMed

    Massa, Federico; Mancini, Giacomo; Schmidt, Helmut; Steindel, Frauke; Mackie, Ken; Angioni, Carlo; Oliet, Stéphane H R; Geisslinger, Gerd; Lutz, Beat

    2010-05-05

    The endocannabinoid (eCB) system plays central roles in the regulation of food intake and energy expenditure. Its alteration in activity contributes to the development and maintenance of obesity. Stimulation of the cannabinoid receptor type 1 (CB(1) receptor) increases feeding, enhances reward aspects of eating, and promotes lipogenesis, whereas its blockade decreases appetite, sustains weight loss, increases insulin sensitivity, and alleviates dysregulation of lipid metabolism. The hypothesis has been put forward that the eCB system is overactive in obesity. Hippocampal circuits are not directly involved in the neuronal control of food intake and appetite, but they play important roles in hedonic aspects of eating. We investigated the possibility whether or not diet-induced obesity (DIO) alters the functioning of the hippocampal eCB system. We found that levels of the two eCBs, 2-arachidonoyl glycerol (2-AG) and anandamide, were increased in the hippocampus from DIO mice, with a concomitant increase of the 2-AG synthesizing enzyme diacylglycerol lipase-alpha and increased CB(1) receptor immunoreactivity in CA1 and CA3 regions, whereas CB(1) receptor agonist-induced [(35)S]GTPgammaS binding was unchanged. eCB-mediated synaptic plasticity was changed in the CA1 region, as depolarization-induced suppression of inhibition and long-term depression of inhibitory synapses were enhanced. Functionality of CB(1) receptors in GABAergic neurons was furthermore revealed, as mice specifically lacking CB(1) receptors on this neuronal population were partly resistant to DIO. Our results show that DIO-induced changes in the eCB system affect not only tissues directly involved in the metabolic regulation but also brain regions mediating hedonic aspects of eating and influencing cognitive processes.

  18. Molecular alterations in non-small-cell lung cancer: perspective for targeted therapy and specimen management for the bronchoscopist.

    PubMed

    Czarnecka-Kujawa, Kasia; Yasufuku, Kazuhiro

    2014-11-01

    Major advances have occurred over the past decade in our understanding of lung cancer pathobiology. Increasing knowledge of molecular aberrations in lung cancer, specifically the discovery of two driver genes in pharmacologically targetable tyrosine kinases involved in growth factor receptor signalling, epidermal growth factor receptor and anaplastic lymphoma kinase, has been of major therapeutic and prognostic importance. This discovery has allowed for new, personalized approach to the management of lung cancer. Recognizing the importance of molecular signatures of lung cancer, the College of American Pathologists, International Association for the Study of Lung Cancer and Association for Molecular Pathology released the first guidelines for molecular testing in lung cancer. The introduction of minimally invasive needle techniques for the evaluation of lung cancer patients, such as endobronchial ultrasound transbronchial needle aspiration and oesophageal ultrasound-fine-needle aspiration, has revolutionized the way lung cancer patients are assessed. Samples obtained using the minimally invasive needle approaches have been shown to be sufficient not only for routine molecular testing but also for multigenic analysis. This allows bronchoscopist to assume an increasingly important role in the diagnostic workup of patients with lung cancer at all stages of the disease and contribute to personalizing the care of lung cancer patients.

  19. Modeling acclimatization by hybrid systems: condition changes alter biological system behavior models.

    PubMed

    Assar, Rodrigo; Montecino, Martín A; Maass, Alejandro; Sherman, David J

    2014-07-01

    In order to describe the dynamic behavior of a complex biological system, it is useful to combine models integrating processes at different levels and with temporal dependencies. Such combinations are necessary for modeling acclimatization, a phenomenon where changes in environmental conditions can induce drastic changes in the behavior of a biological system. In this article we formalize the use of hybrid systems as a tool to model this kind of biological behavior. A modeling scheme called strong switches is proposed. It allows one to take into account both minor adjustments to the coefficients of a continuous model, and, more interestingly, large-scale changes to the structure of the model. We illustrate the proposed methodology with two applications: acclimatization in wine fermentation kinetics, and acclimatization of osteo-adipo differentiation system linking stimulus signals to bone mass. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  20. Perinatal high methyl donor alters gene expression in IGF system in male offspring without altering DNA methylation

    PubMed Central

    Amarger, Valérie; Giudicelli, Fanny; Pagniez, Anthony; Parnet, Patricia

    2017-01-01

    Aim: To investigate the effect of a protein restriction and a supplementation with methyl donor nutrients during fetal and early postnatal life on the expression and epigenetic state of imprinted genes from the IGF system. Materials & methods: Pregnant female rats were fed a protein-restricted diet supplemented or not with methyl donor. Results: Gene expression of the Igf2, H19, Igf1, Igf2r and Plagl1 genes in the liver of male offspring at birth and weaning was strongly influenced by maternal diet. Whereas the methylation profiles of the Igf2, H19 and Igf2r genes were remarkably stable, DNA methylation of Plagl1 promoter was slightly modified. Conclusion: DNA methylation of most, but not all, imprinted gene regulatory regions was resistant to methyl group nutritional supply. PMID:28344827

  1. Perinatal high methyl donor alters gene expression in IGF system in male offspring without altering DNA methylation.

    PubMed

    Amarger, Valérie; Giudicelli, Fanny; Pagniez, Anthony; Parnet, Patricia

    2017-03-01

    To investigate the effect of a protein restriction and a supplementation with methyl donor nutrients during fetal and early postnatal life on the expression and epigenetic state of imprinted genes from the IGF system. Pregnant female rats were fed a protein-restricted diet supplemented or not with methyl donor. Gene expression of the Igf2, H19, Igf1, Igf2r and Plagl1 genes in the liver of male offspring at birth and weaning was strongly influenced by maternal diet. Whereas the methylation profiles of the Igf2, H19 and Igf2r genes were remarkably stable, DNA methylation of Plagl1 promoter was slightly modified. DNA methylation of most, but not all, imprinted gene regulatory regions was resistant to methyl group nutritional supply.

  2. Temperature fluctuations in canonical systems: Insights from molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Hickman, J.; Mishin, Y.

    2016-11-01

    Molecular dynamics simulations of a quasiharmonic solid are conducted to elucidate the meaning of temperature fluctuations in canonical systems and validate a well-known but frequently contested equation predicting the mean square of such fluctuations. The simulations implement two virtual and one physical (natural) thermostat and examine the kinetic, potential, and total energy correlation functions in the time and frequency domains. The results clearly demonstrate the existence of quasiequilibrium states in which the system can be characterized by a well-defined temperature that follows the mentioned fluctuation equation. The emergence of such states is due to the wide separation of time scales between thermal relaxation by phonon scattering and slow energy exchanges with the thermostat. The quasiequilibrium states exist between these two time scales when the system behaves as virtually isolated and equilibrium.

  3. Electronic properties of a molecular system with Platinum

    NASA Astrophysics Data System (ADS)

    Ojeda, J. H.; Medina, F. G.; Becerra-Alonso, David

    2017-10-01

    The electronic properties are studied using a finite homogeneous molecule called Trans-platinum-linked oligo(tetraethenylethenes). This system is composed of individual molecules such as benzene rings, platinum, Phosphore and Sulfur. The mechanism for the study of the electron transport through this system is based on placing the molecule between metal contacts to control the current through the molecular system. We study this molecule based on the tight-binding approach for the calculation of the transport properties using the Landauer-Büttiker formalism and the Fischer-Lee relationship, based on a semi-analytic Green's function method within a real-space renormalization approach. Our results show a significant agreement with experimental measurements.

  4. Microscale Symmetrical Electroporator Array as a Versatile Molecular Delivery System

    NASA Astrophysics Data System (ADS)

    Ouyang, Mengxing; Hill, Winfield; Lee, Jung Hyun; Hur, Soojung Claire

    2017-03-01

    Successful developments of new therapeutic strategies often rely on the ability to deliver exogenous molecules into cytosol. We have developed a versatile on-chip vortex-assisted electroporation system, engineered to conduct sequential intracellular delivery of multiple molecules into various cell types at low voltage in a dosage-controlled manner. Micro-patterned planar electrodes permit substantial reduction in operational voltages and seamless integration with an existing microfluidic technology. Equipped with real-time process visualization functionality, the system enables on-chip optimization of electroporation parameters for cells with varying properties. Moreover, the system’s dosage control and multi-molecular delivery capabilities facilitate intracellular delivery of various molecules as a single agent or in combination and its utility in biological research has been demonstrated by conducting RNA interference assays. We envision the system to be a powerful tool, aiding a wide range of applications, requiring single-cell level co-administrations of multiple molecules with controlled dosages.

  5. Subtle Monte Carlo Updates in Dense Molecular Systems.

    PubMed

    Bottaro, Sandro; Boomsma, Wouter; E Johansson, Kristoffer; Andreetta, Christian; Hamelryck, Thomas; Ferkinghoff-Borg, Jesper

    2012-02-14

    Although Markov chain Monte Carlo (MC) simulation is a potentially powerful approach for exploring conformational space, it has been unable to compete with molecular dynamics (MD) in the analysis of high density structural states, such as the native state of globular proteins. Here, we introduce a kinetic algorithm, CRISP, that greatly enhances the sampling efficiency in all-atom MC simulations of dense systems. The algorithm is based on an exact analytical solution to the classic chain-closure problem, making it possible to express the interdependencies among degrees of freedom in the molecule as correlations in a multivariate Gaussian distribution. We demonstrate that our method reproduces structural variation in proteins with greater efficiency than current state-of-the-art Monte Carlo methods and has real-time simulation performance on par with molecular dynamics simulations. The presented results suggest our method as a valuable tool in the study of molecules in atomic detail, offering a potential alternative to molecular dynamics for probing long time-scale conformational transitions.

  6. No neuronal loss, but alterations of the GDNF system in asymptomatic diverticulosis

    PubMed Central

    Wedel, Thilo; Lange, Christina; Hohmeier, Ines; Cossais, François; Ebsen, Michael; Vogel, Ilka; Böttner, Martina

    2017-01-01

    Background Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor known to promote the survival and maintenance of neurons not only in the developing but also in the adult enteric nervous system. As diverticular disease (DD) is associated with reduced myenteric neurons, alterations of the GDNF system were studied in asymptomatic diverticulosis (diverticulosis) and DD. Methods Morphometric analysis for quantifying myenteric ganglia and neurons were assessed in colonic full-thickness sections of patients with diverticulosis and controls. Samples of tunica muscularis (TM) and laser-microdissected myenteric ganglia from patients with diverticulosis, DD and controls were analyzed for mRNA expression levels of GDNF, GFRA1, and RET by RT-qPCR. Myenteric protein expression of both receptors was quantified by fluorescence-immunohistochemistry of patients with diverticulosis, DD, and controls. Results Although no myenteric morphometric alterations were found in patients with diverticulosis, GDNF, GFRA1 and RET mRNA expression was down-regulated in the TM of patients with diverticulosis as well as DD. Furthermore GFRA1 and RET myenteric plexus mRNA expression of patients with diverticulosis and DD was down-regulated, whereas GDNF remained unaltered. Myenteric immunoreactivity of the receptors GFRα1 and RET was decreased in both asymptomatic diverticulosis and DD patients. Conclusion Our data provide evidence for an impaired GDNF system at gene and protein level not only in DD but also during early stages of diverticula formation. Thus, the results strengthen the idea of a disturbed GDNF-responsiveness as contributive factor for a primary enteric neuropathy involved in the pathogenesis and disturbed intestinal motility observed in DD. PMID:28152033

  7. A 3D visualization system for molecular structures

    NASA Technical Reports Server (NTRS)

    Green, Terry J.

    1989-01-01

    The properties of molecules derive in part from their structures. Because of the importance of understanding molecular structures various methodologies, ranging from first principles to empirical technique, were developed for computing the structure of molecules. For large molecules such as polymer model compounds, the structural information is difficult to comprehend by examining tabulated data. Therefore, a molecular graphics display system, called MOLDS, was developed to help interpret the data. MOLDS is a menu-driven program developed to run on the LADC SNS computer systems. This program can read a data file generated by the modeling programs or data can be entered using the keyboard. MOLDS has the following capabilities: draws the 3-D representation of a molecule using stick, ball and ball, or space filled model from Cartesian coordinates, draws different perspective views of the molecule; rotates the molecule on the X, Y, Z axis or about some arbitrary line in space, zooms in on a small area of the molecule in order to obtain a better view of a specific region; and makes hard copy representation of molecules on a graphic printer. In addition, MOLDS can be easily updated and readily adapted to run on most computer systems.

  8. A 3D visualization system for molecular structures

    NASA Technical Reports Server (NTRS)

    Green, Terry J.

    1989-01-01

    The properties of molecules derive in part from their structures. Because of the importance of understanding molecular structures various methodologies, ranging from first principles to empirical technique, were developed for computing the structure of molecules. For large molecules such as polymer model compounds, the structural information is difficult to comprehend by examining tabulated data. Therefore, a molecular graphics display system, called MOLDS, was developed to help interpret the data. MOLDS is a menu-driven program developed to run on the LADC SNS computer systems. This program can read a data file generated by the modeling programs or data can be entered using the keyboard. MOLDS has the following capabilities: draws the 3-D representation of a molecule using stick, ball and ball, or space filled model from Cartesian coordinates, draws different perspective views of the molecule; rotates the molecule on the X, Y, Z axis or about some arbitrary line in space, zooms in on a small area of the molecule in order to obtain a better view of a specific region; and makes hard copy representation of molecules on a graphic printer. In addition, MOLDS can be easily updated and readily adapted to run on most computer systems.

  9. DCMS: A data analytics and management system for molecular simulation.

    PubMed

    Kumar, Anand; Grupcev, Vladimir; Berrada, Meryem; Fogarty, Joseph C; Tu, Yi-Cheng; Zhu, Xingquan; Pandit, Sagar A; Xia, Yuni

    Molecular Simulation (MS) is a powerful tool for studying physical/chemical features of large systems and has seen applications in many scientific and engineering domains. During the simulation process, the experiments generate a very large number of atoms and intend to observe their spatial and temporal relationships for scientific analysis. The sheer data volumes and their intensive interactions impose significant challenges for data accessing, managing, and analysis. To date, existing MS software systems fall short on storage and handling of MS data, mainly because of the missing of a platform to support applications that involve intensive data access and analytical process. In this paper, we present the database-centric molecular simulation (DCMS) system our team developed in the past few years. The main idea behind DCMS is to store MS data in a relational database management system (DBMS) to take advantage of the declarative query interface (i.e., SQL), data access methods, query processing, and optimization mechanisms of modern DBMSs. A unique challenge is to handle the analytical queries that are often compute-intensive. For that, we developed novel indexing and query processing strategies (including algorithms running on modern co-processors) as integrated components of the DBMS. As a result, researchers can upload and analyze their data using efficient functions implemented inside the DBMS. Index structures are generated to store analysis results that may be interesting to other users, so that the results are readily available without duplicating the analysis. We have developed a prototype of DCMS based on the PostgreSQL system and experiments using real MS data and workload show that DCMS significantly outperforms existing MS software systems. We also used it as a platform to test other data management issues such as security and compression.

  10. Radiofrequency radiation alters the immune system. II. Modulation of in vivo lymphocyte circulation

    SciTech Connect

    Liburdy, R.P.

    1980-07-01

    In vivo lymphocyte circulation was significantly altered in mice exposed to whole-body radiofrequency radiation (RFR). In vivo lymphocyte circulation was followed by quantitating activity of sodium chromate-51-labeled lymphocytes in the lung, spleen, liver, and bone marrow of animals at different times after iv spleen lymphocyte injection. Immediately after cell injection, animals were exposed to 2.6-GHz RFR (CW) at 25 or 5 mW/cm/sup 2/ (3.8 W/kg) for 1 h. At 1,6, and 24 h aftr lymphocyte injection target organs were removed, weighed, and counted. Sham RFR, warm-air, and steroid-treated groups were included as controls. Hyperthermic RFR exposure (25 mW/cm/sup 2/, 2.0/sup 0/C increase in core temperature) led to a 37% reduction in lymphocytes leaving the lung to migrate into the spleen. In addition, a threefold increse in spleen lymphocytes entering the bone marrow occurred. Significantly, this pattern was also observed in the steroid-treated group; nonthermogenic RFR exposure (5 mWcm/sup 2/) and warm-air exposures did not lead to altered lymphocyte traffic. These results support the idea that steroid release associated with thermal stress and the process of thermoregulation is a significant operatnt factor responsible for RFR effects on the immune system.

  11. Altered Mitochondria, Protein Synthesis Machinery, and Purine Metabolism Are Molecular Contributors to the Pathogenesis of Creutzfeldt-Jakob Disease.

    PubMed

    Ansoleaga, Belén; Garcia-Esparcia, Paula; Llorens, Franc; Hernández-Ortega, Karina; Carmona Tech, Margarita; Antonio Del Rio, José; Zerr, Inga; Ferrer, Isidro

    2016-06-12

    Neuron loss, synaptic decline, and spongiform change are the hallmarks of sporadic Creutzfeldt-Jakob disease (sCJD), and may be related to deficiencies in mitochondria, energy metabolism, and protein synthesis. To investigate these relationships, we determined the expression levels of genes encoding subunits of the 5 protein complexes of the electron transport chain, proteins involved in energy metabolism, nucleolar and ribosomal proteins, and enzymes of purine metabolism in frontal cortex samples from 15 cases of sCJD MM1 and age-matched controls. We also assessed the protein expression levels of subunits of the respiratory chain, initiation and elongation translation factors of protein synthesis, and localization of selected mitochondrial components. We identified marked, generalized alterations of mRNA and protein expression of most subunits of all 5 mitochondrial respiratory chain complexes in sCJD cases. Expression of molecules involved in protein synthesis and purine metabolism were also altered in sCJD. These findings point to altered mRNA and protein expression of components of mitochondria, protein synthesis machinery, and purine metabolism as components of the pathogenesis of CJD. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

  12. Somatostatin system: molecular mechanisms regulating anterior pituitary hormones.

    PubMed

    Eigler, Tamar; Ben-Shlomo, Anat

    2014-08-01

    The somatostatin (SRIF) system, which includes the SRIF ligand and receptors, regulates anterior pituitary gland function, mainly inhibiting hormone secretion and to some extent pituitary tumor cell growth. SRIF-14 via its cognate G-protein-coupled receptors (subtypes 1-5) activates multiple cellular signaling pathways including adenylate cyclase/cAMP, MAPK, ion channel-dependent pathways, and others. In addition, recent data have suggested SRIF-independent constitutive SRIF receptor activity responsible for GH and ACTH inhibition in vitro. This review summarizes current knowledge on ligand-dependent and independent SRIF receptor molecular and functional effects on hormone-secreting cells in the anterior pituitary gland.

  13. A complex systems approach to computational molecular biology

    SciTech Connect

    Lapedes, A. |

    1993-09-01

    We report on the containing research program at Santa Fe Institute that applies complex systems methodology to computational molecular biology. Two aspects are stressed here are the use of co-evolving adaptive neutral networks for determining predictable protein structure classifications, and the use of information theory to elucidate protein structure and function. A ``snapshot`` of the current state of research in these two topics is presented, representing the present state of two major research thrusts in the program of Genetic Data and Sequence Analysis at the Santa Fe Institute.

  14. Stem cells and aberrant signaling of molecular systems in skin aging.

    PubMed

    Peng, Yan; Xuan, Min; Leung, Victor Y L; Cheng, Biao

    2015-01-01

    The skin is the body's largest organ and it is able to self-repair throughout an individual's life. With advanced age, skin is prone to degenerate in response to damage. Although cosmetic surgery has been widely adopted to rejuvinate skin, we are far from a clear understanding of the mechanisms responsible for skin aging. Recently, adult skin-resident stem/progenitor cells, growth arrest, senescence or apoptotic death and dysfunction caused by alterations in key signaling genes, such as Ras/Raf/MEK/ERK, PI3K/Akt-kinases, Wnt, p21 and p53, have been shown to play a vital role in skin regeneration. Simultaneously, enhanced telomere attrition, hormone exhaustion, oxidative stress, genetic events and ultraviolet radiation exposure that result in severe DNA damage, genomic instability and epigenetic mutations also contribute to skin aging. Therefore, cell replacement and targeting of the molecular systems found in skin hold great promise for controlling or even curing skin aging.

  15. Diffusion-controlled interface kinetics-inclusive system-theoretic propagation models for molecular communication systems

    NASA Astrophysics Data System (ADS)

    Chude-Okonkwo, Uche A. K.; Malekian, Reza; Maharaj, B. T.

    2015-12-01

    Inspired by biological systems, molecular communication has been proposed as a new communication paradigm that uses biochemical signals to transfer information from one nano device to another over a short distance. The biochemical nature of the information transfer process implies that for molecular communication purposes, the development of molecular channel models should take into consideration diffusion phenomenon as well as the physical/biochemical kinetic possibilities of the process. The physical and biochemical kinetics arise at the interfaces between the diffusion channel and the transmitter/receiver units. These interfaces are herein termed molecular antennas. In this paper, we present the deterministic propagation model of the molecular communication between an immobilized nanotransmitter and nanoreceiver, where the emission and reception kinetics are taken into consideration. Specifically, we derived closed-form system-theoretic models and expressions for configurations that represent different communication systems based on the type of molecular antennas used. The antennas considered are the nanopores at the transmitter and the surface receptor proteins/enzymes at the receiver. The developed models are simulated to show the influence of parameters such as the receiver radius, surface receptor protein/enzyme concentration, and various reaction rate constants. Results show that the effective receiver surface area and the rate constants are important to the system's output performance. Assuming high rate of catalysis, the analysis of the frequency behavior of the developed propagation channels in the form of transfer functions shows significant difference introduce by the inclusion of the molecular antennas into the diffusion-only model. It is also shown that for t > > 0 and with the information molecules' concentration greater than the Michaelis-Menten kinetic constant of the systems, the inclusion of surface receptors proteins and enzymes in the models

  16. High-fat diet alters the dopamine and opioid systems: effects across development

    PubMed Central

    Reyes, T M

    2012-01-01

    Consumption of a high-fat diet has been linked to obesity, dyslipidemia and cardiovascular disease. Less well appreciated are adverse effects on the brain and behavior. Recent research has shown that consumption of a high-fat diet can alter gene expression within the brain, and the dopamine and opioid neurotransmitter systems appear to be vulnerable to dysregulation. This review will focus on recent reports in both humans and animal models that describe adverse effects of high-fat diet consumption on the central reward circuitry. In addition, the importance of different development windows will be discussed, with effects observed in both the prenatal/perinatal time period and with chronic high-fat diet consumption in adulthood. PMID:27152150

  17. Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.

    PubMed

    Martins-de-Souza, Daniel; Gattaz, Wagner F; Schmitt, Andrea; Rewerts, Christiane; Maccarrone, Giuseppina; Dias-Neto, Emmanuel; Turck, Christoph W

    2009-04-01

    Schizophrenia is a complex disease, likely to be caused by a combination of serial alterations in a number of genes and environmental factors. The dorsolateral prefrontal cortex (Brodmann's Area 46) is involved in schizophrenia and executes high-level functions such as working memory, differentiation of conflicting thoughts, determination of right and wrong concepts and attitudes, correct social behavior and personality expression. Global proteomic analysis of post-mortem dorsolateral prefrontal cortex samples from schizophrenia patients and non-schizophrenic individuals was performed using stable isotope labeling and shotgun proteomics. The analysis resulted in the identification of 1,261 proteins, 84 of which showed statistically significant differential expression, reinforcing previous data supporting the involvement of the immune system, calcium homeostasis, cytoskeleton assembly, and energy metabolism in schizophrenia. In addition a number of new potential markers were found that may contribute to the understanding of the pathogenesis of this complex disease.

  18. Molecular Evolution of Freshwater Snails with Contrasting Mating Systems.

    PubMed

    Burgarella, Concetta; Gayral, Philippe; Ballenghien, Marion; Bernard, Aurélien; David, Patrice; Jarne, Philippe; Correa, Ana; Hurtrez-Boussès, Sylvie; Escobar, Juan; Galtier, Nicolas; Glémin, Sylvain

    2015-09-01

    Because mating systems affect population genetics and ecology, they are expected to impact the molecular evolution of species. Self-fertilizing species experience reduced effective population size, recombination rates, and heterozygosity, which in turn should decrease the efficacy of natural selection, both adaptive and purifying, and the strength of meiotic drive processes such as GC-biased gene conversion. The empirical evidence is only partly congruent with these predictions, depending on the analyzed species, some, but not all, of the expected effects have been observed. One possible reason is that self-fertilization is an evolutionary dead-end, so that most current selfers recently evolved self-fertilization, and their genome has not yet been strongly impacted by selfing. Here, we investigate the molecular evolution of two groups of freshwater snails in which mating systems have likely been stable for several millions of years. Analyzing coding sequence polymorphism, divergence, and expression levels, we report a strongly reduced genetic diversity, decreased efficacy of purifying selection, slower rate of adaptive evolution, and weakened codon usage bias/GC-biased gene conversion in the selfer Galba compared with the outcrosser Physa, in full agreement with theoretical expectations. Our results demonstrate that self-fertilization, when effective in the long run, is a major driver of population genomic and molecular evolutionary processes. Despite the genomic effects of selfing, Galba truncatula seems to escape the demographic consequences of the genetic load. We suggest that the particular ecology of the species may buffer the negative consequences of selfing, shedding new light on the dead-end hypothesis.

  19. Subanaesthetic Ketamine Treatment Alters Prefrontal Cortex Connectivity With Thalamus and Ascending Subcortical Systems

    PubMed Central

    Dawson, Neil; Morris, Brian J.; Pratt, Judith A.

    2013-01-01

    Background: Acute treatment with subanaesthetic doses of NMDA receptor antagonists, such as ketamine, provides a translational model with relevance to many of the symptoms of schizophrenia. Previous studies have focused specifically on the prefrontal cortex (PFC) because this region is implicated in many of the functional deficits associated with this disorder and shows reduced activity (hypofrontality) in schizophrenia patients. Chronic NMDA antagonist treatment in rodents can also induce hypofrontality, although paradoxically acute NMDA receptor antagonist administration induces metabolic hyperfrontality. Methods: In this study, we use 2-deoxyglucose imaging data in mice to characterize acute ketamine-induced alterations in regional functional connectivity, a deeper analysis of the consequences of acute NMDA receptor hypofunction. Results: We show that acute ketamine treatment increases PFC metabolic activity while reducing metabolic activity in the dorsal reticular thalamic nucleus (dRT). This is associated with abnormal functional connectivity between the PFC and multiple thalamic nuclei, including the dRT, mediodorsal (MDthal), and anteroventral (AVthal) thalamus. In addition, we show that acute NMDA receptor blockade alters the functional connectivity of the serotonergic (dorsal raphe [DR]), noradrenergic (locus coeruleus [LC]), and cholinergic (vertical limb of the diagonal band of broca [VDB]) systems. Conclusions: Together with other emerging data, these findings suggest that the reticular nucleus of the thalamus, along with the diffusely projecting subcortical aminergic/cholinergic systems, represent a primary site of action for ketamine in reproducing the diverse symptoms of schizophrenia. Our results also demonstrate the added scientific insight gained by characterizing the functional connectivity of discrete brain regions from brain imaging data gained in a preclinical context. PMID:22114100

  20. The display of molecular models with the Ames Interactive Modeling System (AIMS)

    NASA Technical Reports Server (NTRS)

    Egan, J. T.; Hart, J.; Burt, S. K.; Macelroy, R. D.

    1982-01-01

    A visualization of molecular models can lead to a clearer understanding of the models. Sophisticated graphics devices supported by minicomputers make it possible for the chemist to interact with the display of a very large model, altering its structure. In addition to user interaction, the need arises also for other ways of displaying information. These include the production of viewgraphs, film presentation, as well as publication quality prints of various models. To satisfy these needs, the display capability of the Ames Interactive Modeling System (AIMS) has been enhanced to provide a wide range of graphics and plotting capabilities. Attention is given to an overview of the AIMS system, graphics hardware used by the AIMS display subsystem, a comparison of graphics hardware, the representation of molecular models, graphics software used by the AIMS display subsystem, the display of a model obtained from data stored in molecule data base, a graphics feature for obtaining single frame permanent copy displays, and a feature for producing multiple frame displays.

  1. DNA-enabled integrated molecular systems for computation and sensing.

    PubMed

    LaBoda, Craig; Duschl, Heather; Dwyer, Chris L

    2014-06-17

    CONSPECTUS: Nucleic acids have become powerful building blocks for creating supramolecular nanostructures with a variety of new and interesting behaviors. The predictable and guided folding of DNA, inspired by nature, allows designs to manipulate molecular-scale processes unlike any other material system. Thus, DNA can be co-opted for engineered and purposeful ends. This Account details a small portion of what can be engineered using DNA within the context of computer architectures and systems. Over a decade of work at the intersection of DNA nanotechnology and computer system design has shown several key elements and properties of how to harness the massive parallelism created by DNA self-assembly. This work is presented, naturally, from the bottom-up beginning with early work on strand sequence design for deterministic, finite DNA nanostructure synthesis. The key features of DNA nanostructures are explored, including how the use of small DNA motifs assembled in a hierarchical manner enables full-addressability of the final nanostructure, an important property for building dense and complicated systems. A full computer system also requires devices that are compatible with DNA self-assembly and cooperate at a higher level as circuits patterned over many, many replicated units. Described here is some work in this area investigating nanowire and nanoparticle devices, as well as chromophore-based circuits called resonance energy transfer (RET) logic. The former is an example of a new way to bring traditional silicon transistor technology to the nanoscale, which is increasingly problematic with current fabrication methods. RET logic, on the other hand, introduces a framework for optical computing at the molecular level. This Account also highlights several architectural system studies that demonstrate that even with low-level devices that are inferior to their silicon counterparts and a substrate that harbors abundant defects, self-assembled systems can still

  2. International Conference on Intelligent Systems for Molecular Biology (ISMB)

    SciTech Connect

    Goldberg, Debra; Hibbs, Matthew; Kall, Lukas; Komandurglayavilli, Ravikumar; Mahony, Shaun; Marinescu, Voichita; Mayrose, Itay; Minin, Vladimir; Neeman, Yossef; Nimrod, Guy; Novotny, Marian; Opiyo, Stephen; Portugaly, Elon; Sadka, Tali; Sakabe, Noboru; Sarkar, Indra; Schaub, Marc; Shafer, Paul; Shmygelska, Olena; Singer, Gregory; Song, Yun; Soumyaroop, Bhattacharya; Stadler, Michael; Strope, Pooja; Su, Rong; Tabach, Yuval; Tae, Hongseok; Taylor, Todd; Terribilini, Michael; Thomas, Asha; Tran, Nam; Tseng, Tsai-Tien; Vashist, Akshay; Vijaya, Parthiban; Wang, Kai; Wang, Ting; Wei, Lai; Woo, Yong; Wu, Chunlei; Yamanishi, Yoshihiro; Yan, Changhui; Yang, Jack; Yang, Mary; Ye, Ping; Zhang, Miao

    2009-12-29

    The Intelligent Systems for Molecular Biology (ISMB) conference has provided a general forum for disseminating the latest developments in bioinformatics on an annual basis for the past 13 years. ISMB is a multidisciplinary conference that brings together scientists from computer science, molecular biology, mathematics and statistics. The goal of the ISMB meeting is to bring together biologists and computational scientists in a focus on actual biological problems, i.e., not simply theoretical calculations. The combined focus on "intelligent systems" and actual biological data makes ISMB a unique and highly important meeting, and 13 years of experience in holding the conference has resulted in a consistently well organized, well attended, and highly respected annual conference. The ISMB 2005 meeting was held June 25-29, 2005 at the Renaissance Center in Detroit, Michigan. The meeting attracted over 1,730 attendees. The science presented was exceptional, and in the course of the five-day meeting, 56 scientific papers, 710 posters, 47 Oral Abstracts, 76 Software demonstrations, and 14 tutorials were presented. The attendees represented a broad spectrum of backgrounds with 7% from commercial companies, over 28% qualifying for student registration, and 41 countries were represented at the conference, emphasizing its important international aspect. The ISMB conference is especially important because the cultures of computer science and biology are so disparate. ISMB, as a full-scale technical conference with refereed proceedings that have been indexed by both MEDLINE and Current Contents since 1996, bridges this cultural gap.

  3. The generation of meaningful information in molecular systems.

    PubMed

    Wills, Peter R

    2016-03-13

    The physico-chemical processes occurring inside cells are under the computational control of genetic (DNA) and epigenetic (internal structural) programming. The origin and evolution of genetic information (nucleic acid sequences) is reasonably well understood, but scant attention has been paid to the origin and evolution of the molecular biological interpreters that give phenotypic meaning to the sequence information that is quite faithfully replicated during cellular reproduction. The near universality and age of the mapping from nucleotide triplets to amino acids embedded in the functionality of the protein synthetic machinery speaks to the early development of a system of coding which is still extant in every living organism. We take the origin of genetic coding as a paradigm of the emergence of computation in natural systems, focusing on the requirement that the molecular components of an interpreter be synthesized autocatalytically. Within this context, it is seen that interpreters of increasing complexity are generated by series of transitions through stepped dynamic instabilities (non-equilibrium phase transitions). The early phylogeny of the amino acyl-tRNA synthetase enzymes is discussed in such terms, leading to the conclusion that the observed optimality of the genetic code is a natural outcome of the processes of self-organization that produced it.

  4. Pipe Phantoms With Applications in Molecular Imaging and System Characterization.

    PubMed

    Wang, Shiying; Herbst, Elizabeth B; Pye, Stephen D; Moran, Carmel M; Hossack, John A

    2017-01-01

    Pipe (vessel) phantoms mimicking human tissue and blood flow are widely used for cardiovascular related research in medical ultrasound. Pipe phantom studies require the development of materials and liquids that match the acoustic properties of soft tissue, blood vessel wall, and blood. Over recent years, pipe phantoms have been developed to mimic the molecular properties of the simulated blood vessels. In this paper, the design, construction, and functionalization of pipe phantoms are introduced and validated for applications in molecular imaging and ultrasound imaging system characterization. There are three major types of pipe phantoms introduced: 1) a gelatin-based pipe phantom; 2) a polydimethylsiloxane-based pipe phantom; and 3) the "Edinburgh pipe phantom." These phantoms may be used in the validation and assessment of the dynamics of microbubble-based contrast agents and, in the case of a small diameter tube phantom, for assessing imaging system spatial resolution/contrast performance. The materials and procedures required to address each of the phantoms are described.

  5. Obesity alters molecular and functional cardiac responses to ischemia/reperfusion and glucagon-like peptide-1 receptor agonism.

    PubMed

    Sassoon, Daniel J; Goodwill, Adam G; Noblet, Jillian N; Conteh, Abass M; Herring, B Paul; McClintick, Jeanette N; Tune, Johnathan D; Mather, Kieren J

    2016-07-01

    This study tested the hypothesis that obesity alters the cardiac response to ischemia/reperfusion and/or glucagon like peptide-1 (GLP-1) receptor activation, and that these differences are associated with alterations in the obese cardiac proteome and microRNA (miRNA) transcriptome. Ossabaw swine were fed normal chow or obesogenic diet for 6 months. Cardiac function was assessed at baseline, during a 30-minutes coronary occlusion, and during 2 hours of reperfusion in anesthetized swine treated with saline or exendin-4 for 24 hours. Cardiac biopsies were obtained from normal and ischemia/reperfusion territories. Fat-fed animals were heavier, and exhibited hyperinsulinemia, hyperglycemia, and hypertriglyceridemia. Plasma troponin-I concentration (index of myocardial injury) was increased following ischemia/reperfusion and decreased by exendin-4 treatment in both groups. Ischemia/reperfusion produced reductions in systolic pressure and stroke volume in lean swine. These indices were higher in obese hearts at baseline and relatively maintained throughout ischemia/reperfusion. Exendin-4 administration increased systolic pressure in lean swine but did not affect the blood pressure in obese swine. End-diastolic volume was reduced by exendin-4 following ischemia/reperfusion in obese swine. These divergent physiologic responses were associated with obesity-related differences in proteins related to myocardial structure/function (e.g. titin) and calcium handling (e.g. SERCA2a, histidine-rich Ca(2+) binding protein). Alterations in expression of cardiac miRs in obese hearts included miR-15, miR-27, miR-130, miR-181, and let-7. Taken together, these observations validate this discovery approach and reveal novel associations that suggest previously undiscovered mechanisms contributing to the effects of obesity on the heart and contributing to the actions of GLP-1 following ischemia/reperfusion.

  6. Preclinical renal chemo-protective potential of Prunus amygdalus Batsch seed coat via alteration of multiple molecular pathways.

    PubMed

    Pandey, Preeti; Bhatt, Prakash Chandra; Rahman, Mahfoozur; Patel, Dinesh Kumar; Anwar, Firoz; Al-Abbasi, Fahad; Verma, Amita; Kumar, Vikas

    2017-08-24

    Prunus amygdalus Batsch (almond) is a classical nutritive traditional Indian medicine. Along with nutritive with anti-oxidant properties, it is, clinically, used in the treatment of various diseases with underlying anti-oxidant mechanism. This study is an effort to scrutinise the renal protective effect of P. amygdalus Batsch or green almond (GA) seed coat extract and its underlying mechanism in animal model of Ferric nitrilotriacetate (Fe-NTA) induced renal cell carcinoma (RCC). RCC was induced in Swiss Albino Wistar rats by intraperitoneal injection of Fe-NTA. The rats were then treated with ethanolic extract of GA (25, 50 and 100 mg/kg per oral) for 22 weeks. Efficacy of GA administration was evaluated by change in biochemical, renal, macroscopical and histopathological parameters and alterations. Additionally, interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and inflammatory mediator including prostaglandin E2 (PGE2), nuclear factor-kappa B (NF-κB) were also observed to explore the possible mechanisms. The oral administration of GA significantly (p < .001) altered the Fe-NTA induced RCC in rats by inhibition of renal nodules, decolourisation of tissues, tumour promoter marker including thymidine (3)[H] incorporation, ornithine decarboxylase, renal parameters and anti-oxidant parameters in serum. Additionally, GA treatment significantly (p < .001) down-regulated the IL-6, IL-1β, TNF-α, inflammatory mediators PGE2 and NF-κB in a dose-dependent manner. Histopathology observation supported the renal protective effect of GA by alteration in necrosis, size of Bowman capsules and inflammatory cells. Hence, it can be concluded that GA possesses observable chemo-protective action and effect on Fe-NTA induced RCC via dual inhibition mechanism one by inhibiting free radical generation and second by inhibiting inflammation.

  7. Molecular basis of inherited antithrombin deficiency in Portuguese families: identification of genetic alterations and screening for additional thrombotic risk factors.

    PubMed

    David, Dezsö; Ribeiro, Sofia; Ferrão, Lénia; Gago, Teresa; Crespo, Francisco

    2004-06-01

    Antithrombin (AT), the most important coagulation serine proteases inhibitor, plays an important role in maintaining the hemostatic balance. Inherited AT deficiency, mainly characterized by predisposition to recurrent venous thromboembolism, is transmitted in an autosomal dominant manner. In this study, we analyzed the underlying genetic alterations in 12 unrelated Portuguese thrombophilic families with AT deficiency. At the same time, the modulating effect of the FV Leiden mutation, PT 20210A, PAI-1 4G, and MTHFR 677T allelic variants, on the thrombotic risk of AT deficient patients was also evaluated. Three novel frameshift alterations, a 4-bp deletion in exon 4 and two 1-bp insertions in exon 6, were identified in six unrelated type I AT deficient families. A novel missense mutation in exon 3a, which changes the highly conserved F147 residue, and a novel splice site mutation in the invariant acceptor AG dinucleotide of intron 2 were also identified in unrelated type I AT deficient families. In addition to these, two previously reported missense mutations changing the AT reactive site bond (R393-S394) and leading to type II-RS deficiency, and a previously reported cryptic splice site mutation (IVS4-14G-->A), were also identified. In these families, increased thrombotic risk associated with co-inheritance of the FV Leiden mutation and of the PAI-1 4G variant was also observed. In conclusion, we present the first data regarding the underlying genetic alterations in Portuguese thrombophilic families with AT deficiency, and confirm that the FV Leiden mutation and probably the PAI-1 4G variant represent additional thrombotic risk factors in these families.

  8. Characterization of ionic, dipolar and molecular mobility in polymer systems

    NASA Astrophysics Data System (ADS)

    Guo, Zhenrong

    Changes in the ionic and dipolar molecular mobility in a polymer system are the basis for the changes in the dielectric mechanical properties of polymer materials. Frequency Dependent Dielectric Measurements (FDEMS) and Ion Time-of-Flight (ITOF) are two important techniques to investigate ionic and dipolar molecular mobility in polymer systems. The results can be related to the macro- and molecular dielectric, electrical and dynamic properties of polymeric materials. The combination of these two methods provides a full view of electric, dielectric and dynamic behavior for the systems as they undergo chemical and/or physical changes during polymerization crystallization, vitrification, and/or phase separation. The research on microscopic mass mobility in polymer systems was done on three aspects: (1) ion mobility in an epoxy-amine reaction system; (2) dipolar mobility and relaxation during dimethacrylate resin cure and (3) dye molecule migration and diffusion in polymer films. In the ion mobility study, we separately monitor the changes in the ion mobility and the number of charge carriers during the epoxy-amine polymerization with FDEMS and ITOF measurements. The isolation of the number of carriers and their mobility allows significant improvement in monitoring changes in the state and structure of a material as it cures. For the dipolar mobility and relaxation study, FDEMS measurements were used to detect structural evolution and spatial heterogeneity formation during the polymerization process of dimethacrylate resins. The dielectric spectra, glass transition (Tg) profiles and dynamic mechanical measurements were used to investigate the existence of two cooperative regions of sufficient size to create two alpha-relaxation processes representing oligomer rich and polymer microgel regions during the polymerization. For the dye migration research, we tried to develop a visually color changing paper (VCP) due to dye molecule migration in polymer films. The mobility

  9. Hepatic Circadian-Clock System Altered by Insulin Resistance, Diabetes and Insulin Sensitizer in Mice

    PubMed Central

    Yang, Shih-Hsien; Shieh, Kun-Ruey

    2015-01-01

    Circadian rhythms are intrinsic rhythms that are coordinated with the rotation of the Earth and are also generated by a set of circadian-clock genes at the intracellular level. Growing evidence suggests a strong link between circadian rhythms and energy metabolism; however, the fundamental mechanisms remain unclear. In the present study, neonatal streptozotocin (STZ)-treated mice were used to model the molecular and physiological progress from insulin resistance to diabetes. Two-day-old male C57BL/6 mice received a single injection of STZ and were tested for non-obese, hyperglycemic and hyperinsulinemic conditions in the early stage, insulin resistance in the middle stage, and diabetes in the late stage. Gene expression levels of the hepatic circadian-clock system were examined by real-time quantitative PCR. Most of the components of the hepatic circadian-clock gene expression system, such as the mRNAs of Bmal1 (brain and muscle Arnt-like protein-1), Per2 (period 2) and Cry1 (cryptochrome 1), were elevated, and circadian patterns were retained in the early and middle stages of insulin-resistant conditions. The insulin sensitizer, rosiglitazone, returns the physiological and molecular changes associated with the diabetic phenotype to normal levels through peroxisome proliferator-activated receptor γ (PPARγ) rather than PPARα. Early and chronic treatment with rosiglitazone has been shown to be effective to counter the diabetic condition. Over time, this effect acts to attenuate the increased gene expression levels of the hepatic circadian-clock system and delay the severity of diabetic conditions. Together, these results support an essential role for the hepatic circadian-clock system in the coordinated regulation and/or response of metabolic pathways. PMID:25799429

  10. Hepatic circadian-clock system altered by insulin resistance, diabetes and insulin sensitizer in mice.

    PubMed

    Tseng, Huey-Ling; Yang, Shu-Chuan; Yang, Shih-Hsien; Shieh, Kun-Ruey

    2015-01-01

    Circadian rhythms are intrinsic rhythms that are coordinated with the rotation of the Earth and are also generated by a set of circadian-clock genes at the intracellular level. Growing evidence suggests a strong link between circadian rhythms and energy metabolism; however, the fundamental mechanisms remain unclear. In the present study, neonatal streptozotocin (STZ)-treated mice were used to model the molecular and physiological progress from insulin resistance to diabetes. Two-day-old male C57BL/6 mice received a single injection of STZ and were tested for non-obese, hyperglycemic and hyperinsulinemic conditions in the early stage, insulin resistance in the middle stage, and diabetes in the late stage. Gene expression levels of the hepatic circadian-clock system were examined by real-time quantitative PCR. Most of the components of the hepatic circadian-clock gene expression system, such