Experimental study of the isovector giant dipole resonance in 80Zr and 81Rb

NASA Astrophysics Data System (ADS)

Ceruti, S.; Camera, F.; Bracco, A.; Mentana, A.; Avigo, R.; Benzoni, G.; Blasi, N.; Bocchi, G.; Bottoni, S.; Brambilla, S.; Crespi, F. C. L.; Giaz, A.; Leoni, S.; Million, B.; Morales, A. I.; Nicolini, R.; Pellegri, L.; Riboldi, S.; Wieland, O.; Bazzacco, D.; Ciemala, M.; Farnea, E.; Gottardo, A.; Kmiecik, M.; Maj, A.; Mengoni, D.; Michelagnoli, C.; Modamio, V.; Montanari, D.; Napoli, D.; Recchia, F.; Sahin, E.; Ur, C.; Valiente-Dobón, J. J.; Wasilewska, B.; Zieblinski, M.

2017-01-01

The isovector giant dipole resonance (IVGDR) γ decay was measured in the compound nuclei 80Zr and 81Rb at an excitation energy of E*=54 MeV. The fusion reaction 40Ca+40Ca at Ebeam=136 MeV was used to form the compound nucleus 80Zr, while the reaction 37Cl+44Ca at Ebeam=95 MeV was used to form the compound nucleus 81Rb at the same excitation energy. The IVGDR parameters extracted from the analysis were compared with the ones found at higher excitation energy (E*=83 MeV). The comparison allows one to observe two different nuclear mechanisms: (i) the IVGDR intrinsic width remains constant with the excitation energy in the nucleus 81Rb; (ii) the isospin-violating spreading width (i.e., Coulomb spreading width) remains constant with the excitation energy in the nucleus 80Zr. The experimental setup used for the γ -ray detection was composed by the AGATA demonstrator array coupled to the large-volume LaBr3:Ce detectors of the HECTOR+ array.

Survival Mediated Heavy Element Capture Cross Sections

NASA Astrophysics Data System (ADS)

Loveland, Walter; Yao, Larry

2017-11-01

Formally, the cross section for producing a heavy evaporation residue, σEVR, in a fusion reaction can be written as where E is the center of mass energy, and T is the probability of the colliding nuclei to overcome the potential barrier in the entrance channel and reach the contact point. PCN is the probability that the projectile-target system will evolve from the contact point to the compound nucleus. Wsur is the probability that the compound nucleus will decay to produce an evaporation residue rather than fissioning. However, one must remember that the Wsur term effectively sets the allowed values of the spin, which in turn, restricts the values of the capture and fusion cross sections. We point out the implications of this fact for capture cross sections for heavy element formation reactions.

Quest for consistent modelling of statistical decay of the compound nucleus

NASA Astrophysics Data System (ADS)

Banerjee, Tathagata; Nath, S.; Pal, Santanu

2018-01-01

A statistical model description of heavy ion induced fusion-fission reactions is presented where shell effects, collective enhancement of level density, tilting away effect of compound nuclear spin and dissipation are included. It is shown that the inclusion of all these effects provides a consistent picture of fission where fission hindrance is required to explain the experimental values of both pre-scission neutron multiplicities and evaporation residue cross-sections in contrast to some of the earlier works where a fission hindrance is required for pre-scission neutrons but a fission enhancement for evaporation residue cross-sections.

Comparative study of sister chromatid exchange induction and antitumor effects by homo-aza-steroidal esters of [p-[bis(2-chloroethyl)amino]phenyl]butyric acid.

PubMed

Camoutsis, C; Catsoulacos, D; Karayiann, V; Papageorgiou, A; Mourelatos, D; Mioglou, E; Kritsi, Z; Nikolaropoulos, S

2001-01-01

The present work was undertaken in order to test the hypothesis that the Sister Chromatid Exchange (SCE) assay in vitro can be used for the prediction of in vivo tumor response to newly synthesized potential chemotherapeutics. The effect of three homo-aza-steroidal esters containing the -CONH- in the steroidal nucleus, 1, 2, and 3 on SCE rates and on cell kinetics in cultured human lymphocytes was studied. The antitumor activity of these compounds was tested on leukemia P388- and leukemia L1210-bearing mice. The three substances induced statistically significant enhancement of SCEs and of cell division delays. Compounds 1 and 3 were identified, on a molar basis, as more effective inducers of SCEs and of cell division delays compared with compound 2. Compounds 1 and 3 had upon both experimental tumors better therapeutic effects compared with compound 2 at equitoxic doses. Therefore, the order of the antitumor effectiveness of the three compounds coincided with the order of the cytogenetic effects they induced.

Probing the effect of neutron excess on the dynamics of Hf compound system

NASA Astrophysics Data System (ADS)

Sharma, Ishita; Kumar, Raj; Sharma, Manoj K.

2018-05-01

The reaction dynamics of 170Hf* and 174Hf* compound systems formed in 46,50Ti +124Sn reactions have been analyzed within the framework of Dynamical Cluster-decay Model (DCM) over an energy range of Ec.m.=115-156 MeV. The experimental data of fusion evaporation cross sections for 170,174Hf* systems is successfully addressed by optimizing the value of neck length ΔR. It is to be noted that calculations are performed by taking quadrupole deformations β2 with the optimum orientation of decaying fragments. Here, the effect of neutron excess has been examined on the structural properties of decaying fragments via fragmentation potential and preformation probability. The observation depicts that the isotopic effect prevails at fission region and as we move from lighter nucleus i.e. 170Hf* to heavier nucleus i.e. 174Hf*, the heavy mass fragments (HMF) start contributing along with fission fragments which are equally evident for 170Hf* as well. The ΔR values so obtained are compared at center of mass-energies which consequently provides information regarding the relative time scale of decaying fragments.

The therapeutic journey of benzimidazoles: a review.

PubMed

Bansal, Yogita; Silakari, Om

2012-11-01

Presence of benzimidazole nucleus in numerous categories of therapeutic agents such as antimicrobials, antivirals, antiparasites, anticancer, anti-inflammatory, antioxidants, proton pump inhibitors, antihypertensives, anticoagulants, immunomodulators, hormone modulators, CNS stimulants as well as depressants, lipid level modulators, antidiabetics, etc. has made it an indispensable anchor for development of new therapeutic agents. Varied substitutents around the benzimidazole nucleus have provided a wide spectrum of biological activities. Importance of this nucleus in some activities like, Angiotensin I (AT(1)) receptor antagonism and proton-pump inhibition is reviewed separately in literature. Even some very short reviews on biological importance of this nucleus are also known in literature. However, owing to fast development of new drugs possessing benzimidazole nucleus many research reports are generated in short span of time. So, there is a need to couple the latest information with the earlier information to understand the current status of benzimidazole nucleus in medicinal chemistry research. In the present review, various derivatives of benzimidazole with different pharmacological activities are described on the basis of substitution pattern around the nucleus with an aim to help medicinal chemists for developing an SAR on benzimidazole derived compounds for each activity. This discussion will further help in the development of novel benzimidazole compounds. Copyright © 2012 Elsevier Ltd. All rights reserved.

Informing neutron capture nucleosynthesis on short-lived nuclei with (d,p) reactions

NASA Astrophysics Data System (ADS)

Cizewski, Jolie A.; Ratkiewicz, Andrew; Escher, Jutta E.; Lepailleur, Alexandre; Pain, Steven D.; Potel, Gregory

2018-01-01

Neutron capture on unstable nuclei is important in understanding abundances in r-process nucleosynthesis. Previously, the non-elastic breakup of the deuteron in the (d,p) reaction has been shown to provide a neutron that can be captured by the nucleus and the gamma-ray decay of the subsequent compound nucleus can be modelled to predict the gamma-ray decay of the compound nucleus in the (n,γ) reaction. Preliminary results from the 95Mo(d,pγ) reaction in normal kinematics support the (d,pγ) reaction as a valid surrogate for neutron capture. The techniques to measure the (d,pγ) reaction in inverse kinematics have been developed.

Hoechst tagging: a modular strategy to design synthetic fluorescent probes for live-cell nucleus imaging.

PubMed

Nakamura, Akinobu; Takigawa, Kazumasa; Kurishita, Yasutaka; Kuwata, Keiko; Ishida, Manabu; Shimoda, Yasushi; Hamachi, Itaru; Tsukiji, Shinya

2014-06-11

We report a general strategy to create small-molecule fluorescent probes for the nucleus in living cells. Our strategy is based on the attachment of the DNA-binding Hoechst compound to a fluorophore of interest. Using this approach, simple fluorescein, BODIPY, and rhodamine dyes were readily converted to novel turn-on fluorescent nucleus-imaging probes.

Selective Inhibitor of Nuclear Export (SINE) Compounds Alter New World Alphavirus Capsid Localization and Reduce Viral Replication in Mammalian Cells.

PubMed

Lundberg, Lindsay; Pinkham, Chelsea; de la Fuente, Cynthia; Brahms, Ashwini; Shafagati, Nazly; Wagstaff, Kylie M; Jans, David A; Tamir, Sharon; Kehn-Hall, Kylene

2016-11-01

The capsid structural protein of the New World alphavirus, Venezuelan equine encephalitis virus (VEEV), interacts with the host nuclear transport proteins importin α/β1 and CRM1. Novel selective inhibitor of nuclear export (SINE) compounds, KPT-185, KPT-335 (verdinexor), and KPT-350, target the host's primary nuclear export protein, CRM1, in a manner similar to the archetypical inhibitor Leptomycin B. One major limitation of Leptomycin B is its irreversible binding to CRM1; which SINE compounds alleviate because they are slowly reversible. Chemically inhibiting CRM1 with these compounds enhanced capsid localization to the nucleus compared to the inactive compound KPT-301, as indicated by immunofluorescent confocal microscopy. Differences in extracellular versus intracellular viral RNA, as well as decreased capsid in cell free supernatants, indicated the inhibitors affected viral assembly, which led to a decrease in viral titers. The decrease in viral replication was confirmed using a luciferase-tagged virus and through plaque assays. SINE compounds had no effect on VEEV TC83_Cm, which encodes a mutated form of capsid that is unable to enter the nucleus. Serially passaging VEEV in the presence of KPT-185 resulted in mutations within the nuclear localization and nuclear export signals of capsid. Finally, SINE compound treatment also reduced the viral titers of the related eastern and western equine encephalitis viruses, suggesting that CRM1 maintains a common interaction with capsid proteins across the New World alphavirus genus.

Some actions of substituted choline phenyl ethers, particularly of choline 2:6-xylyl ether

PubMed Central

Edge, N. D.; Mason, D. F. J.; Wyllie, J. H.

1957-01-01

Marked nicotine-like stimulant properties are possessed by choline phenyl ether and choline o-tolyl ether, and to a decreasing extent by choline 2:6-xylyl ether and choline 2:4:6-mesityl ether. The compounds all show neuromuscular blocking properties, which are of short duration and pass from mainly decamethonium-like to mainly curare-like as more methyl groups are added to the phenyl nucleus. This series of compounds also possesses muscarinic, weak anti-adrenaline and vasodilator properties, as well as long-lasting local anaesthetic effects in the two compounds tested by intradermal injection. PMID:13460236

Influence of fusion dynamics on fission observables: A multidimensional analysis

NASA Astrophysics Data System (ADS)

Schmitt, C.; Mazurek, K.; Nadtochy, P. N.

2018-01-01

An attempt to unfold the respective influence of the fusion and fission stages on typical fission observables, and namely the neutron prescission multiplicity, is proposed. A four-dimensional dynamical stochastic Langevin model is used to calculate the decay by fission of excited compound nuclei produced in a wide set of heavy-ion collisions. The comparison of the results from such a calculation and experimental data is discussed, guided by predictions of the dynamical deterministic HICOL code for the compound-nucleus formation time. While the dependence of the latter on the entrance-channel properties can straigthforwardly explain some observations, a complex interplay between the various parameters of the reaction is found to occur in other cases. A multidimensional analysis of the respective role of these parameters, including entrance-channel asymmetry, bombarding energy, compound-nucleus fissility, angular momentum, and excitation energy, is proposed. It is shown that, depending on the size of the system, apparent inconsistencies may be deduced when projecting onto specific ordering parameters. The work suggests the possibility of delicate compensation effects in governing the measured fission observables, thereby highlighting the necessity of a multidimensional discussion.

Intra-nucleus accumbens shell injections of R(+)- and S(-)-baclofen bidirectionally alter binge-like ethanol, but not saccharin, intake in C57Bl/6J mice

PubMed Central

Kasten, Chelsea R.; Boehm, Stephen L.

2014-01-01

The GABAB agonist baclofen has been widely researched clinically and preclinically as a treatment of alcohol use disorders (AUDs). However, the efficacy of baclofen remains uncertain. The clinically used racemic compound can be separated into separate enantiomers. These enantiomers have produced different profiles in behavioral assays, with the S- compound often being ineffective compared to the R- compound, or the S- compound antagonizing the effects of the R- compound. We have previously demonstrated that the R(+)-baclofen enantiomer decreases binge-like ethanol intake in the Drinking-in-the-Dark (DID) paradigm, whereas the S(-)-baclofen enantiomer increases ethanol intake. One area implicated in drug abuse is the nucleus accumbens shell (NACsh).The current study sought to define the role of the NACsh in the enantioselective effects of baclofen on binge-like ethanol consumption by directly microinjecting each enantiomer into the structure. Following bilateral cannulation of the NACsh, C57Bl/6J mice were given 5 days of access to ethanol or saccharin for 2 hours, 3 hours into the dark cycle. On Day 5 mice were given an injection of aCSF, 0.02 R(+)-, 0.04R(+)-, 0.08 S(-)-, or 0.16 S(-)-baclofen (μg/side dissolved in 200nl of aCSF). It was found that the R(+)-baclofen dose-dependently decreased ethanol consumption, whereas the high S(-)-baclofen dose increased ethanol consumption, compared to the aCSF group. Saccharin consumption was not affected. These results further confirm that GABAB receptors and the NACsh shell are integral in mediating ethanol intake. They also demonstrate that baclofen displays bidirectional, enantioselective effects which are important when considering therapeutic uses of the drug. PMID:25026094

Intra-nucleus accumbens shell injections of R(+)- and S(-)-baclofen bidirectionally alter binge-like ethanol, but not saccharin, intake in C57Bl/6J mice.

PubMed

Kasten, Chelsea R; Boehm, Stephen L

2014-10-01

The GABAB agonist baclofen has been widely researched clinically and preclinically as a treatment of alcohol use disorders (AUDs). However, the efficacy of baclofen remains uncertain. The clinically used racemic compound can be separated into separate enantiomers. These enantiomers have produced different profiles in behavioral assays, with the S- compound often being ineffective compared to the R- compound, or the S- compound antagonizing the effects of the R- compound. We have previously demonstrated that the R(+)-baclofen enantiomer decreases binge-like ethanol intake in the Drinking-in-the-Dark (DID) paradigm, whereas the S(-)-baclofen enantiomer increases ethanol intake. One area implicated in drug abuse is the nucleus accumbens shell (NACsh).The current study sought to define the role of the NACsh in the enantioselective effects of baclofen on binge-like ethanol consumption by directly microinjecting each enantiomer into the structure. Following bilateral cannulation of the NACsh, C57Bl/6J mice were given 5 days of access to ethanol or saccharin for 2h, 3h into the dark cycle. On Day 5 mice were given an injection of aCSF, 0.02 R(+)-, 0.04R(+)-, 0.08 S(-)-, or 0.16 S(-)-baclofen (μg/side dissolved in 200nl of aCSF). It was found that the R(+)-baclofen dose-dependently decreased ethanol consumption, whereas the high S(-)-baclofen dose increased ethanol consumption, compared to the aCSF group. Saccharin consumption was not affected. These results further confirm that GABAB receptors and the NACsh shell are integral in mediating ethanol intake. They also demonstrate that baclofen displays bidirectional, enantioselective effects which are important when considering therapeutic uses of the drug. Copyright © 2014 Elsevier B.V. All rights reserved.

Gentiopicroside attenuates morphine rewarding effect through downregulation of GluN2B receptors in nucleus accumbens.

PubMed

Liu, Shui-Bing; Ma, Lan; Guo, Hong-Ju; Feng, Bin; Guo, Yan-Yan; Li, Xiao-Qiang; Sun, Wen-Ji; Zheng, Lian-He; Zhao, Ming-Gao

2012-08-01

Gentiopicroside (Gent) is one of the secoiridoid compound isolated from Gentiana lutea. This compound exhibits analgesic activities and inhibits the expression of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the anterior cingulate cortex in mice. Nucleus accumbens (NAc) is a forebrain structure known for its role in drug addiction. However, little is known about the role of Gent on morphine dependence and synaptic transmission changes in the NAc. Conditioned place preference (CPP) test and behavioral sensitization of locomotor activity were used to investigate drug-seeking related behaviors. Brain slices containing NAc were prepared, and whole-cell patch-clamp recordings were performed to record the excitatory postsynaptic currents (EPSCs). Expression of proteins was detected by Western blot analysis. Systemic administration of Gent attenuated the CPP effect induced by morphine, but had no effect on morphine-induced behavioral sensitization. Gent significantly reversed overexpression of GluN2B-containing NMDA receptors and dopamine D2 receptors in NAc during the first week of morphine withdrawal. However, the compound did not affect the overexpression of GluN2A-containing NMDA receptors, GluA1, and dopamine D1 receptors. Lastly, Gent significantly reduced NMDA receptors-mediated EPSCs in the NAc. Our study provides strong evidence that Gent inhibits morphine dependence through downregulation of GluN2B-containing NMDA receptors in the NAc. © 2012 Blackwell Publishing Ltd.

Spin differences in the Zr 90 compound nucleus induced by ( p , p ' ) , ( p , d ) , and ( p , t ) surrogate reactions

DOE PAGES

Ota, S.; Burke, J. T.; Casperson, R. J.; ...

2015-11-04

Here, the effect of the production mechanism on the decay of a compound nucleus is investigated. The nucleus 90Zr was produced by three different reactions, namely 90Zr (p,p') 90Zr, 91Zr (p,d) 90Zr, and 92Zr (p,t) 90Zr , which served as surrogate reactions for 89Zr (n,γ). The spin-parity (J π) distributions of the states populated by these reactions were studied to investigate the surrogate reaction approach, which aims at indirectly determining cross sections for compound-nuclear reactions involving unstable targets such as 89Zr. Discrete γ rays, associated with transitions in 90Zr and 89Zr, were measured in coincidence with light ions for scatteringmore » angles of 25°–60° and 90Zr excitation energies extending above the neutron separation energy. The measured transition systematics were used to gain insights into the J π distributions of 90Zr. The 90Zr (p,p') reaction was found to produce fewer γ rays associated with transitions involving high spin states (J = 6–8 ℏ) than the other two reactions, suggesting that inelastic scattering preferentially populates states in 90Zr that have lower spins than those populated in the transfer reactions investigated. The γ-ray production was also observed to vary by factors of 2–3 with the angle at which the outgoing particle was detected. These findings are relevant to the application of the surrogate reaction approach.« less

Competition between the compound and the pre-compound emission processes in α-induced reactions at near astrophysical energy to well above it

NASA Astrophysics Data System (ADS)

Sharma, Manoj Kumar; Sharma, Vijay Raj; Yadav, Abhiskek; Singh, Pushpendra P.; Singh, B. P.; Prasad, R.

2016-04-01

The study of pre-compound emission in α-induced reactions, particularly at the low incident energies, is of considerable interest as the pre-compound emission is more likely to occur at higher energies. With a view to study the competition between the compound and the pre-compound emission processes in α-induced reactions at different energies and with different targets, a systematics for neutron emission channels in targets 51V, 55Mn, 93Nb, 121, 123Sb and 141Pr at energy ranging from astrophysical interest to well above it, has been developed. The off-line γ-ray-spectrometry based activation technique has been adopted to measure the excitation functions. The experimental excitation functions have been analysed within the framework of the compound nucleus mechanism based on the Weisskopf-Ewing model and the pre-compound emission calculations based on the geometry dependent hybrid model. The analysis of the data shows that experimental excitation functions could be reproduced only when the pre-compound emission, simulated theoretically, is taken into account. The strength of pre-compound emission process for each system has been obtained by deducing the pre-compound fraction. Analysis of data indicates that in α-induced reactions, the pre-compound emission process plays an important role, particularly at the low incident energies, where the pure compound nucleus process is likely to dominate.

Real causes of apparent abnormal results in heavy ion reactions

NASA Astrophysics Data System (ADS)

Mandaglio, G.; Nasirov, A. K.; Anastasi, A.; Curciarello, F.; De Leo, V.; Fazio, G.; Giardina, G.

2015-06-01

We study the effect of the static characteristics of nuclei and dynamics of the nucleus-nucleus interaction in the capture stage of reaction, in the competition between quasifission and complete fusion processes, as well as the angular momentum dependence of the competition between fission and evaporation processes along the de-excitation cascade of the compound nucleus. The results calculated for the mass-asymmetric and less mass-asymmetric reactions in the entrance channel are analyzed in order to investigate the role of the dynamical effects on the yields of the evaporation residue nuclei. We also discuss about uncertainties at the extraction of such relevant physical quantities as Γn/Γtot ratio or also excitation functions from the experimental results due to the not always realistic assumptions in the treatment and analysis of the detected events. This procedure can lead to large ambiguity when the complete fusion process is strongly hindered or when the fast fission contribution is large. We emphasize that a refined multiparameter model of the reaction dynamics as well as a more detailed and checked data analysis are strongly needed in heavy-ion collisions.

Reactivity of lignin with different composition of aromatic syringyl/guaiacyl structures and erythro/threo side chain structures in β-O-4 type during alkaline delignification: as a basis for the different degradability of hardwood and softwood lignin.

PubMed

Shimizu, Satoko; Yokoyama, Tomoya; Akiyama, Takuya; Matsumoto, Yuji

2012-07-04

The reactivity of lignin during alkaline delignification was quantitatively investigated focusing on the effect of the structural differences between syringyl and guaiacyl aromatic nuclei and between erythro and threo in the side chain of β-O-4 type lignin substructure on the β-O-4 bond cleavage rate. It was known that the ratio of this reaction rate of the erythro to threo isomers of the dimeric β-O-4 type lignin model compound with two guaiacyl aromatic nuclei was ca. 4. However, the presence of a syringyl nucleus strongly influenced the rate, and the ratio of the syringyl type analogue was in the range between 2.7 and 8.0 depending on the reaction temperature. The effect of syringyl nucleus on the enhancement of the reaction rate appeared to be greater when the syringyl nucleus consists of the cleaving ether bond rather than being a member of the carbon framework.

High-throughput docking for the identification of new influenza A virus polymerase inhibitors targeting the PA-PB1 protein-protein interaction.

PubMed

Tintori, Cristina; Laurenzana, Ilaria; Fallacara, Anna Lucia; Kessler, Ulrich; Pilger, Beatrice; Stergiou, Lilli; Botta, Maurizio

2014-01-01

A high-throughput molecular docking approach was successfully applied for the selection of potential inhibitors of the Influenza RNA-polymerase which act by targeting the PA-PB1 protein-protein interaction. Commercially available compounds were purchased and biologically evaluated in vitro using an ELISA-based assay. As a result, some compounds possessing a 3-cyano-4,6-diphenyl-pyridine nucleus emerged as effective inhibitors with the best ones showing IC50 values in the micromolar range. Copyright © 2013 Elsevier Ltd. All rights reserved.

Comparison of new nitrosoureas esters with modified steroidal nucleus for cytogenetic and antineoplastic activity.

PubMed

Hussein, A; Mioglou-Kalouptsi, E; Papageorgiou, A; Karapidaki, I; Iakovidou-Kritsi, Z; Lialiaris, T; Xrysogelou, E; Camoutsis, C; Mourelatos, D

2007-01-01

Nitrosourea is decomposed under physiological conditions to react with biological macromolecules by two mechanisms: alkylation (with proteins and nucleic acids) and carbamoylation (with proteins but not nucleic acids). It has been suggested that the alkylating action is responsible for the therapeutic effects of nitrosoureas, and that the carbamoylation activity leads to toxicity effects. In order to reduce systemic toxicity and improve specificity and distribution for cancer therapy, 2-haloethyl nitrosourea has been esterified with modified steroids, which are used as biological platforms for transporting the alkylating agent to the tumor site in a specific manner. The cytogenetic and antineoplastic effect were studied of seven newly synthesized esters of N,N-bis(2-chloroethyl)alanyl carboxyl derivatives with a modified steroidal nucleus (compounds 1-7). As a very sensitive indicator of genotoxicity the Sister Chromatid Exchange (SCE) assay was used and as a valuable marker of cytostatic activity the cell Proliferation Rate Index (PRI) in cultures of normal human lymphocytes was used. The order of magnitude of the cytogenetic activity on a molar basis (15, 30, 120 microM) of the compounds was 7>6>3>5>2>4>1. The most active compound 7 has an enlarged (seven carbon atoms) A ring modified with a lactam group (-NHCO-) with the nitrosourea moiety esterified at position 17 In the group of seven substances a correlation was observed between the magnitude of SCE response and the depression in PRI (r=-O, 65, p<0.001). According to the criterion of activity of National Cancer Institute (NCI), the order of antineoplastic activity of compounds on lymphoid L1210 leukemia is 7>6>2>5>4>3>1 and on lympocytic P388 leukemia cells is 7>2>6>5>4>3>1. The present results are in agreement with previous suggestions that the effectiveness in cytogenetic activity may well be correlated with antitumor effects [T/C: 248% for the compound 7 in 250 mg/kg b.w.; T/C: mean survival time of drug-treated animals (T) (excluding long term survivals) vs. corn-oil-treated controls (C)].

Breit interaction effects in relativistic theory of the nuclear spin-rotation tensor.

PubMed

Aucar, I Agustín; Gómez, Sergio S; Giribet, Claudia G; Ruiz de Azúa, Martín C

2013-09-07

In this work, relativistic effects on the nuclear spin-rotation (SR) tensor originated in the electron-nucleus and electron-electron Breit interactions are analysed. To this end, four-component numerical calculations were carried out in model systems HX (X=H,F,Cl,Br,I). The electron-nucleus Breit interaction couples the electrons and nuclei dynamics giving rise to a purely relativistic contribution to the SR tensor. Its leading order in 1/c is of the same value as that of relativistic corrections on the usual second order expression of the SR tensor considered in previous work [I. A. Aucar, S. S. Gómez, J. I. Melo, C. G. Giribet, and M. C. Ruiz de Azúa, J. Chem. Phys. 138, 134107 (2013)], and therefore it is absolutely necessary to establish its relative importance. For the sake of completeness, the corresponding effect originating in the electron-electron Breit interaction is also considered. It is verified that in all cases these Breit interactions yield only very small corrections to the SR tensors of both the X and H nuclei in the present series of compounds. Results of the present work strongly suggest that in order to achieve experimental accuracy in the theoretical study of the SR tensor both electron-nucleus and electron-electron Breit effects can be safely neglected.

Distribution of Off-Diagonal Cross Sections in Quantum Chaotic Scattering: Exact Results and Data Comparison.

PubMed

Kumar, Santosh; Dietz, Barbara; Guhr, Thomas; Richter, Achim

2017-12-15

The recently derived distributions for the scattering-matrix elements in quantum chaotic systems are not accessible in the majority of experiments, whereas the cross sections are. We analytically compute distributions for the off-diagonal cross sections in the Heidelberg approach, which is applicable to a wide range of quantum chaotic systems. Thus, eventually, we fully solve a problem that already arose more than half a century ago in compound-nucleus scattering. We compare our results with data from microwave and compound-nucleus experiments, particularly addressing the transition from isolated resonances towards the Ericson regime of strongly overlapping ones.

Distribution of Off-Diagonal Cross Sections in Quantum Chaotic Scattering: Exact Results and Data Comparison

NASA Astrophysics Data System (ADS)

Kumar, Santosh; Dietz, Barbara; Guhr, Thomas; Richter, Achim

2017-12-01

The recently derived distributions for the scattering-matrix elements in quantum chaotic systems are not accessible in the majority of experiments, whereas the cross sections are. We analytically compute distributions for the off-diagonal cross sections in the Heidelberg approach, which is applicable to a wide range of quantum chaotic systems. Thus, eventually, we fully solve a problem that already arose more than half a century ago in compound-nucleus scattering. We compare our results with data from microwave and compound-nucleus experiments, particularly addressing the transition from isolated resonances towards the Ericson regime of strongly overlapping ones.

Mass spectral analysis of long chain alkyl aromatic compounds synthesized from alpha-olefin alkylation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cheng, M.T.; Hudson, J.D.

1994-12-31

Long chain alkyl aromatic compounds are important petrochemicals with many applications. They are generally synthesized by alkylating the corresponding aromatic nucleus. In this report, the authors will describe the mass spectral fragmentation of alkylphenols and alkylsalicylates.

Discovery of novel 4-anilinoquinazoline derivatives as potent inhibitors of epidermal growth factor receptor with antitumor activity.

PubMed

Xu, Yun-Yun; Li, Si-Ning; Yu, Gao-Jian; Hu, Qing-Hua; Li, Huan-Qiu

2013-10-01

Two new series of new compounds containing a 6-amino-substituted group or 6-acrylamide-substituted group linked to a 4-anilinoquinazoline nucleus have been discovered as potential EGFR inhibitors. These compounds proved efficient effects on antiproliferative activity and EGFR-TK inhibitory activity. Especially, N(6)-((5-bromothiophen-2-yl)methyl)-N(4)-(3-chlorophenyl)quinazoline-4,6-diamine (5e), showed the most potent inhibitory activity (IC50=3.11μM for Hep G2, IC50=0.82μM for A549). The EGFR molecular docking model suggested that the new compound is nicely bound to the region of EGFR, and cell morphology by Hoechst stain experiment suggested that these compounds efficiently induced apoptosis of A549 cells. Copyright © 2013 Elsevier Ltd. All rights reserved.

Abuse-Related Neurochemical Effects of Para-Substituted Methcathinone Analogs in Rats: Microdialysis Studies of Nucleus Accumbens Dopamine and Serotonin

PubMed Central

Suyama, Julie A.; Sakloth, Farhana; Kolanos, Renata; Glennon, Richard A.; Lazenka, Matthew F.; Negus, S. Stevens

2016-01-01

Methcathinone (MCAT) is a monoamine releaser and parent compound to a new class of designer drugs that includes the synthetic cathinones mephedrone and flephedrone. Using MCAT and a series of para-substituted (or 4-substituted) MCAT analogs, it has been previously shown that expression of abuse-related behavioral effects in rats correlates both with the volume of the para substituent and in vitro neurochemical selectivity to promote monoamine release via the dopamine (DA) versus serotonin (5-HT) transporters in rat brain synaptosomes. The present study used in vivo microdialysis to determine the relationship between these previous measures and the in vivo neurochemical selectivity of these compounds to alter nucleus accumbens (NAc) DA and 5-HT levels. Male Sprague-Dawley rats were implanted with bilateral guide cannulae targeting the NAc. MCAT and five para-substituted analogs (4-F, 4-Cl, 4-Br, 4-CH3, and 4-OCH3) produced dose- and time-dependent increases in NAc DA and/or 5-HT levels. Selectivity was determined as the dose required to increase peak 5-HT levels by 250% divided by the dose required to increase peak DA levels by 250%. This measure of in vivo neurochemical selectivity varied across compounds and correlated with 1) in vivo expression of abuse-related behavioral effects (r = 0.89, P = 0.02); 2) in vitro selectivity to promote monoamine release via DA and 5-HT transporters (r = 0.95, P < 0.01); and 3) molecular volume of the para substituent (r = −0.85, P = 0.03). These results support a relationship between these molecular, neurochemical, and behavioral measures and support a role for molecular structure as a determinant of abuse-related neurochemical and behavioral effects of MCAT analogs. PMID:26645638

The administration of endocannabinoid uptake inhibitors OMDM-2 or VDM-11 promotes sleep and decreases extracellular levels of dopamine in rats.

PubMed

Murillo-Rodríguez, Eric; Palomero-Rivero, Marcela; Millán-Aldaco, Diana; Di Marzo, Vincenzo

2013-01-17

The family of the endocannabinoid system comprises endogenous lipids (such as anandamide [ANA]), receptors (CB(1)/CB(2) cannabinoid receptors), metabolic enzymes (fatty acid amide hydrolase [FAAH]) and a putative membrane transporter (anandamide membrane transporter [AMT]). Although the role of ANA, FAAH or the CB(1) cannabinoid receptor in sleep modulation has been reported, the effects of the inhibition of AMT on sleep remain unclear. In the present study, we show that microdialysis perfusion in rats of AMT inhibitors, (9Z)-N-[1-((R)-4-hydroxbenzyl)-2-hydroxyethyl]-9-octadecenamide (OMDM-2) or N-(4-hydroxy-2-methylphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (VDM-11; 10, 20 or 30 μM; each compound) delivered into the paraventricular thalamic nucleus (PVA) increased sleep and decreased waking. In addition, the infusion of compounds reduced the extracellular levels of dopamine collected from nucleus accumbens. Taken together, these findings illustrate a critical role of AMT in sleep modulation. Copyright © 2012 Elsevier Inc. All rights reserved.

Total and Compound Formation Cross Sections for Americium Nuclei: Recommendations for Coupled-Channels Calculations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Escher, J. E.

Calculations for total cross sections and compound-nucleus (CN) formation cross sections for americium isotopes are described, for use in the 2017 NA-22 evaluation effort. The code ECIS 2006 was used in conjunction with Frank Dietrich's wrapper `runtemplate'.

New quasibound states of the compound nucleus in α -particle capture by the nucleus

NASA Astrophysics Data System (ADS)

Maydanyuk, Sergei P.; Zhang, Peng-Ming; Zou, Li-Ping

2017-07-01

We generalize the theory of nuclear decay and capture of Gamow that is based on tunneling through the barrier and internal oscillations inside the nucleus. In our formalism an additional factor is obtained, which describes distribution of the wave function of the the α particle inside the nuclear region. We discover new most stable states (called quasibound states) of the compound nucleus (CN) formed during the capture of α particle by the nucleus. With a simple example, we explain why these states cannot appear in traditional calculations of the α capture cross sections based on monotonic penetrabilities of a barrier, but they appear in a complete description of the evolution of the CN. Our result is obtained by a complete description of the CN evolution, which has the advantages of (1) a clear picture of the formation of the CN and its disintegration, (2) a detailed quantum description of the CN, (3) tests of the calculated amplitudes based on quantum mechanics (not realized in other approaches), and (4) high accuracy of calculations (not achieved in other approaches). These peculiarities are shown with the capture reaction of α +44Ca . We predict quasibound energy levels and determine fusion probabilities for this reaction. The difference between our approach and theory of quasistationary states with complex energies applied for the α capture is also discussed. We show (1) that theory does not provide calculations for the cross section of α capture (according to modern models of the α capture), in contrast with our formalism, and (2) these two approaches describe different states of the α capture (for the same α -nucleus potential).

Electron Spin Resonance (ESR) studies of returned comet nucleus samples

NASA Technical Reports Server (NTRS)

Tsay, Fun-Dow; Kim, Soon Sam; Liang, Ranty H.

1989-01-01

The most important objective of the Comet Nucleus Sample Returm Mission is to return samples which could reflect formation conditions and evolutionary processes in the early solar nebula. It is expected that the returned samples will consist of fine-grained silicate materials mixed with ices composed of simple molecules such as H2O, NH3, CH4 as well as organics and/or more complex compounds. Because of the exposure to ionizing radiation from cosmic-ray, gamma-ray, and solar wind protons at low temperature, free radicals are expected to be formed and trapped in the solid ice matrices. The kind of trapped radical species together with their concentration and thermal stability can be used as a dosimeter as well as a geothermometer to determine thermal and radiation histories as well as outgassing and other possible alternation effects since the nucleus material was formed. Since free radicals that are known to contain unpaired electrons are all paramagnetic in nature, they can be readily detected and characterized in their native form by the Electron Spin Resonance (ESR) method. In fact, ESR has been shown to be a non-destructive, highly sensitive tool for the detection and characterization of paramagnetic, ferromagnetic, and radiation damage centers in terrestrial and extraterrestrial geological samples. The potential use of ESR as an effective method in the study of returned comet nucleus samples, in particular, in the analysis of fine-grained solid state icy samples is discussed.

Sedative Effect of Sophora flavescens and Matrine

PubMed Central

Lee, Hyun-ju; Lee, Sun-young; Jang, Daehyuk; Chung, Sun-Yong; Shim, Insop

2017-01-01

The present study investigated the sedative effects of Sophora flavescens (SF) and its bioactive compound, matrine through performing locomotor activity test and the electroencephalography (EEG) analysis in the rat. The underlying neural mechanism of their beneficial effects was determined by assessing c-Fos immunoreactivity and serotonin (5-HT) in the brain utilizing immunohistochemical method and enzyme-linked immunosorbent assay. The results showed that SF and matrine administration had an effect on normalization of caffeine-induced hyperactivity and promoting a shift toward non-rapid eye movement (NREM) sleep. c-Fos-immunoreactivity and 5-HT level in the ventrolateral preoptic nucleus (VLPO), a sleep promoting region, were increased in the both SF and matrine-injected groups. In conclusion, SF and its bioactive compound, matrine alleviated caffeine-induced hyperactivity and promoted NREM sleep by activating VLPO neurons and modulating serotonergic transmission. It is suggested that SF might be a useful natural alternatives for hypnotic medicine. PMID:28190318

Sedative Effect of Sophora flavescens and Matrine.

PubMed

Lee, Hyun-Ju; Lee, Sun-Young; Jang, Daehyuk; Chung, Sun-Yong; Shim, Insop

2017-07-01

The present study investigated the sedative effects of Sophora flavescens (SF) and its bioactive compound, matrine through performing locomotor activity test and the electroencephalography (EEG) analysis in the rat. The underlying neural mechanism of their beneficial effects was determined by assessing c-Fos immunoreactivity and serotonin (5-HT) in the brain utilizing immunohistochemical method and enzyme-linked immunosorbent assay. The results showed that SF and matrine administration had an effect on normalization of caffeine-induced hyperactivity and promoting a shift toward non-rapid eye movement (NREM) sleep. c-Fos-immunoreactivity and 5-HT level in the ventrolateral preoptic nucleus (VLPO), a sleep promoting region, were increased in the both SF and matrine-injected groups. In conclusion, SF and its bioactive compound, matrine alleviated caffeine-induced hyperactivity and promoted NREM sleep by activating VLPO neurons and modulating serotonergic transmission. It is suggested that SF might be a useful natural alternatives for hypnotic medicine.

Cytotoxicity of three new triazolo-pyrimidine derivatives against the plant trypanosomatid: Phytomonas sp. isolated from Euphorbia characias.

PubMed

Magán, Rosa; Marín, Clotilde; Salas, Juan M; Barrera-Pérez, Mario; Rosales, Maria J; Sánchez-Moreno, Manuel

2004-10-01

There is no effective chemotherapy against diseases caused by Phytomonas sp., a plant trypanosomatid responsible for economic losses in major crops. We tested three triazolo-pyrimidine complexes [two with Pt(II), and another with Ru(III)] against promastigotes of Phytomonas sp. isolated from Euphorbia characias. The incorporation of radiolabelled precursors, ultrastructural alterations and changes in the pattern of metabolite excretion were examined. Different degrees of toxicity were found for each complex: the platinum compound showed an inhibition effect on nucleic acid synthesis, provoking alterations on the levels of mitochondria, nucleus and glycosomes. These results, together with others reported previously in our laboratory about the activity of pyrimidine derivatives, reflect the potential of these compounds as agents in the treatment of Phytomonas sp.

Pharmacological studies upon neurones of the lateral geniculate nucleus of the cat

PubMed Central

Curtis, D. R.; Davis, R.

1962-01-01

Indoles related to 5-hydroxytryptamine, lysergic acid derivatives, phenethylamine derivatives and some other compounds have been applied electrophoretically to the neurones of the lateral geniculate nucleus of the cat anaesthetized with pentobarbitone sodium. Many of these compounds, particularly 4-, 5- and 7-hydroxytryptamine and ergometrine, depress the orthodromic excitation of the neurones by volleys in optic nerve fibres, but do not affect antidromic excitation by volleys in the optic radiation or chemical excitation by L-glutamic acid. It is concluded that the active depressants either block the access of the excitatory transmitter to subsynaptic receptors or prevent the release of the transmitter from optic nerve terminals. The structure-activity relationships of the depressant substances are discussed. PMID:13882768

5Beta,6beta-epoxy-17-oxoandrostan-3beta-yl acetate and 5beta,6beta-epoxy-20-oxopregnan-3beta-yl acetate.

PubMed

Pinto, Rui M A; Salvador, Jorge A R; Paixão, José A

2008-05-01

In the title compounds, C(21)H(30)O(4), (I), and C(23)H(34)O(4), (II), respectively, which are valuable intermediates in the synthesis of important steroid derivatives, rings A and B are cis-(5beta,10beta)-fused. The two molecules have similar conformations of rings A, B and C. The presence of the 5beta,6beta-epoxide group induces a significant twist of the steroid nucleus and a strong flattening of the B ring. The different C17 substituents result in different conformations for ring D. Cohesion of the molecular packing is achieved in both compounds only by weak intermolecular interactions. The geometries of the molecules in the crystalline environment are compared with those of the free molecules as given by ab initio Roothan Hartree-Fock calculations. We show in this work that quantum mechanical ab initio methods reproduce well the details of the conformation of these molecules, including a large twist of the steroid nucleus. The calculated twist values are comparable, but are larger than the observed values, indicating a possible small effect of the crystal packing on the twist angles.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ryabov, E.G.; Adeev, G.D.

A macroscopic temperature-dependent model that takes into account nuclear forces of finite range is used to calculate the static and statistical properties of hot rotating compound nuclei. The level-density parameter is approximated by an expression of the leptodermous type. The resulting expansion coefficients are in good agreement with their counterparts proposed previously by A.V. Ignatyuk and his colleagues. The effect of taking simultaneously into account the temperature of a nucleus and its angular momentum on the quantities under study, such as the heights and positions of fission barriers and the effective moments of inertia of nuclei at the barrier, ismore » considered, and the importance of doing this is demonstrated. The fissility parameter (Z{sup 2}/A){sub crit} and the position of the Businaro-Gallone point are studied versus temperature. It is found that, with increasing temperature, both parameters are shifted to the region of lighter nuclei. It is shown that the inclusion of temperature leads to qualitatively the same effects as the inclusion of the angular momentum of a nucleus, but, quantitatively, thermal excitation leads to smaller effects than rotational excitation.« less

ANABOLIC ANDROGENIC STEROID ABUSE: MULTIPLE MECHANISMS OF REGULATION OF GABAERGIC SYNAPSES IN NEUROENDOCRINE CONTROL REGIONS OF THE RODENT FOREBRAIN

PubMed Central

Oberlander, Joseph G.; Porter, Donna M.; Penatti, Carlos A. A.; Henderson, Leslie P.

2011-01-01

Anabolic-androgenic steroids (AAS) are synthetic derivatives of testosterone originally developed for clinical purposes, but now predominantly taken at suprapharmacological levels as drugs of abuse. To date, nearly 100 different AAS compounds that vary in metabolic fate and physiological effects have been designed and synthesised. While administered for their ability to enhance muscle mass and performance, untoward side effects of AAS use include changes in reproductive and sexual behaviours. Specifically, AAS, depending on the type of compound administered, can delay or advance pubertal onset, lead to irregular oestrous cyclicity, diminished male and female sexual behaviours, and accelerate reproductive senescence. Numerous brains regions and neurotransmitter signalling systems are involved in the generation of these behaviours, and are potential targets for both chronic and acute actions of the AAS. However critical to all of these behaviours is neurotransmission mediated by GABAA receptors within a nexus of interconnected forebrain regions that includes the medial preoptic area (mPOA), the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus of the hypothalamus. Here we review how exposure to AAS alters GABAergic transmission and neural activity within these forebrain regions, taking advantage of in vitro systems and both wild-type and genetically altered mouse strains, in order to better understand how these synthetic steroids affect the neural systems that underlie the regulation of reproduction and the expression of sexual behaviours. PMID:21554430

Arousal effect of caffeine depends on adenosine A2A receptors in the shell of the nucleus accumbens

PubMed Central

Lazarus, Michael; Shen, Hai-Ying; Cherasse, Yoan; Qu, Wei-Min; Huang, Zhi-Li; Bass, Caroline E.; Winsky-Sommerer, Raphaelle; Semba, Kazue; Fredholm, Bertil B.; Boison, Detlev; Hayaishi, Osamu; Urade, Yoshihiro; Chen, Jiang-Fan

2011-01-01

Caffeine, the most widely used psychoactive compound, is an adenosine receptor antagonist. It promotes wakefulness by blocking adenosine A2A receptors (A2ARs) in the brain, but the specific neurons on which caffeine acts to produce arousal have not been identified. Using selective gene deletion strategies based on the Cre/loxP technology in mice and focal RNA interference to silence the expression of A2ARs in rats by local infection with adeno-associated virus carrying short-hairpin RNA, we report that the A2ARs in the shell region of the nucleus accumbens (NAc) are responsible for the effect of caffeine on wakefulness. Caffeine-induced arousal was not affected in rats when A2ARs were focally removed from the NAc core or other A2AR-positive areas of the basal ganglia. Our observations suggest that caffeine promotes arousal by activating pathways that traditionally have been associated with motivational and motor responses in the brain. PMID:21734299

Effect of branched-chain fatty acids, 3-methylindole and 4-methylphenol on consumer sensory scores of grilled lamb meat.

PubMed

Watkins, P J; Kearney, G; Rose, G; Allen, D; Ball, A J; Pethick, D W; Warner, R D

2014-02-01

Tenderness, flavour, overall liking and odour are important components of sheepmeat eating quality. Consumer assessment of these attributes has been made for carcasses from the Information Nucleus Flock (INF) of the Cooperative Research Centre for Sheep Industry Innovation. The concentrations of three branched chain fatty acids, 4-methyloctanoic (MOA), 4-ethyloctanoic (EOA) and 4-methylnonanoic acids (compounds related to 'mutton flavour' in cooked sheepmeat) and 3-methylindole and 4-methylphenol (compounds related to 'pastoral' flavour) were determined for 178 fat samples taken from INF carcasses. Statistical modelling revealed that both MOA and EOA impacted on the 'Like Smell' consumer sensory score of the cooked meat product (P<0.05), with increasing concentration causing lower consumer acceptance of the product. None of the compounds though had an effect on the liking of flavour. Obviously, reducing the effect of MOA and EOA on the odour of grilled lamb will improve consumer acceptance of the cooked product but other factors affecting the eating quality also need to be considered. Copyright © 2012 The Authors. Published by Elsevier Ltd.. All rights reserved.

Integer ratios of S{sub n}/E{sub n} in {sup 40}Ca+n resonances suggesting two-oscillator excitations in the target nucleus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ohkubo, Makio

2009-08-15

In s-wave neutron resonances of {sup 40}Ca at E{sub n}{<=}2.5 MeV, S{sub n}/E{sub n} for many levels is found to be of the form 17(n/m) where n, m are small integers. Statistical tests show small probabilities for the observed dispositions of many levels at E{sub n}=(j/k)(1/70)G (j, k; small integers). To meet the requirement of time periodicity of the compound nucleus at resonance, a breathing model is developed, where the excitation energies E{sub x} are written as a sum of inverse integers; E{sub x}=S{sub n}+E{sub n}=G{sigma}(1/k) (k: integer). In {sup 40}Ca+n, the separation energy S{sub n}=8362 keV is written asmore » S{sub n}=(17/70)G=(1/7+1/10)G, where G=34.4 MeV. G is almost equal to the Fermi energy of the nucleus. It is suggested that two oscillators of energy (1/7)G and (1/10)G are excited in {sup 40}Ca by neutron incidence, in which the recurrence energy (1/70)G is resonant with neutrons of energies at (j/k)(1/70)G, forming a simple compound nucleus.« less

High doses of S-methylcysteine cause hypoxia-induced cardiomyocyte apoptosis accompanied by engulfment of mitochondaria by nucleus.

PubMed

El-Magd, Mohammed A; Abdo, Walied S; El-Maddaway, Mustafa; Nasr, Nasr M; Gaber, Rasha A; El-Shetry, Eman S; Saleh, Ayman A; Alzahrani, Faisal Abdulrahman Ali; Abdelhady, Doaa H

2017-10-01

Despite its important role as a medicinal plant, some studies reported a toxic effect for garlic (Allium sativum) when given in higher doses. Herein, we investigated the possible cardiotoxic effects of high doses of S-methylcysteine (SMC), a water soluble organosulfur compound present in garlic. Rats were orally administered SMC at a low dose (50mg), high dose (150mg) and very high dose (300mg)/kg body weight, or saline (control) for 10days. High and very high doses of SMC resulted in a significant increase in serum cardiac injury biomarkers [aspartate transaminase (AST), lactate dehydrogenase (LDH), creatine kinase (CK) and cardiac troponin T (cTnT)], as well as oxidative stress marker nitric oxide (NO) concentration in heart and a significant decrease in cardiac superoxide dismutase (SOD) activity. Moreover, ultrastructure findings in myocardium of rats treated by high and very high doses showed inter-bundle vacuolation, loss of myofibrils, and centripetal movement of mitochondria towards nucleus. The mitochondria were partially surrounded by nuclear membrane at high dose SMC, and completely engulfed by nucleus at very high dose. This centripetal movement of mitochondria accompanied by cardiomyocytes hypoxia-induced apoptosis as evident by increasing TUNEL positive cells as well as upregulation of apoptotic genes (caspase3 and Bax), hypoxia inducible factor 1 alpha (HIF1α), dynein light chain 1 (DYNLL1) and downregulation of the anti-apoptotic marker, Bcl2. We conclude that high and very high doses of SMC cause hypoxia induced cardiomyocyte apoptosis accompanied by engulfment of mitochondria by nucleus. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Coalescence Effects on Neutron Production in High Energy Nucleus-Nucleus Collisions

DTIC Science & Technology

2001-08-01

25/Jun/2001 THESIS 1 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER COALESCENCE EFFECTS ON NEUTRON PRODUCTION IN HIGH- ENERGY NUCLEUS-NUCLEUS COLLISIONS 5b... Energy Nucleus-Nucleus Collisions." I have examined the final copy of this thesis for form and content and recommend that it be accepted in partial...School COALESCENCE EFFECTS ON NEUTRON PRODUCTION IN HIGH ENERGY NUCLEUS-NUCLEUS COLLISIONS A Thesis Presented for the Master of Science Degree The

Chemical Genetics of 14-3-3 Regulation and Role in Tumor Development

DTIC Science & Technology

2005-11-01

inhibitors , our group had identified a series of inhibitory compounds. When tested one of these, TK10, shows an inhibitory effect on 14-3-3 sigma nuclear...potential regulators of 14-3-3 sigma function. 5 BODY Determine the biological activity of the newly identified inhibitor of 14-3- &T nuclear export TKI0 I...have previously shown that an inhibitor of FOXOla nuclear export, TK10, inhibits the export of 14- 3-3 from the nucleus while TK10 does not affect

Compound-nuclear Reactions with Unstable Isotopes: Constraining Capture Cross Sections with Indirect Data and Theory

NASA Astrophysics Data System (ADS)

Escher, Jutta

2016-09-01

Cross sections for compound-nuclear reactions involving unstable targets are important for many applications, but can often not be measured directly. Several indirect methods have recently been proposed to determine neutron capture cross sections for unstable isotopes. These methods aim at constraining statistical calculations of capture cross sections with data obtained from the decay of the compound nucleus relevant to the desired reaction. Each method produces this compound nucleus in a different manner (via a light-ion reaction, a photon-induced reaction, or β decay) and requires additional ingredients to yield the sought-after cross section. This contribution focuses on the process of determining capture cross sections from inelastic scattering and transfer experiments. Specifically, theoretical descriptions of the (p,d) transfer reaction have been developed to complement recent measurements in the Zr-Y region. The procedure for obtaining constraints for unknown capture cross sections is illustrated. The main advantages and challenges of this approach are compared to those of the proposed alternatives. This work is performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344.

The role of nucleus accumbens shell in learning about neutral versus excitatory stimuli during Pavlovian fear conditioning.

PubMed

Bradfield, Laura A; McNally, Gavan P

2010-07-01

We studied the role of nucleus accumbens shell (AcbSh) in Pavlovian fear conditioning. Rats were trained to fear conditioned stimulus A (CSA) in Stage I, which was then presented in compound with a neutral stimulus and paired with shock in Stage II. AcbSh lesions had no effect on fear-learning to CSA in Stage I, but selectively prevented learning about the neutral conditioned stimulus (CS) in Stage II. These results add to a growing body of evidence indicating an important role for the ventral striatum in fear-learning. They suggest that the ventral striatum and AcbSh, in particular, directs learning toward or away from a CS as a consequence of how well that CS predicts the shock unconditioned stimulus (US). AcbSh is required to reduce the processing of established predictors, thereby permitting neutral or less predictive stimuli to be learned about.

Chemical Carcinogen (Hydrazine et al.) Induced Carcinogenesis of Human Diploid Cells in Vitro

DTIC Science & Technology

1982-09-07

analyzed by HPLC it was found to be the parent non-oxygenated BP. The complex for transporting the BP in the nucleus following movement of the PNH from...pyrene may not require metabolic O activation of the parent polynuclear hydrocarbon at the plasma membrane level, * (Tejwani et al., Molecular...its transport into the nucleus as the parent compound. When the LP and HP cells were treated with BP for 24 h and the DNA was isolated and

Formation of the 50-Year Element 94 from Deuteron Bombardment of U{sup 238}

DOE R&D Accomplishments Database

Kennedy, J. W.; Perlman, M. L.; Segre, E.; Wahl, A. C.

1942-06-01

It has been shown by bombardment with deuterons of a sample of U{sup 238}, greatly depleted in U{sup 235} and U{sup 234}, that the 50-year 94 activity and 2.0 day 93 activity are formed in approximately the same yield as with the natural mixture of uranium isotopes. The activities are thus shown to arise from the U{sup 238} nucleus, and from considerations of the energy of the compound nucleus (U{sup 238} + d).

Neuroanatomical distribution of oxytocin and vasopressin 1a receptors in the socially monogamous coppery titi monkey (Callicebus cupreus)

PubMed Central

Freeman, Sara M.; Walum, Hasse; Inoue, Kiyoshi; Smith, Aaron L.; Goodman, Mark M.; Bales, Karen L.; Young, Larry J.

2014-01-01

The coppery titi monkey (Callicebus cupreus) is a socially monogamous New World primate that has been studied in the field and the laboratory to investigate the behavioral neuroendocrinology of primate pair bonding and parental care. Arginine vasopressin has been shown to influence male titi monkey pair-bonding behavior, and studies are currently underway to examine the effects of oxytocin on titi monkey behavior and physiology. Here, we use receptor autoradiography to identify the distribution of arginine vasopressin 1a (AVPR1a) and oxytocin receptors (OXTR) in hemispheres of titi monkey brain (n=5). AVPR1a are diffuse and widespread throughout the brain, but the OXTR distribution is much more limited, with the densest binding being in the hippocampal formation (dentate gyrus, CA1 field) and the presubiculum (layers I and III). Moderate OXTR binding was detected in the nucleus basalis of Meynert, pulvinar, superior colliculus, layer 4C of primary visual cortex, periaqueductal gray, pontine gray, nucleus prepositus, and spinal trigeminal nucleus. OXTR mRNA overlapped with OXTR radioligand binding, confirming that the radioligand was detecting OXTR protein. AVPR1a binding is present throughout the cortex, especially in cingulate, insular, and occipital cortices, as well as in the caudate, putamen, nucleus accumbens, central amygdala, endopiriform nucleus, hippocampus (CA4 field), globus pallidus, lateral geniculate nucleus, infundibulum, habenula, periaqueductal gray, substantia nigra, olivary nucleus, hypoglossal nucleus, and cerebellum. Furthermore, we show that, in titi monkey brain, the OXTR antagonist ALS-II-69 is highly selective for OXTR and that the AVPR1a antagonist SR49059 is highly selective for AVPR1a. Based on these results and the fact that both ALS-II-69 and SR49059 are non-peptide, small-molecule antagonists that should be capable of crossing the blood brain barrier, these two compounds emerge as excellent candidates for the pharmacological manipulation of OXTR and AVPR1a in future behavioral experiments in titi monkeys and other primate species. PMID:24814726

Nuclear Poincaré cycle synchronizes with the incident de Broglie wave to predict regularity in neutron resonance energies

NASA Astrophysics Data System (ADS)

Ohkubo, Makio

2016-06-01

In observed neutron resonances, long believed to be a form of quantum chaos, regular family structures are found in the s-wave resonances of many even-even nuclei in the tens keV to MeV region [M.Ohkubo, Phys. Rev. C 87, 014608(2013)]. Resonance reactions take place when the incident de Broglie wave synchronizes with the Poincaré cycle of the compound nucleus, which is composed of several normal modes with periods that are time quantized by inverse Fermi energy. Based on the breathing model of the compound nucleus, neutron resonance energies in family structures are written by simple arithmetic expressions using Sn and small integers. Family structures in observed resonances of 40Ca+n and 37Cl+n are described as simple cases. A model for time quantization is discussed.

Synthesis, Structural Characterization and Antinociceptive Activities of New Arylated Quinolines via Suzuki-Miyaura Cross Coupling Reaction.

PubMed

Ullah, Malik A; Adeel, Muhammad; Tahir, Muhammad N; Rauf, Abdur; Akram, Muhammad; Hadda, Taibi B; Mabkhot, Yahia N; Muhammad, Naveed; Naseer, Fehmida; Mubarak, Mohammad S

2017-01-01

The quinoline ring system is one of the most commonly encountered heterocycles in medicinal chemistry, due to the pharmaceutical and medicinal uses of derivatives containing this ring. These quinoline-based compounds have remarkable biological activity, as they are employed as antimalarial, antibacterial, antifungal, and antitumor agents. The quinoline nucleus can be synthesized by various traditional methods such as the Skraup reaction, Friedlaender synthesis, Combes quinoline synthesis, Larock quinoline synthesis, among others. The aim of the present work is to synthesize a number of new arylated quninolines having significant antinoceciptive effect through the Suzuki-Miyaura cross coupling reaction using 3- bromoquinoline as a starting material. A number of new quinoline derivatives have been synthesized. Structures of the newly synthesized compounds were confirmed by means of IR, NMR, and mass spectrometry, and by elemental analysis. In addition, the molecular structures of two representative derivatives were determined with the aid of X-ray crystallography. Additionally, the antinociceptive activity of the prepared compounds was evaluated in vivo; results revealed that most of the tested compounds exhibited a dosedependent antinociceptive effect. Prepared compounds were found to exhibit significant antinociceptive activities and could be used as potential analgesic agents. Further work, however, may be required to establish the safety and efficacy of these compounds. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Sequential character of low-energy ternary and quaternary nuclear fission

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kadmensky, S. G., E-mail: kadmensky@phys.vsu.ru; Bulychev, A. O.

2016-09-15

An analysis of low-energy true ternary (quaternary) nuclear fission leads to the conclusion that these fission modes have a sequential two-step (three-step) character such that the emission of a third particle (third and fourth particles) and the separation of fission fragments occur at distinctly different instants, in contrast to the simultaneous emergence of all fission products in the case of onestep ternary (quaternary) fission. This conclusion relies on the following arguments. First, the emission of a third particle (third and fourth particles) from a fissile nucleus is due to a nonevaporative mechanism associated with a nonadiabatic character of the collectivemore » deformation motion of this nucleus at the stages preceding its scission. Second, the axial symmetry of the deformed fissile compound nucleus and the direction of its symmetry axis both remain unchanged at all stages of ternary (quaternary) fission. This circumstancemakes it possible to explain themechanism of the appearance of observed anisotropies and T — odd asymmeries in the angular distributions of products of ternary (quaternary) nuclear fission. Third, the T —odd asymmetry discovered experimentally in ternary nuclear fission induced by cold polarized neutrons obeys the T —invariance condition only in the case of a sequential two-step (three-step) character of true ternary (quaternary) nuclear fission. At the same time, this asymmetry is not a T —invariant quantity in the case of the simultaneous emission of products of true ternary (quaternary) nuclear fission from the fissile compound nucleus.« less

Benzimidazole--ibuprofen/mesalamine conjugates: potential candidates for multifactorial diseases.

PubMed

Bansal, Yogita; Kaur, Maninder; Silakari, Om

2015-01-07

Ibuprofen (IB) and mesalamine (MES) are commonly used NSAIDs whereas benzimidazole (BZ) and 2-aminobenzimidazole (ABZ) are important pharmacophore for immunomodulatory activities. In the present study, IB and MES were coupled with variedly substituted BZ or ABZ nucleus to synthesize IB-BZ (2a-2e), IB-ABZ (3a-3e), MES-BZ (4a-4e) and MES-ABZ (5a-5e) chimeric conjugates as novel compounds that could elicit both anti-inflammatory and immunomodulatory activities. Each compound retained the anti-inflammatory activity of the parent NSAID. The BZ conjugates (2 and 4) were found immunostimulatory whereas the ABZ conjugates (3 and 5) were immunosuppressive. Each compound also exhibited good antioxidant activity, which is attributed to the electron rich BZ and ABZ nuclei. Compound 2a, 2e, 3a, 3e and 5b exhibited the most significant anti-inflammatory and immunomodulatory activities. Hence, these were evaluated for in vivo acute gastric ulcerogenicity. The compounds were safe to gastric mucosa, probably due to masking of the free -COOH group of IB and MES, and/or to the BZ nucleus itself. A benzoyl group at 5-position of BZ and ABZ incurred maximum immunostimulatory activity. In contrast, a -NO2 group incurred the maximum immunosuppressive action. Docking analysis revealed the compounds to be more selective towards COX-2 enzyme, which support the gastroprotective activity. These results suggest that the compounds can be taken as lead for development of new drugs for the treatment of immune related inflammatory disorders, such as cancer and rheumatoid arthritis. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Molecular descriptors calculation as a tool in the analysis of the antileishmanial activity achieved by two series of diselenide derivatives. An insight into its potential action mechanism.

PubMed

Font, María; Baquedano, Ylenia; Plano, Daniel; Moreno, Esther; Espuelas, Socorro; Sanmartín, Carmen; Palop, Juan Antonio

2015-07-01

A molecular modeling study has been carried out on two previously reported series of symmetric diselenide derivatives that show remarkable antileishmanial in vitro activity against Leishmania infantum intracellular amastigotes and in infected macrophages (THP-1 cells), in addition to showing favorable selectivity indices. Series 1 consists of compounds that can be considered as central scaffold constructed with a diaryl/dialkylaryl diselenide central nucleus, decorated with different substituents located on the aryl rings. Series 2 consists of compounds constructed over a diaryl diselenide central nucleus, decorated in 4 and 4' positions with an aryl or heteroaryl sulfonamide fragment, thus forming the diselenosulfonamide derivatives. With regard to the diselenosulfonamide derivatives (2 series), the activity can be related, as a first approximation, with (a) the ability to release bis(4-aminophenyl) diselenide, the common fragment which can be ultimately responsible for the activity of the compounds. (b) the anti-parasitic activity achieved by the sulfonamide pharmacophore present in the analyzed derivatives. The data that support this connection include the topography of the molecules, the conformational behavior of the compounds, which influences the bond order, as well as the accessibility of the hydrolysis point, and possibly the hydrophobicity and polarizability of the compounds. Copyright © 2015 Elsevier Inc. All rights reserved.

Identification of novel indole based heterocycles as selective estrogen receptor modulator.

PubMed

Singla, Ramit; Prakash, Kunal; Bihari Gupta, Kunj; Upadhyay, Shishir; Dhiman, Monisha; Jaitak, Vikas

2018-04-24

In the present study, we have designed and synthesized indole derivatives by coalescing the indole nucleus with chromene carbonitrile and dihydropyridine nucleus. Two compounds 5c and 6d were selected from series I and II after sequential combinatorial library generation, docking, absorption, distribution, metabolism and excretion (ADME) filtering, anti-proliferative activity, cytotoxicity, and ER-α competitor assay kit by utilizing estrogen receptor-α (ER-α) dominant T47D BC cells line and PBMCs (Peripheral Blood Mononuclear Cells). Cell imaging experiment suggested that both the compounds successfully cross cellular biomembrane and accumulate in nuclear, cytoplasmic and plasma membrane region. Semiquantitative RT-PCR and Western blotting experiments further supported that both compounds reduced the expression of mRNA and receptor protein of ER-α, thereby preventing downstream transactivation and signaling pathway in T47D cells line. Current findings imply that 5c and 6d represent novel ER-α antagonists and may be used in the development of chemotherapy for the management of BC. Copyright © 2018 Elsevier Inc. All rights reserved.

Estradiol regulates responsiveness of the dorsal premammillary nucleus of the hypothalamus and affects fear- and anxiety-like behaviors in female rats.

PubMed

Litvin, Yoav; Cataldo, Giuseppe; Pfaff, Donald W; Kow, Lee-Ming

2014-07-01

Research suggests a causal link between estrogens and mood. Here, we began by examining the effects of estradiol (E2 ) on rat innate and conditioned defensive behaviors in response to cat odor. Second, we utilized whole-cell patch clamp electrophysiological techniques to assess noradrenergic effects on neurons within the dorsal premammillary nucleus of the hypothalamus (PMd), a nucleus implicated in fear reactivity, and their regulation by E2 . Our results show that E2 increased general arousal and modified innate defensive reactivity to cat odor. When ovariectomized females treated with E2 as opposed to oil were exposed to cat odor, they showed elevations in risk assessment and reductions in freezing, indicating a shift from passive to active coping. In addition, animals previously exposed to cat odor showed clear cue + context conditioning 24 h later. However, although E2 persisted in its effects on general arousal in the conditioning task, its effects on fear disappeared. In the patch clamp experiments noradrenergic compounds that typically induce fear clearly excited PMd neurons, producing depolarizations and action potentials. E2 treatment shifted some excitatory effects of noradrenergic agonists to inhibitory, possibly by differentially affecting α- and β-adrenoreceptors. In summary, our results implicate E2 in general arousal and fear reactivity, and suggest these may be governed by changes in noradrenergic responsivity in the PMd. These effects of E2 may have ethological relevance, serving to promote mate seeking even in contexts of ambiguous threat and shed light on the involvement of estrogen in mood and its associated disorders. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Interaction Between New Anti-cancer Drug Syndros and CNT(6,6-6) Nanotube for Medical Applications: Geometry Optimization, Molecular Structure, Spectroscopic (NMR, UV/Vis, Excited state), FMO, MEP and HOMO-LUMO Investigation

NASA Astrophysics Data System (ADS)

Sheikhi, Masoome; Shahab, Siyamak; Khaleghian, Mehrnoosh; Kumar, Rakesh

2018-03-01

In the present work, Density Functional Theory (DFT) was first time employed to investigate the interaction between new drug (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol (Syndros) and the CNT(6,6-6) Nanotube in the gaseous phase. The interaction effects of compounds Syndros and CNT (6,6-6) nanotube on the electronic properties, chemical shift tensors and natural charge was also determined and discussed. The electronic spectra of the Syndros and the complex CNT(6,6-6)/Syndros in the gas phase were calculated by Time Dependent Density Functional Theory (TD-DFT) for the formation of adsorption effect on maximum wavelength of the Syndros. Nucleus-Independent Chemical Shifts (NICS) calculations have also been carried out for the compound Syndors and the complex CNT(6,6-6)/Syndros and the aromaticity of the compound Syndors before and after interaction with the CNT(6,6-6) Nanotube was investigated.

Photoproduction of lepton pairs in proton-nucleus and nucleus-nucleus collisions at RHIC and LHC energies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moreira, B. D.; Goncalves, V. P.; De Santana Amaral, J. T.

2013-03-25

In this contribution we study coherent interactions as a probe of the nonlinear effects in the Quantum Electrodynamics (QED). In particular, we study the multiphoton effects in the production of leptons pairs for proton-nucleus and nucleus-nucleus collisions for heavy nuclei. In the proton-nucleus we assume the ultrarelativistic proton as a source of photons and estimate the photoproduction of lepton pairs on nuclei at RHIC and LHC energies considering the multiphoton effects associated to multiple rescattering of the projectile photon on the proton of the nucleus. In nucleus - nucleus colllisions we consider the two nuclei as a source of photons.more » As each scattering contributes with a factor {alpha}Z to the cross section, this contribution must be taken into account for heavy nuclei. We consider the Coulomb corrections to calculate themultiple scatterings and estimate the total cross section for muon and tau pair production in proton-nucleus and nucleus-nucleus collisions at RHIC and LHC energies.« less

[Dynamic variation of components in exocarp of Juglans mandshurica with browning based on UPLC-Q-TOF/MS].

PubMed

Sun, Guo-Dong; Huo, Jin-Hai; Xie, Rong-Juan; Wang, Wei-Ming

2017-08-01

To analyze the dynamic changes in components in exocarp of Juglans mandshurica at different browning periods. Twenty-six batches of exocarp of J. mandshurica samples from thirteen browning periods were assessed by UPLC-Q-TOF-MS/MS. The formula of different compounds were determined by accurate mass and isotopic abundance ratio from target screening function of Peakview 2.0/masterview1.0 software. Then their structures were determined by analysis of MS/MS fragment or comparison with standard substances and references. The contents of chemical components were changed significantly in different browning periods and twenty five compounds were identified or inferred. Of the 13 naphthoquinone compounds, the contents of 6 compounds with similar parent nucleus as juglone and 3 naphthoquinone glycosides compounds were decreased significantly, and 4 naphthoquinone derivatives such as regiolone were produced; the contents of four flavones and two phenolic acids compounds were decreased significantly; and the contents of 6 diarylheptanoids compounds were increased significantly. UPLC-Q-TOF/MS method can be used to identify and analyze the chemical constituents from exocarp of J. mandshurica rapidly and accurately, and analyze the rules of dynamic changes, to reveal the browning of Chinese medicinal materials and its effects on compositions of fruits and vegetables. Copyright© by the Chinese Pharmaceutical Association.

Insights into the nature of cometary organic matter from terrestrial analogues

NASA Astrophysics Data System (ADS)

Court, Richard W.; Sephton, Mark A.

2012-04-01

The nature of cometary organic matter is of great interest to investigations involving the formation and distribution of organic matter relevant to the origin of life. We have used pyrolysis-Fourier transform infrared (FTIR) spectroscopy to investigate the chemical effects of the irradiation of naturally occurring bitumens, and to relate their products of pyrolysis to their parent assemblages. The information acquired has then been applied to the complex organic matter present in cometary nuclei and comae. Amalgamating the FTIR data presented here with data from published studies enables the inference of other comprehensive trends within hydrocarbon mixtures as they are progressively irradiated in a cometary environment, namely the polymerization of lower molecular weight compounds; an increased abundance of polycyclic aromatic hydrocarbon structures; enrichment in 13C; reduction in atomic H/C ratio; elevation of atomic O/C ratio and increase in the temperature required for thermal degradation. The dark carbonaceous surface of a cometary nucleus will display extreme levels of these features, relative to the nucleus interior, while material in the coma will reflect the degree of irradiation experienced by its source location in the nucleus. Cometary comae with high methane/water ratios indicate a nucleus enriched in methane, favouring the formation of complex organic matter via radiation-induced polymerization of simple precursors. In contrast, production of complex organic matter is hindered in a nucleus possessing a low methane/water ration, with the complex organic matter that does form possessing more oxygen-containing species, such as alcohol, carbonyl and carboxylic acid functional groups, resulting from reactions with hydroxyl radicals formed by the radiolysis of the more abundant water. These insights into the properties of complex cometary organic matter should be of particular interest to both remote observation and space missions involving in situ analyses and sample return of cometary materials.

Effects of Serotonin 2C Receptor Agonists on the Behavioral and Neurochemical Effects of Cocaine in Squirrel Monkeys

PubMed Central

Manvich, Daniel F.; Kimmel, Heather L.

2012-01-01

Accumulating evidence indicates that the serotonin system modulates the behavioral and neurochemical effects of cocaine, but the receptor subtypes mediating these effects remain unknown. Recent studies have demonstrated that pharmacological activation of the serotonin 2C receptor (5-HT2CR) attenuates the behavioral and neurochemical effects of cocaine in rodents, but such compounds have not been systematically evaluated in nonhuman primates. The present experiments sought to determine the impact of pretreatment with the preferential 5-HT2CR agonist m-chlorophenylpiperazine (mCPP) and the selective 5-HT2CR agonist Ro 60-0175 [(α-S)-6-chloro-5-fluoro-α-methyl-1H-indole-1-ethanamine fumarate] on the behavioral and neurochemical effects of cocaine in squirrel monkeys. In subjects trained to lever-press according to a 300-s fixed-interval schedule of stimulus termination, pretreatment with either 5-HT2CR agonist dose-dependently and insurmountably attenuated the behavioral stimulant effects of cocaine. In subjects trained to self-administer cocaine, both compounds dose-dependently and insurmountably attenuated cocaine-induced reinstatement of previously extinguished responding in an antagonist-reversible manner, and the selective agonist Ro 60-0175 also attenuated the reinforcing effects of cocaine during ongoing cocaine self-administration. It is noteworthy that the selective agonist Ro 60-0175 exhibited behavioral specificity because it did not significantly alter nondrug-maintained responding. Finally, in vivo microdialysis studies revealed that pretreatment with Ro 60-0175 caused a reduction of cocaine-induced dopamine increases within the nucleus accumbens, but not the caudate nucleus. These results suggest that 5-HT2CR agonists functionally antagonize the behavioral effects of cocaine in nonhuman primates, possibly via a selective modulation of cocaine-induced dopamine increases within the mesolimbic dopamine system and may therefore represent a novel class of pharmacotherapeutics for the treatment of cocaine abuse. PMID:22328576

Influence of Li₂Sb Additions on Microstructure and Mechanical Properties of Al-20Mg₂Si Alloy.

PubMed

Yu, Hong-Chen; Wang, Hui-Yuan; Chen, Lei; Zha, Min; Wang, Cheng; Li, Chao; Jiang, Qi-Chuan

2016-03-29

It is found that Li₂Sb compound can act as the nucleus of primary Mg₂Si during solidification, by which the particle size of primary Mg₂Si decreased from ~300 to ~15-25 μm. Owing to the synergistic effect of the Li₂Sb nucleus and adsorption-poisoning of Li atoms, the effect of complex modification of Li-Sb on primary Mg₂Si was better than that of single modification of Li or Sb. When Li-Sb content increased from 0 to 0.2 and further to 0.5 wt.%, coarse dendrite changed to defective truncated octahedron and finally to perfect truncated octahedral shape. With the addition of Li and Sb, ultimate compression strength (UCS) of Al-20Mg₂Si alloys increased from ~283 to ~341 MPa and the yield strength (YS) at 0.2% offset increased from ~112 to ~179 MPa while almost no change was seen in the uniform elongation. Our study offers a simple method to control the morphology and size of primary Mg₂Si, which will inspire developing new Al-Mg-Si alloys with improved mechanical properties.

Counting the peaks in the excitation function for precompound processes

NASA Astrophysics Data System (ADS)

Bonetti, R.; Hussein, M. S.; Mello, P. A.

1983-08-01

The "counting of maxima" method of Brink and Stephen, conventionally used for the extraction of the correlation width of statistical (compound nucleus) reactions, is generalized to include precompound processes as well. It is found that this method supplies an important independent check of the results obtained from autocorrelation studies. An application is made to the reaction 25Mg(3He,p). NUCLEAR REACTIONS Statistical multistep compound processes discussed.

Chromium oxidation state mapping in human cells

NASA Astrophysics Data System (ADS)

Ortega, R.; Fayard, B.; Salomé, M.; Devès, G.; Susini, J.

2003-03-01

The widespread use of chromium in industrial applications such as chemical production of pigments, refractory brick production, tanning, metallurgy, electroplating, and combustion of fuels has lead to human occupational exposure and to its increased introduction into the environment. Hexavalent chromium compounds are established carcinogens but their mechanism of cell transformation is not known. Up to now, no microanalytical technique was sensitive enough to allow the observation of chromium distribution, and oxidation state identification, within isolated cells at carcinogenic concentrations. In this experiment, we used successfully the ID-21 X-ray microscope to map Cr(VI) and total Cr distributions in cells exposed in vitro to soluble, and insoluble, Cr(VI) compounds. Exposure to soluble compounds, weak carcinogens, resulted in a homogeneous intracellular distribution of Cr, confirming by in situ measurement that Cr is present in the cell nucleus. Cr(VI) was never detected in cells which suggests a mechanism of rapid intracellular reducticn. On the other hand, exposure to insoluble compounds, strong carcinogens, also resulted in a homogeneous distribution of reduced forms of Cr in cells, and their nucleus. However, in this case, Cr(VI)-rich structures were observed into the cells suggesting that carcinogenicity is enhanced when oxidation reactions due to Cr(VI) chronic exposure are associated to Cr-DNA alterations.

Dual targeting and retrograde translocation: regulators of plant nuclear gene expression can be sequestered by plastids.

PubMed

Krause, Kirsten; Oetke, Svenja; Krupinska, Karin

2012-01-01

Changes in the developmental or metabolic state of plastids can trigger profound changes in the transcript profiles of nuclear genes. Many nuclear transcription factors were shown to be controlled by signals generated in the organelles. In addition to the many different compounds for which an involvement in retrograde signaling is discussed, accumulating evidence suggests a role for proteins in plastid-to-nucleus communication. These proteins might be sequestered in the plastids before they act as transcriptional regulators in the nucleus. Indeed, several proteins exhibiting a dual localization in the plastids and the nucleus are promising candidates for such a direct signal transduction involving regulatory protein storage in the plastids. Among such proteins, the nuclear transcription factor WHIRLY1 stands out as being the only protein for which an export from plastids and translocation to the nucleus has been experimentally demonstrated. Other proteins, however, strongly support the notion that this pathway might be more common than currently believed.

Specificity of the Antibody Receptor Site to D-Lysergamide: Model of a Physiological Receptor for Lysergic Acid Diethylamide

PubMed Central

Vunakis, Helen Van; Farrow, John T.; Gjika, Hilda B.; Levine, Lawrence

1971-01-01

Antibodies to D-lysergic acid have been produced in rabbits and guinea pigs and a radioimmunoassay for the hapten was developed. The specificity of this lysergamide-antilysergamide reaction was determined by competitive binding with unlabeled lysergic acid diethylamide (LSD), psychotomimetic drugs, neurotransmitters, and other compounds with diverse structures. LSD and several related ergot alkaloids were potent competitors, three to seven times more potent than lysergic acid itself. The N,N-dimethyl derivatives of several compounds, including tryptamine, 5-hydroxytryptamine, 4-hydroxytryptamine, 5-methoxytryptamine, tyramine, and mescaline, were only about ten times less effective than lysergic acid, even though these compounds lack some of the ring systems of lysergic acid. The pattern of inhibition by related compounds with various substituents suggests that the antibody receptor site recognizes structural features resembling the LSD molecule. In particular, the aromatic nucleus and the dimethylated ethylamine side chain in phenylethylamine and tryptamine derivatives may assume in solution a conformation resembling ring A and the methylated nitrogen in ring C of LSD. Among the tryptamine derivatives, a large percentage of the most potent competitors are also psychotomimetic compounds. PMID:5283939

Evaluation of the Protective Effects of Sarains on H2O2-Induced Mitochondrial Dysfunction and Oxidative Stress in SH-SY5Y Neuroblastoma Cells.

PubMed

Alvariño, Rebeca; Alonso, Eva; Tribalat, Marie-Aude; Gegunde, Sandra; Thomas, Olivier P; Botana, Luis M

2017-10-01

Sarains are diamide alkaloids isolated from the Mediterranean sponge Haliclona (Rhizoniera) sarai that have previously shown antibacterial, insecticidal and anti-fouling activities. In this study, we examined for the first time the neuroprotective effects of sarains 1, 2 and A against oxidative stress in a human neuronal model. SH-SY5Y cells were co-incubated with sarains at concentrations ranging from 0.01 to 10 μM, and the well-known oxidant hydrogen peroxide at 150 μM for 6 h and the protective effects of the compounds were evaluated. Among the sarains tested, sarain A was the most promising compound, improving mitochondrial function and decreasing reactive oxygen species levels in human neuroblastoma cells treated with the compound at 0.01, 0.1 and 1 μM. This compound was also able to increase the activity of the antioxidant enzymes superoxide dismutases by inducing the translocation of the nuclear factor E2-related factor 2 (Nrf2) to the nucleus at the lower concentrations tested (0.01 and 0.1 μM). Moreover, sarain A at 0.1 and 1 μM blocked the mitochondrial permeability transition pore (mPTP) opening through cyclophilin D inhibition. These results suggest that the protective effects produced by the treatment with sarain A are related with its ability to block the mPTP and to enhance the Nrf2 pathway, indicating that sarain A may be a candidate compound for further studies in neurodegenerative diseases.

The amalgamation stage of fusion reactions

NASA Astrophysics Data System (ADS)

Mouze, Genevieve

2005-04-01

There is no need of a repulsive potential in the amalgamation stage for explaining the small fusion cross sections. The repulsive potential proposed by A. Adamian et al.(1) can advantageously be replaced by the affinity of the reaction of re-dissociation of the compound nucleus into its entrance-channel configuration. This reaction, which occurs after the penetration of the Coulomb barrier, is an equilibrium between dual and compact form of the compound nucleus, and the energy Q released in the dissociation is equal to the energy required for amalgamating. The total energy of the confined system being equal to the height B of the Coulomb barrier, the intrinsic excitation energy of the compact nucleus is equal to (B - Q). In the reaction 82Se+ 138Ba (2), the dissociation of 220Th releases 180.524 MeV, and B= 196.08 MeV. With an intrinsic excitation energy of 15.56 MeV, the confined compact 220Th has enough energy for emitting two neutrons ( S(2n) = 13.85 MeV). Thus the favored xn channel of fusion reactions can be precisely predicted. This new, mass-data-based model of fusion is completely parameter-free. 1 G.G. Adamian et al., PRC 69 (2004) 044601. 2 K. Satou et al. PRC C 65(2002) 054602.

Optical model with multiple band couplings using soft rotator structure

NASA Astrophysics Data System (ADS)

Martyanov, Dmitry; Soukhovitskii, Efrem; Capote, Roberto; Quesada, Jose Manuel; Chiba, Satoshi

2017-09-01

A new dispersive coupled-channel optical model (DCCOM) is derived that describes nucleon scattering on 238U and 232Th targets using a soft-rotator-model (SRM) description of the collective levels of the target nucleus. SRM Hamiltonian parameters are adjusted to the observed collective levels of the target nucleus. SRM nuclear wave functions (mixed in K quantum number) have been used to calculate coupling matrix elements of the generalized optical model. Five rotational bands are coupled: the ground-state band, β-, γ-, non-axial- bands, and a negative parity band. Such coupling scheme includes almost all levels below 1.2 MeV of excitation energy of targets. The "effective" deformations that define inter-band couplings are derived from SRM Hamiltonian parameters. Conservation of nuclear volume is enforced by introducing a monopolar deformed potential leading to additional couplings between rotational bands. The present DCCOM describes the total cross section differences between 238U and 232Th targets within experimental uncertainty from 50 keV up to 200 MeV of neutron incident energy. SRM couplings and volume conservation allow a precise calculation of the compound-nucleus (CN) formation cross sections, which is significantly different from the one calculated with rigid-rotor potentials with any number of coupled levels.

Localization and characterization of angiotensin II receptor binding and angiotensin converting enzyme in the human medulla oblongata.

PubMed

Allen, A M; Chai, S Y; Clevers, J; McKinley, M J; Paxinos, G; Mendelsohn, F A

1988-03-08

Angiotensin II receptor and angiotensin converting enzyme distributions in the human medulla oblongata were localised by quantitative in vitro autoradiography. Angiotensin II receptors were labelled with the antagonist analogue 125I-[Sar1, Ile8] AII while angiotensin converting enzyme was labelled with 125I-351A, a derivative of the specific converting enzyme inhibitor, lisinopril. Angiotensin II receptor binding and angiotensin converting enzyme are present in high concentrations in the nucleus of the solitary tract, the dorsal motor nucleus of vagus, the rostral and caudal ventrolateral reticular nucleus, and in a band connecting the dorsal and ventral regions. In the rostral and caudal ventrolateral reticular nucleus, angiotensin II receptors are distributed in a punctate pattern that registers with neuronal cell bodies. The distribution and density of these cell bodies closely resemble those of catecholamine-containing neurones mapped by others. In view of the known interactions of angiotensin II with both central and peripheral catecholamine-containing neurons of laboratory animals, the current anatomical findings suggest similar interactions between these neuroactive compounds in the human central nervous system. The presence of angiotensin II receptors and angiotensin converting enzyme in the nucleus of the solitary tract, dorsal motor nucleus of vagus, and rostral and caudal ventrolateral reticular nucleus demonstrates sites for central angiotensin II to exert its known actions on vasopressin release and autonomic functions including blood pressure control. These data also suggest a possible interaction between angiotensin II and central catecholeminergic systems.

[Site of prelingual cochlear stimulation and its effect on electrically evoked compound action potentials and refractory using the Nucleus 24 standard].

PubMed

Ma, R Y; Li, W; Jiang, X J

2016-12-01

Objective: To investigate the correlation between the site of prelingual cochlear stimulation and its effect on electrically evoked compound action potentials. Method: Recordings of auditory nerve responses were conducted in 32 prelingual subjects to demonstrate the feasibility of ECAP recordings using the nerve response telemetry(NRT) feature of the Nucleus CI24R(CA) system software. These recordings were then analyzed based on the site of cochlear stimulation defined as basal, middle and apical to determine if the amplitude, threshold and slope of the amplitude growth function and the refractory time differs depending on the region of stimulation. Result: Findings of our prelingual children showed significant differences in the ECAP recordings depending on the stimulation site. Comparing the apical with the basal region, on average higher amplitudes, lower thresholds and steeper slopes of the amplitude growth function hadbeen observed. The refractory time showed an overall dependence on cochlear region; however post-hoc tests showed no significant effect between individual regions. Conclusion: Obtaining ECAP recordings is also possible in the most apical region of the cochlea. However, differences can be observed depending on the region of the cochlea stimulated. Specifically, significant higher ECAP amplitude, lower thresholds and steeper amplitude growth function slopes have been observed in the apical region. These differences between prelingual children and adults could be explained by the location of the stimulating electrode with respect to the neural tissue in the cochlea, a higher density, or an increased neural survival rate of neural tissue in the apex. Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ota, S.; Burke, J. T.; Casperson, R. J.

Here, the effect of the production mechanism on the decay of a compound nucleus is investigated. The nucleus 90Zr was produced by three different reactions, namely 90Zr (p,p') 90Zr, 91Zr (p,d) 90Zr, and 92Zr (p,t) 90Zr , which served as surrogate reactions for 89Zr (n,γ). The spin-parity (J π) distributions of the states populated by these reactions were studied to investigate the surrogate reaction approach, which aims at indirectly determining cross sections for compound-nuclear reactions involving unstable targets such as 89Zr. Discrete γ rays, associated with transitions in 90Zr and 89Zr, were measured in coincidence with light ions for scatteringmore » angles of 25°–60° and 90Zr excitation energies extending above the neutron separation energy. The measured transition systematics were used to gain insights into the J π distributions of 90Zr. The 90Zr (p,p') reaction was found to produce fewer γ rays associated with transitions involving high spin states (J = 6–8 ℏ) than the other two reactions, suggesting that inelastic scattering preferentially populates states in 90Zr that have lower spins than those populated in the transfer reactions investigated. The γ-ray production was also observed to vary by factors of 2–3 with the angle at which the outgoing particle was detected. These findings are relevant to the application of the surrogate reaction approach.« less

Pion emission in α-particle interactions with various targets of nuclear emulsion detector

NASA Astrophysics Data System (ADS)

Abdelsalam, A.; Abou-Moussa, Z.; Rashed, N.; M. Badawy, B.; A. Amer, H.; Osman, W.; M. El-Ashmawy, M.; Abdallah, N.

2015-09-01

The behavior of relativistic hadron multiplicity for 4He-nucleus interactions is investigated. The experiment is carried out at 2.1 A and 3.7 A GeV (Dubna energy) to search for the incident energy effect on the interactions inside different emulsion target nuclei. Data are presented in terms of the number of emitted relativistic hadrons in both forward and backward angular zones. The dependence on the target size is presented. For this purpose the statistical events are discriminated into groups according to the interactions with H, CNO, Em, and AgBr target nuclei. The separation of events, into the mentioned groups, is executed based on Glauber's multiple scattering theory approach. Features suggestive of a decay mechanism seem to be a characteristic of the backward emission of relativistic hadrons. The results strongly support the assumption that the relativistic hadrons may already be emitted during the de-excitation of the excited target nucleus, in a behavior like that of compound-nucleus disintegration. Regarding the limiting fragmentation hypothesis beyond 1 A GeV, the target size is the main parameter affecting the backward production of the relativistic hadron. The incident energy is a principal factor responsible for the forward relativistic hadron production, implying that this system of particle production is a creation system. However, the target size is an effective parameter as well as the projectile size considering the geometrical concept regarded in the nuclear fireball model. The data are analyzed in the framework of the FRITIOF model.

A Nuclear Attack on Traumatic Brain Injury: Sequestration of Cell Death in the Nucleus.

PubMed

Tajiri, Naoki; De La Peña, Ike; Acosta, Sandra A; Kaneko, Yuji; Tamir, Sharon; Landesman, Yosef; Carlson, Robert; Shacham, Sharon; Borlongan, Cesar V

2016-04-01

Exportin 1 (XPO1/CRM1) plays prominent roles in the regulation of nuclear protein export. Selective inhibitors of nuclear export (SINE) are small orally bioavailable molecules that serve as drug-like inhibitors of XPO1, with potent anti-cancer properties. Traumatic brain injury (TBI) presents with a secondary cell death characterized by neuroinflammation that is putatively regulated by nuclear receptors. Here, we report that the SINE compounds (KPT-350 or KPT-335) sequestered TBI-induced neuroinflammation-related proteins (NF-(k)B, AKT, FOXP1) within the nucleus of cultured primary rat cortical neurons, which coincided with protection against TNF-α (20 ng/mL)-induced neurotoxicity as shown by at least 50% and 100% increments in preservation of cell viability and cellular enzymatic activity, respectively, compared to non-treated neuronal cells (P's < 0.05). In parallel, using an in vivo controlled cortical impact (CCI) model of TBI, we demonstrate that adult Sprague-Dawley rats treated post-injury with SINE compounds exhibited significant reductions in TBI-induced behavioral and histological deficits. Animals that received KPT-350 orally starting at 2 h post-TBI and once a day thereafter over the next 4 days exhibited significantly better motor coordination, and balance in the rotorod test and motor asymmetry test by 100-200% improvements, as early as 4 h after initial SINE compound injection that was sustained during subsequent KPT-350 dosing, and throughout the 18-day post-TBI study period compared to vehicle treatment (P's < 0.05). Moreover, KPT-350 reduced cortical core impact area and peri-impact cell death compared to vehicle treatment (P's < 0.05). Both in vitro and in vivo experiments revealed that KPT-350 increased XPO1, AKT, and FOXP1 nuclear expression and relegated NF-(k)B expression within the neuronal nuclei. Altogether, these findings advance the utility of SINE compounds to stop trafficking of cell death proteins within the nucleus as an efficacious treatment for TBI. © 2016 John Wiley & Sons Ltd.

Nuclear magnetic resonance shielding constants and chemical shifts in linear 199Hg compounds: a comparison of three relativistic computational methods.

PubMed

Arcisauskaite, Vaida; Melo, Juan I; Hemmingsen, Lars; Sauer, Stephan P A

2011-07-28

We investigate the importance of relativistic effects on NMR shielding constants and chemical shifts of linear HgL(2) (L = Cl, Br, I, CH(3)) compounds using three different relativistic methods: the fully relativistic four-component approach and the two-component approximations, linear response elimination of small component (LR-ESC) and zeroth-order regular approximation (ZORA). LR-ESC reproduces successfully the four-component results for the C shielding constant in Hg(CH(3))(2) within 6 ppm, but fails to reproduce the Hg shielding constants and chemical shifts. The latter is mainly due to an underestimation of the change in spin-orbit contribution. Even though ZORA underestimates the absolute Hg NMR shielding constants by ∼2100 ppm, the differences between Hg chemical shift values obtained using ZORA and the four-component approach without spin-density contribution to the exchange-correlation (XC) kernel are less than 60 ppm for all compounds using three different functionals, BP86, B3LYP, and PBE0. However, larger deviations (up to 366 ppm) occur for Hg chemical shifts in HgBr(2) and HgI(2) when ZORA results are compared with four-component calculations with non-collinear spin-density contribution to the XC kernel. For the ZORA calculations it is necessary to use large basis sets (QZ4P) and the TZ2P basis set may give errors of ∼500 ppm for the Hg chemical shifts, despite deceivingly good agreement with experimental data. A Gaussian nucleus model for the Coulomb potential reduces the Hg shielding constants by ∼100-500 ppm and the Hg chemical shifts by 1-143 ppm compared to the point nucleus model depending on the atomic number Z of the coordinating atom and the level of theory. The effect on the shielding constants of the lighter nuclei (C, Cl, Br, I) is, however, negligible. © 2011 American Institute of Physics

Elastic and inelastic scattering of neutrons on 238U nucleus

NASA Astrophysics Data System (ADS)

Capote, R.; Trkov, A.; Sin, M.; Herman, M. W.; Soukhovitskiĩ, E. Sh.

2014-04-01

Advanced modelling of neutron induced reactions on the 238U nucleus is aimed at improving our knowledge of neutron scattering. Capture and fission channels are well constrained by available experimental data and neutron standard evaluation. A focus of this contribution is on elastic and inelastic scattering cross sections. The employed nuclear reaction model includes - a new rotational-vibrational dispersive optical model potential coupling the low-lying collective bands of vibrational character observed in even-even actinides; - the Engelbrecht-Weidenmüller transformation allowing for inclusion of compound-direct interference effects; - and a multi-humped fission barrier with absorption in the secondary well described within the optical model for fission. Impact of the advanced modelling on elastic and inelastic scattering cross sections including angular distributions and emission spectra is assessed both by comparison with selected microscopic experimental data and integral criticality benchmarks including measured reaction rates (e.g. JEMIMA, FLAPTOP and BIG TEN). Benchmark calculations provided feedback to improve the reaction modelling. Improvement of existing libraries will be discussed.

Density functional theory calculations of 95Mo NMR parameters in solid-state compounds.

PubMed

Cuny, Jérôme; Furet, Eric; Gautier, Régis; Le Pollès, Laurent; Pickard, Chris J; d'Espinose de Lacaillerie, Jean-Baptiste

2009-12-21

The application of periodic density functional theory-based methods to the calculation of (95)Mo electric field gradient (EFG) and chemical shift (CS) tensors in solid-state molybdenum compounds is presented. Calculations of EFG tensors are performed using the projector augmented-wave (PAW) method. Comparison of the results with those obtained using the augmented plane wave + local orbitals (APW+lo) method and with available experimental values shows the reliability of the approach for (95)Mo EFG tensor calculation. CS tensors are calculated using the recently developed gauge-including projector augmented-wave (GIPAW) method. This work is the first application of the GIPAW method to a 4d transition-metal nucleus. The effects of ultra-soft pseudo-potential parameters, exchange-correlation functionals and structural parameters are precisely examined. Comparison with experimental results allows the validation of this computational formalism.

Evaluation of new iodinated acridine derivatives for targeted radionuclide therapy of melanoma using 125I, an Auger electron emitter.

PubMed

Gardette, Maryline; Papon, Janine; Bonnet, Mathilde; Desbois, Nicolas; Labarre, Pierre; Wu, Ting-Dee; Miot-Noirault, Elisabeth; Madelmont, Jean-Claude; Guerquin-Kern, Jean-Luc; Chezal, Jean-Michel; Moins, Nicole

2011-12-01

The increasing incidence of melanoma and the lack of effective therapy on the disseminated form have led to an urgent need for new specific therapies. Several iodobenzamides or analogs are known to possess specific affinity for melanoma tissue. New heteroaromatic derivatives have been designed with a cytotoxic moiety and termed DNA intercalating agents. These compounds could be applied in targeted radionuclide therapy using (125)I, which emits Auger electrons and gives high-energy, localized irradiation. Two iodinated acridine derivatives have been reported to present an in vivo kinetic profile conducive to application in targeted radionuclide therapy. The aim of the present study was to perform a preclinical evaluation of these compounds. The DNA intercalating property was confirmed for both compounds. After radiolabeling with (125)I, the two compounds induced in vitro a significant radiotoxicity to B16F0 melanoma cells. Nevertheless, the acridine compound appeared more radiotoxic than the acridone compound. While cellular uptake was similar for both compounds, SIMS analysis and in vitro protocol showed a stronger affinity for melanin with acridone derivative, which was able to induce a predominant scavenging process in the melanosome and restrict access to the nucleus. In conclusion, the acridine derivative with a higher nuclear localization appeared a better candidate for application in targeted radionuclide therapy using (125)I.

Bioactive compounds isolated from apple, tea, and ginger protect against dicarbonyl induced stress in cultured human retinal epithelial cells.

PubMed

Sampath, Chethan; Zhu, Yingdong; Sang, Shengmin; Ahmedna, Mohamed

2016-02-15

Methylglyoxal (MGO) is known to be a major precursor of advanced glycation end products (AGEs) which are linked to diabetes and its related complications. Naturally occurring bioactive compounds could play an important role in countering AGEs thereby minimizing the risk associated with their formation. In this study, eight specific bioactive compounds isolated from apple, tea and ginger were evaluated for their AGEs scavenging activity using Human Retinal Pigment Epithelial (H-RPE) cells treated with MGO. Among the eight specific compounds evaluated, (-)-epigallocatechin 3-gallate (EGCG) from tea, phloretin in apple, and [6]-shogaol and [6]-gingerol from ginger were found to be most effective in preventing MGO-induced cytotoxicity in the epithelial cells. Investigation of possible underlying mechanisms suggests that that these compounds could act by modulating key regulative detoxifying enzymes via modifying nuclear factor-erythroid 2-related factor 2 (Nrf2) function. MGO-induced cytotoxicity led to increased levels of AGEs causing increase in Nε-(Carboxymethyl) lysine (CML) and glutathione (GSH) levels and over expression of receptor for advanced glycation end products (RAGE). Data also showed that translocation of Nrf2 from cytosol to nucleus was inhibited, which decreased the expression of detoxifying enzyme like heme oxygenase-1 (HO-1). The most potent bioactive compounds scavenged dicarbonyl compounds, inhibited AGEs formation and significantly reduced carbonyl stress by Nrf2 related pathway and restoration of HO-1 expression. These findings demonstrated the protective effect of bioactive compounds derived from food sources against MGO-induced carbonyl stress through activation of the Nrf2 related defense pathway, which is of significant importance for therapeutic interventions in complementary treatment/management of diabetes-related complications. Copyright © 2016. Published by Elsevier GmbH.

Synthesis reactions and radioactive properties of transactinoid elements

NASA Astrophysics Data System (ADS)

Oganessian, Yu. Ts.

1994-10-01

It is well known that the heaviest elements of the periodic table have been synthesized in the cold fusion of magic nuclei of Pb with Z less than 26 ions. Because of dynamic limitations for fusion under strong Coulomb interaction of nuclei, the cross-sections of cold fusion reactions diminish exponentially with growing compound nucleus atomic number. For element Z = 110 produced in the reaction Pb-208(Ni-62,n)(sub 271)110, the expected cross-section is 10(exp -36) sq cm. In still more asymmetric reactions, when isotopes of actinoid elements irradiated with relatively light ions (Z less than or equal 12) are used as the target material, the compound nuclei possess an excitation energy of approx. 50 MeV. At this energy the nuclear shell effects are strongly suppressed and, as a result, in the case of hot compound nuclei of transactinoid elements the fission barrier is practically absent. The transition of these nuclei into the ground state depends strongly on the dynamic properties of the system with respect to the fission degree of freedom. Experimental studies were going on in two directions: (1) determination of the fission time by measuring the prefission neutrons (of Cf-Fm nuclei) in a wide interval of excitation energies; (2) direct synthesis of known nuclides with Z = 102-105 in reactions with ions of Ne-22, Mg-26, Al-27 and P-31 when final nuclei are produced in the ground state after the evaporation of five or six neutrons from the excited compound nuclei (E(sub x) = 50-60 MeV). The dependence of the reaction cross-section (HI, 5-6n) on the atomic number of the compound nucleus in different target-ion combinations points to the possibility of synthesizing new elements in hot fusion reactions. The advantage of these reactions arises from the use of neutron-rich nuclei like Cm-248 and Cf-249 which allows us to synthesize nuclei close to the deformed shell N = 162, for which a considerable growth of stability against spontaneous fission is predicted. Experimental set-ups and methods of detecting rare events of formation and decay of transactinide nuclei are described.

Influence of sticking vs non-sticking limits of moment of inertia and higher order deformations in the decay of 214,216Rn* compound systems

NASA Astrophysics Data System (ADS)

Mittal, Rajni; Jain, Deepika; Sharma, Manoj K.

2017-12-01

The dynamical cluster decay model (DCM) is employed to explore the relative effect of sticking (IS) and non-sticking (INS) limits of moment of inertia (MOI) in the decay of hot and rotating 214,216Rn* compound nuclei, formed in 16,18O + 198Pt reactions. Beside this, the nuclear deformation effects i.e. quadrupole β2 (static and dynamic) and higher order static deformations up to hexadecapole (β4) are duly incorporated and studied within DCM. The influence of both 'INS/IS' addressing rotational energy component and 'deformations' is gauged through the barrier characteristics, preformation factor and barrier lowering effects. The experimentally given ER and ff data is addressed by optimizing the neck-length ΔR, that strongly depends on the limiting angular momentum, which in turn depends on the sticking or non-sticking limits of interaction. In addition to this, the influence of increase in energy and neutron number is probed in reference to ER survival probability of Rn compound nucleus. Finally, the ff cross-sections of 214,216Rn* nuclei are predicted within sticking limit of moment of inertia as the same seems to be more suitable for such decay paths.

Ablation effects in oxygen-lead fragmentation at 2.1 GeV/nucleon

NASA Technical Reports Server (NTRS)

Townsend, L. W.

1984-01-01

The mechanism of particle evaporation was used to examine ablation effects in the fragmentation of 2.1 GeV/nucleon oxygen nuclei by lead targets. Following the initial abrasion process, the excited projectile prefragment is assumed to statistically decay in a manner analogous to that of a compound nucleus. The decay probabilities for the various particle emission channels are calculated by using the EVAP-4 Monte Carlo computer program. The input excitation energy spectrum for the prefragment is estimated from the geometric ""clean cut'' abrasion-ablation model. Isotope production cross sections are calculated and compared with experimental data and with the predictions from the standard geometric abrasion-ablation fragmentation model.

Development of differential cytotoxic compounds containing nitrosourea and benzothiazine nucleus.

PubMed

Nyati, M K; Rai, D; Gupta, R R; Dev, P K

1997-01-01

The in vivo activity of 4 new benzothiazinyl-nitrosourea compounds was investigated against Sarcoma-180 (S-180) and Ehrlich Ascitic Carcinoma (EAC) induced ascitic and solid tumors. EAC solid tumor was found to be the most sensitive, where one compound (no 4) inhibited tumor growth to only 3 per cent of the control value. All the 4 compounds tested were found to be toxicologically more selective than 5-fluorouracil and 6-mercaptopurine drugs. The reason for this selective toxicity may be attributed to the inhibition of isocyanate moiety in these compounds which causes toxicity to normal cells via a carbamoylation reaction. However, they may still remain potent, since they decompose into an alkylating carbonium species and a charge transfer complex which may interact with DNA via alkylation and intercalation reactions, respectively.

Pathophysiology of disk-related low back pain and sciatica. II. Evidence supporting treatment with TNF-alpha antagonists.

PubMed

Mulleman, Denis; Mammou, Saloua; Griffoul, Isabelle; Watier, Hervé; Goupille, Philippe

2006-05-01

Strong evidence suggests that TNF-alpha may be among the chemical factors involved in disk-related sciatica. TNF-alpha is involved in the genesis of nerve pain in animal models and may promote pain-signal production from nerve roots previously subjected to mechanical deformation. In animal experiments, TNF-alpha has been identified in nucleus pulposus and Schwann cells. Local production of endogenous TNF-alpha may occur early in the pathogenic process. Exposure to exogenous TNF-alpha induces electrophysiological, histological, and behavioral changes similar to those seen after exposure to nucleus pulposus, and these changes are more severe when mechanical compression is applied concomitantly. TNF-alpha antagonists diminish or abolish abnormalities in animal models. Other cytokines may be involved also, as suggested by the potent inhibitory effects of compounds such as doxycycline. Two open-label studies in humans suggest dramatic efficacy of TNF-alpha antagonists in alleviating disk-related sciatica. In contrast, the results of the only controlled study available to date do not support a therapeutic effect of TNF-alpha antagonists. Thus, whether TNF-alpha antagonist therapy is warranted in patients with disk-related sciatica remains an open question, and further randomized controlled studies are needed.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nishino, Tomonori G.; Department of Biotechnology, University of Tokyo, Bunkyo-ku, Tokyo 113-8657; Miyazaki, Masaya

Class IIa histone deacetylases (HDACs) form complexes with a class of transcriptional repressors in the nucleus. While screening for compounds that could block the association of HDAC4 with the BTB domain-containing transcriptional repressor Bach2, we discovered that phorbol 12-myristate 13-acetate (PMA) induced the cytoplasmic retention of HDAC4 mutants lacking a nuclear export signal (NES). Although PMA treatment and PKD overexpression has been proposed to facilitate the nuclear export of class IIa HDACs by creating 14-3-3 binding sites containing phosphoserines, our experiments using HDAC mutants demonstrated that PMA greatly reduces nuclear import. PMA treatment repressed the NLS activity in a mannermore » dependent on 14-3-3 binding. These results suggest that nuclear HDAC4 is not tethered in the nucleus, but instead shuttles between the nucleus and the cytoplasm. Phosphorylation-induced 14-3-3 binding biases the balance of nucleo-cytoplasmic shuttling toward the cytoplasm by inhibiting nuclear import.« less

Structure-activity relationships of selected phenazines against Mycobacterium leprae in vitro.

PubMed Central

Franzblau, S G; O'Sullivan, J F

1988-01-01

Structure-activity relationships of phenazines against Mycobacterium leprae were investigated by using an in vitro radiorespirometric assay. In general, activity in ascending order was observed in compounds containing no chlorine atoms, a monochlorinated phenazine nucleus, and chlorines in the para positions of both the anilino and phenyl rings. The most active compounds contained a 2,2,6,6-tetramethylpiperidine substitution at the imino nitrogen. Most of these chlorinated phenazines were considerably more active in vitro than clofazimine (B663). PMID:3056241

18-Methoxycoronaridine (18-MC) and ibogaine: comparison of antiaddictive efficacy, toxicity, and mechanisms of action.

PubMed

Glick, S D; Maisonneuve, I M; Szumlinski, K K

2000-09-01

18-MC, a novel iboga alkaloid congener, is being developed as a potential treatment for multiple forms of drug abuse. Like ibogaine (40 mg/kg), 18-MC (40 mg/kg) decreases the intravenous self-administration of morphine and cocaine and the oral self-administration of ethanol and nicotine in rats; unlike ibogaine, 18-MC does not affect responding for a nondrug reinforcer (water). Both ibogaine and 18-MC ameliorate opioid withdrawal signs. Both ibogaine and 18-MC decrease extracellular levels of dopamine in the nucleus accumbens, but only ibogaine increases extracellular levels of serotonin in the nucleus accumbens. Both ibogaine and 18-MC block morphine-induced and nicotine-induced dopamine release in the nucleus accumbens; only ibogaine enhances cocaine-induced increases in accumbal dopamine. Both ibogaine and 18-MC enhance the locomotor and/or stereotypic effects of stimulants. Ibogaine attenuates, but 18-MC potentiates, the acute locomotor effects of morphine; both compounds attenuate morphine-induced locomotion in morphine-experienced rats. Ibogaine produces whole body tremors and, at high doses (> or = 100 mg/kg), cerebellar damage; 18-MC does not produce these effects. Ibogaine, but not 18-MC, decreases heart rate at high doses. While 18-MC and ibogaine have similar affinities for kappa opioid and possibly nicotinic receptors, 18-MC has much lower affinities than ibogaine for NMDA and sigma-2 receptors, sodium channels, and the 5-HT transporter. Both 18-MC and ibogaine are sequestered in fat and, like ibogaine, 18-MC probably has an active metabolite. The data suggest that 18-MC has a narrower spectrum of actions and will have a substantially greater therapeutic index than ibogaine.

Novel thiazole derivatives: a patent review (2008 - 2012; Part 1).

PubMed

Leoni, Alberto; Locatelli, Alessandra; Morigi, Rita; Rambaldi, Mirella

2014-02-01

Thiazole is a well-known five-membered heterocyclic compound. Various methods have been worked out for its synthesis. In the last few decades, a lot of work has been done on thiazole ring in order to find new compounds related to this scaffold acting as an antioxidant, analgesic, anti-inflammatory, antimicrobial, antifungal, antiviral, diuretic, anticonvulsant, neuroprotective and antitumor or cytotoxic drugs with lesser side effects. This review presents the up to date development of different thiazole derivatives. This review gives an account of the recent therapeutic patent literature (2008 - 2012) describing the applications of thiazole and its derivatives on selected activities. In this review, many of the therapeutic applications of thiazole derivatives reported in international patents have been discussed. In addition to selected biological data, some of pharmaceutical applications are also summarized. Because of the large number of patents registered in this period relative to thiazole derivatives the attention was focused, in this first part of the review, on inhibitors of phosphatidylinositol-3-kinase, inhibitors of protein kinase and derivatives modulating enzymes related to metabolism. This review of patented products presents the thiazole ring as the nucleus of the derivatives considered from a medicinal chemistry perspective. The applications are based firstly on the specific enzyme target with very low development in the disease treatment. Most of the described compounds are shown to have beneficial therapeutic effects but at the same time these compounds, selective for 'multi-signaling pathway' targets, may also increase the side-effect potential.

A new approach for the assessment of the toxicity of polyphenol-rich compounds with the use of high content screening analysis

PubMed Central

Golanski, Jacek; Lukasiak, Magdalena; Redzynia, Malgorzata; Dastych, Jaroslaw; Watala, Cezary

2017-01-01

The toxicity of in vitro tested compounds is usually evaluated based on AC50 values calculated from dose-response curves. However, there is a large group of compounds for which a standard four-parametric sigmoid curve fitting may be inappropriate for estimating AC50. In the present study, 22 polyphenol-rich compounds were prioritized from the least to the most toxic based on the total area under and over the dose-response curves (AUOC) in relation to baselines. The studied compounds were ranked across three key cell indicators (mitochondrial membrane potential, cell membrane integrity and nuclear size) in a panel of five cell lines (HepG2, Caco-2, A549, HMEC-1, and 3T3), using a high-content screening (HCS) assay. Regarding AUOC score values, naringin (negative control) was the least toxic phenolic compound. Aronox, spent hop extract and kale leaf extract had very low cytotoxicity with regard to mitochondrial membrane potential and cell membrane integrity, as well as nuclear morphology (nuclear area). Kaempferol (positive control) exerted strong cytotoxic effects on the mitochondrial and nuclear compartments. Extracts from buckthorn bark, walnut husk and hollyhock flower were highly cytotoxic with regard to the mitochondrion and cell membrane, but not the nucleus. We propose an alternative algorithm for the screening of a large number of agents and for identifying those with adverse cellular effects at an early stage of drug discovery, using high content screening analysis. This approach should be recommended for series of compounds producing a non-sigmoidal cell response, and for agents with unknown toxicity or mechanisms of action. PMID:28662177

Effects of Nicotine and Nicotinic Antagonists on the Acoustic Startle Response and on Pre-Pulse Inhibition in Rats

DTIC Science & Technology

1996-06-07

the auditory nerve, the ventral cochlear nucleus , nuclei of the lateral lemniscus, nucleus reticularis pontis caudalis, spinal neuron, and lower... nucleus , nuclei of the lateral lemniscus, nucleus reticularis pontis caudalis, hippocampus, and striatum (Davis, et al., 1982; Swerdlow, et aI, 1992...Davis, M. (1985) Cocaine effects on acoustic startle and startle elicited electrically from cochlear nucleus . P§ychQpharmacology, 87, 396-399 James

CP5484, a novel quaternary carbapenem with potent anti-MRSA activity and reduced toxicity.

PubMed

Maruyama, Takahisa; Yamamoto, Yasuo; Kano, Yuko; Kurazono, Mizuyo; Matsuhisa, Eiji; Takata, Hiromi; Takata, Toshihiko; Atsumi, Kunio; Iwamatsu, Katsuyoshi; Shitara, Eiki

2007-10-01

A new series of 1beta-methyl carbapenems possessing a 6,7-disubstituted imidazo[5,1-b]thiazol-2-yl group directly attached to the C-2 position of the carbapenem nucleus was prepared, and the activities of these compounds against methicillin-resistant Staphylococcus aureus (MRSA) were evaluated. To study the effect of basic moieties on anti-MRSA activity, we introduced an amino, or imino, or amidino group at the 6-position of imidazo[5,1-b]thiazole in place of the carbamoylmethyl moiety of CP5068. Anti-MRSA activities of almost all basic group-substituted carbapenems were improved, though some of the compounds showed stronger acute toxicity in mice than IPM. In order to decrease the toxicity without decreasing the activity, we introduced various additional functionalities around the basic moiety. Finally, we obtained CP5484, which has excellent anti-MRSA activity and low acute toxicity.

Synthesis, structural characterization, antimicrobial activities and theoretical investigations of some 4-(4-aminophenylsulfonyl) phenylimino) methyl)-4-(aryldiazenyl) phenol

NASA Astrophysics Data System (ADS)

Ghasemian, Motaleb; Kakanejadifard, Ali; Karami, Tahereh

2016-11-01

The azo-azomethine dyes with a different substitution have been designed from the reaction of 4,4‧-diaminodiphenyl sulfone with 2-hydroxy-5-(aryldiazenyl)benzaldehyde. The compounds have been characterized by elemental analysis, Mass, IR, UV-Vis, TGA-DTA and NMR spectroscopy. The solvatochromism behaviors, effects of substitution and pH on the electronic absorption spectra of dyes were evaluated. The in vitro antimicrobial activities were also screened for their potential for antibiotic activities by broth micro dilution method. Also, the optimum molecular geometries, molecular electrostatic potential (MEP), nucleus-independent chemical shift (NICS) and frontier molecular orbitals (FMO), vibrational spectra (IR) and electronic absorption (UV-Vis) spectra of the title compounds have been investigated with the help of DFT and TDDFT methods with 6-311 ++G(d,p) basis sets and PCM calculations. The results of the calculations show excellent agreement with the experimental value.

N/Z effect on reaction mechanisms cross sections in the 78 Kr +40 Ca and 86 Kr +48 Ca collisions at 10 AMeV

NASA Astrophysics Data System (ADS)

Gnoffo, B.; Pirrone, S.; Politi, G.; La Commara, M.; Wieleczko, J. P.; De Filippo, E.; Russotto, P.; Trimarchi, M.; Vigilante, M.; Ademard, G.; Auditore, L.; Beck, C.; Bercenau, I.; Bonnet, E.; Borderie, B.; Cardella, G.; Chibihi, A.; Colonna, M.; Dell'Aquila, D.; De Luca, S.; D'Onofrio, A.; Frankland, J. D.; Lanzalone, G.; Lautesse, P.; Lebhertz, D.; Le Neidre, N.; Lombardo, I.; Martorana, N. S.; Mazurek, K.; Norella, S.; Pagano, A.; Pagano, E. V.; Papa, M.; Piasecki, E.; Porto, F.; Quattrocchi, L.; Rizzo, F.; Spadaccini, G.; Trifirò, A.; Verde, G.

2017-06-01

Nuclear reactions between medium-mass nuclei at low energy are characterized by the competition between binary and evaporation process in the compound nucleus de-excitation. A study of the influence of the neutron richness of the entrance channel on the decay paths of the compound nuclei formed in the 78 Kr +40 Ca and 86 Kr +48 Ca at 10 MeV/A is presented. The experiment has been performed at Laboratori Nazionali del Sud by using the CHIMERA 4π multidetector for charged particles. The Kinematical characteristics of the two reactions support the conclusion of a production via long lived system. Besides the results relative to the n-poor system are compared to those obtained at GANIL, performed at 5.5 AMeV, in order to study the energy influence.

A role of nucleus accumbens dopamine receptors in the nucleus accumbens core, but not shell, in fear prediction error.

PubMed

Li, Susan S Y; McNally, Gavan P

2015-08-01

Two experiments used an associative blocking design to study the role of dopamine receptors in the nucleus accumbens shell (AcbSh) and core (AcbC) in fear prediction error. Rats in the experimental groups were trained to a visual fear-conditioned stimulus (conditional stimulus [CS]) A in Stage I, whereas rats in the control groups were not. In Stage II, all rats received compound fear conditioning of the visual CSA and an auditory CSB. Rats were later tested for their fear responses to CSB. All rats received microinjections of saline or the D1-D2 receptor antagonist cis-(z)-flupenthixol prior to Stage II. These microinjections targeted either the AcbSh (Experiment 1) or the AcbC (Experiment 2). In each experiment, Stage I fear conditioning of CSA blocked fear learning to CSB. Microinjection of cis-(z)-flupenthixol (10 or 20 μg) into the AcbSh (Experiment 1) had no effect on fear learning or associative blocking. In contrast, microinjection of cis-(z)-flupenthixol (10 or 20 μg) into the AcbC (Experiment 2) attenuated blocking and so enabled fear learning to CSB. These results identify the AcbC as the critical locus for dopamine receptor contributions to fear prediction error and the associative blocking of fear learning. (c) 2015 APA, all rights reserved).

VIRTIS/Rosetta Observes Comet 67P/Churyumov-Gerasimenko: Nucleus and Coma Derived Composition and Physical Properties.

NASA Astrophysics Data System (ADS)

Capaccioni, F.; Filacchione, G.; Erard, S.; Arnold, G.; De Sanctis, M. C.; Bockelée-Morvan, D.; Leyrat, C.; Tosi, F.; Ciarniello, M.; Raponi, A.; Migliorini, A.; Quirico, E.; Rinaldi, G.; Schmitt, B.; Carlson, R. W.; Combi, M. R.; Fink, U.; Tozzi, G. P.; Palomba, E.; Longobardo, A.; Formisano, M.; Debout, V.; Drossart, P.; Piccioni, G.; Fougere, N.

2015-12-01

The paper will describe the major results obtained throughout the nominal mission by the instrument VIRTIS (Visible, Infrared and Thermal Imaging Spectrometer), the dual channel spectrometer onboard Rosetta, on the surface composition and thermal properties of the nucleus of comet 67P/Churyumov-Gerasimenko and on the 2D distribution of H2O and CO2 in the coma. VIRTIS is a dual channel spectrometer; VIRTIS-M (M for Mapper) is a hyper spectral imager covering a wide spectral range from 0.25 through 5μm. VIRTIS-M uses a slit and a scan mirror to generate images with spatial resolution of 250 μrad over a FOV of 3.7°. The second channel is VIRTIS-H (H for High-resolution), a point spectrometer with high spectral resolution (λ/Δλ=3000 @3μm) in the range 2-5 μm. The nucleus observations have been performed in a wide range of conditions with best spatial resolution of 2.5m. The surface temperature has been determined since the first distant observations when the nucleus filled one single VIRTIS-M pixel and continuously monitored since. Maximum temperature determined until April 2015 are as high as 300K at the subsolar point. Modeling of the thermophysical properties allowed to derive the thermal inertia of the crust. The VIRTIS composition analysis has showed evidence of carbon-bearing compounds on the nucleus of the comet 67P/Churyumov-Gerasimenko. The very low reflectance of the nucleus (normal albedo of 0.060 ± 0.003 at 0.55 μm), the spectral slopes in VIS and IR ranges (5-25 and 1.5-5 % kÅ-1) and the broad absorption feature in the 2.9-3.6 μm range present across the entire illuminated surface, are compatible with a surface crust made of a complex mixture of dark disordered poly-aromatic compounds, opaque minerals and several chemical species containing: -COOH, CH2 / CH3, -OH (in Alcohols) and possibly NH4+. Both channels are contributing to the determination of the spatial distribution of H2O and CO2 in the coma; their abundances as a function of altitude and of time of day. Authors acknowledge the support from national funding agencies.

Proof of mechanism study of a novel serotonin transporter blocker, DA-8031, using [11C]DASB positron emission tomography and in vivo microdialysis.

PubMed

Park, Hyun Soo; Jung, In Soon; Lim, Nam Hee; Sung, Ji Hyun; Lee, Sukhyang; Moon, Byung Seok; Lee, Byung Chul; Kang, Kyung Koo; Kim, Sang Eun

2014-07-01

To investigate the efficacy of DA-8031, a novel compound for the treatment of premature ejaculation, we measured serotonin transporter (SERT) occupancy by DA-8031, as well as DA-8031-induced changes in extracellular serotonin levels, in the rat brain using positron emission tomography (PET) and 11C-N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine ([11C]DASB) and in vivo microdialysis, respectively. [11C]DASB PET scans were performed in rats with graded doses of DA-8031 (vehicle: 10, 30, and 100 mg/kg). SERT occupancy in the midbrain was determined using binding potentials for [11C]DASB calculated by the multilinear reference tissue model. Extracellular serotonin levels were monitored in the dorsal raphe nucleus of rats after the administration of DA-8031 (10-100 mg/kg) using in vivo microdialysis. PET data indicated a reduction of [11C]DASB binding to SERTs in the midbrain as a function of DA-8031 dose. SERT occupancy for each DA-8031 dose (10-100 mg/kg) ranged between 31% and 84%. The drug dose required for 50% occupancy of SERT was 13.5 mg/kg in the midbrain, comparable with previous preclinical behavioral data (∼10-30 mg/kg). In vivo microdialysis showed that DA-8031 produced a dose-dependent increase in extracellular serotonin levels in the dorsal raphe nucleus (33%-81% increase for doses of 10-100 mg/kg). These preclinical data provide a proof of mechanism for DA-8031 as a novel compound of targeting the SERT for the treatment of premature ejaculation, warranting further clinical trials. They also offer insight into the optimal drug dose needed to exert therapeutic effects while minimizing adverse effects in humans. Copyright © 2014 Elsevier Inc. All rights reserved.

Effects of adolescent treatment with nicotine, harmane, or norharmane in male Sprague-Dawley rats.

PubMed

Goodwin, Amy K; Lantz-McPeak, Susan M; Robinson, Bonnie L; Law, C Delbert; Ali, Syed F; Ferguson, Sherry A

2015-01-01

The initiation of tobacco use occurs most often in adolescence and may be especially detrimental as the adolescent brain is undergoing substantial development. In addition to nicotine, there are over 9000 other compounds present in tobacco products, including the β-carbolines harmane and norharmane. The present study aimed to determine the long-term effects of adolescent exposure to nicotine (NIC), harmane (HAR), or norharmane (NOR) on locomotor activity, learning and memory, anxiety-like behavior, motor coordination, and monoamine/metabolite concentrations in the striatum and nucleus accumbens of male Sprague-Dawley rats. Beginning on postnatal day (PND) 27 and continuing through PND 55, subjects received twice daily intraperitoneal injections of 1ml/kg saline (CON), 0.5mg NIC/kg, 0.5mg HAR/kg, or 0.5mg NOR/kg. Body weight, food, and water intake were measured daily (PNDs 27-96). Locomotor activity was assessed on PND 40 or 41, PND 55, and PNDs 81 and 82. Other behaviors (anxiety-like behavior, motor coordination, and spatial learning and memory) were assessed at least 25 days after drug exposure ended (PNDs 80-91). On PND 97, subjects were decapitated and the striatum and nucleus accumbens were dissected and frozen for analysis. NIC treatment significantly decreased food intake, but did not alter locomotor activity during or after treatment. HAR and NOR treatment, however, caused significant open field hypoactivity. Motor coordination, water maze performance, and concentrations of monoamines and metabolites in the striatum and nucleus accumbens were unaltered by any drug treatment. These results indicate a long-lasting effect on activity levels from adolescent HAR or NOR treatment; however, there were few long-lasting NIC effects. Given the paucity of data describing effects of HAR or NOR exposure, these data should encourage additional studies of these tobacco constituents as well as constituent combination studies. Published by Elsevier Inc.

α versus non-α cluster decays of the excited compound nucleus *124Ce using various formulations of the nuclear proximity potential

NASA Astrophysics Data System (ADS)

Kaur, Arshdeep; Chopra, Sahila; Gupta, Raj K.

2015-06-01

The earlier study of *124Ce formed in the 32S+92Mo reaction at an above barrier beam energy of 150 MeV, using the pocket formula of Blocki et al. for the nuclear proximity potential in the dynamical cluster-decay model (DCM), is extended to the use of other nuclear interaction potentials derived from the Skyrme energy density functional (SEDF) based on the semiclassical extended Thomas Fermi (ETF) approach under the frozen density approximation. The Skyrme forces used are the old SII, SIII, SIV, SKa, SkM, and SLy4 and new GSkI and KDE0(v1), given for both normal and isospin-rich nuclei. It is found that the α -nucleus structure, over the non-α nucleus structure, is preferred for only two Skyrme forces, the SIII and KDE0(v1). An extended intermediate mass fragments (IMFs) window, along with the new decay region of heavy mass fragments (HMFs) and the near-symmetric and symmetric fission fragments which, on adding the complementary heavy fragments, corresponds to (A /2 )±12 mass region of the fusion-fission (ff) process, are predicted by considering cross sections of orders observed in the experiment under study. For the predicted (total) fusion cross section, the survival probability Psurv of the compound nucleus (CN) against fission is shown to be very small because of the very large predicted ff component. On the other hand, the CN formation probability PCN is found to be nearly equal to 1, and hence the decay under study is a pure CN decay for all the nuclear potentials considered, since the estimated noncompound nucleus (nCN) content is almost negligible. We have also applied the extended-Wong model of Gupta and collaborators, and find that the ℓmax values and total fusion cross sections are of the same order as for the DCM. Thus, the extended-Wong model, which describes only the total fusion cross section in terms of the barrier characteristics of the entrance channel nuclei, could be useful for initial experimental studies to be fully treated using the DCM for all the observed decay products.

Substituent and solvent effects on the UV/Vis absorption spectra of 5-(4-substituted arylazo)-6-hydroxy-4-methyl-3-cyano-2-pyridones

NASA Astrophysics Data System (ADS)

Ušćumlić, Gordana S.; Mijin, Dusanˇ Z. ˇ; Valentić, Nataša V.; Vajs, Vlatka V.; Sušić, Biljana M.

2004-10-01

Absorption spectra of ten 5-(4-substituted arylazo)-6-hydroxy-4-methyl-3-cyano-2-pyridones have been recorded in fifteen solvents in the range 200-600 nm. The substituents at the phenyl nucleus are as follows: OH, OCH 3, CH 3, C 2H 5, H, Cl, Br, I, COOH and NO 2. The effects of substituents on the absorption spectra of investigated compounds are interpreted by correlation of absorption frequencies with simple Hammett equation. The effects of solvent polarity and solvent/solute hydrogen bonding interactions are analyzed by means of linear solvation energy relationships concept proposed by Kamlet and Taft. The azo-hydrazone tuatomeric equilibration is found to depend upon substituents as well as on solvents.

Features of Electron Density Distribution in Delafossite Cualo2

NASA Astrophysics Data System (ADS)

Pogoreltsev, A. I.; Schmidt, S. V.; Gavrilenko, A. N.; Shulgin, D. A.; Korzun, B. V.; Matukhin, V. L.

2015-07-01

We have used pulsed 63,65Cu nuclear quadrupole resonance at room temperature to study the semiconductor compound CuAlO2 with a delafossite crystal structure, and we have determined the quadrupole frequency νQ = 28.12 MHz and the asymmetry parameter η ~ 0, which we used to study the features of the electron density distribution in the vicinity of the quadrupolar nucleus. In order to take into account the influence of correlation effects on the electric field gradient, we carried out ab initio calculations within the density functional theory (DFT) approximation using a set of correlation functionals VWN1RPA, VWN5, PW91LDA, CPW91, and B3LYP1. We mapped the electron density distribution in the vicinity of the quadrupolar copper nucleus for the Cu7Al6o{14/- 1} cluster and we calculated the size of the LUMO-HOMO gap, Δ ~ 3.33 eV. We established the anisotropy of the spatial electron density distribution. Based on analysis of the electron density distribution obtained, we suggest that the bond in CuAlO2 is not purely covalent.

Evolution from a natural flavones nucleus to obtain 2-(4-Propoxyphenyl)quinoline derivatives as potent inhibitors of the S. aureus NorA efflux pump.

PubMed

Sabatini, Stefano; Gosetto, Francesca; Manfroni, Giuseppe; Tabarrini, Oriana; Kaatz, Glenn W; Patel, Diixa; Cecchetti, Violetta

2011-08-25

Overexpression of efflux pumps is an important mechanism by which bacteria evade the effects of substrate antimicrobial agents. Inhibition of such pumps is a promising strategy to circumvent this resistance mechanism. NorA is a Staphylococcus aureus efflux pump that confers reduced susceptibility to many structurally unrelated agents, including fluoroquinolones, resulting in a multidrug resistant phenotype. In this work, a series of 2-phenyl-4(1H)-quinolone and 2-phenyl-4-hydroxyquinoline derivatives, obtained by modifying the flavone nucleus of known efflux pump inhibitors (EPIs), were synthesized in an effort to identify more potent S. aureus NorA EPIs. The 2-phenyl-4-hydroxyquinoline derivatives 28f and 29f display potent EPI activity against SA-1199B, a strain that overexpresses norA, in an ethidium bromide efflux inhibition assay. The same compounds, in combination with ciprofloxacin, were able to completely restore its antibacterial activity against both S. aureus SA-K2378 and SA-1199B, norA-overexpressing strains. © 2011 American Chemical Society

Visual discrimination in the pigeon (Columba livia): effects of selective lesions of the nucleus rotundus

NASA Technical Reports Server (NTRS)

Laverghetta, A. V.; Shimizu, T.

1999-01-01

The nucleus rotundus is a large thalamic nucleus in birds and plays a critical role in many visual discrimination tasks. In order to test the hypothesis that there are functionally distinct subdivisions in the nucleus rotundus, effects of selective lesions of the nucleus were studied in pigeons. The birds were trained to discriminate between different types of stationary objects and between different directions of moving objects. Multiple regression analyses revealed that lesions in the anterior, but not posterior, division caused deficits in discrimination of small stationary stimuli. Lesions in neither the anterior nor posterior divisions predicted effects in discrimination of moving stimuli. These results are consistent with a prediction led from the hypothesis that the nucleus is composed of functional subdivisions.

From the Old to the New World of Nuclear Physics

NASA Astrophysics Data System (ADS)

Stuewer, Roger H.

Physicists passed from the Old to the New World of Nuclear Physics in the two decades between the first and second world wars. The transition occurred against the background of the Great War, the postwar hyperinflation in Germany and Austria, and the greatest intellection migrations in history after the Nazi Civil Service law of 1933, the Anschlussof Austria in March 1938, and the Fascist anti-Semitic laws that fall. It involved Rutherford's discovery of artificial disintegration, Pettersson and Kirsch's challenge of it, and the concomitant rise and fall of Rutherford's satellite model of the nucleus; Gamow's quantum-mechanical theory of alpha decay and his liquid-drop model of the nucleus; the discoveries of deuterium and the deuteron, neutron, and positron, and the inventions of the Cockcroft-Walton accelerator and the cyclotron; the influence of the seventh Solvay Conference; Joliot and Curie's discovery of artificial radioactivity; Pauli's neutrino hypothesis, Fermi's theory of beta decay, and his discovery of the efficacy of slow neutrons in producing nuclear reactions; Bohr's theory of the compound nucleus and Breit and Wigner's theory of neutron-nucleus resonances; and the discovery of nuclear fission, Meitner and Frisch's interpretation of it, and Bohr and Fermi revelation of both in America.

Nuclear Fusion Rate Study of a Muonic Molecule via Nuclear Threshold Resonances

NASA Astrophysics Data System (ADS)

Faghihi, F.; Eskandari, M. R.

This work follows our previous calculations of the ground state binding energy, size, and the effective nuclear charge of the muonic T3 molecule, using the Born-Oppenheimer adiabatic approximation. In our past articles, we showed that the system possesses two minimum positions, the first one at the muonic distance and the second at the atomic distance. Also, the symmetric planner vibrational model assumed between the two minima and the approximated potential were calculated. Following from the previous studies, we now calculate the fusion rate of the T3 muonic molecule according to the overlap integral of the resonance nuclear compound nucleus and the molecular wave functions.

Discovery of Tyk2 inhibitors via the virtual site-directed fragment-based drug design.

PubMed

Jang, Woo Dae; Kim, Jun-Tae; Son, Hoon Young; Park, Seung Yeon; Cho, Young Sik; Koo, Tae-sung; Lee, Hyuk; Kang, Nam Sook

2015-09-15

In this study, we synthesized compound 12 with potent Tyk2 inhibitory activity from FBDD study and carried out a cell-based assay for Tyk2/STAT3 signaling activation upon IFNα5 stimulation. Compound 12 completely suppressed the IFNα5-mediated Tyk2/STAT3 signaling pathway as well as the basal levels of pSTAT3. Stimulation with IFNα/β leads to the tyrosine phosphorylation of the JAK1 and Tyk2 receptor-associated kinases with subsequent STATs activation, transmitting signals from the cell surface receptor to the nucleus. In conclusion, the potency of compound 12 to interrupt the signal transmission of Tyk2/STAT3 appeared to be equivalent or superior to that of the reference compound. Copyright © 2015 Elsevier Ltd. All rights reserved.

Fluorine in psychedelic phenethylamines.

PubMed

Trachsel, Daniel

2012-01-01

The so-called psychedelic phenethylamines represent a class of drugs with a large range of psychoactive properties in humans, ranging from naturally occurring mescaline to amphetamine analogues and homologues. The interest in many of these compounds, occasionally referred to as designer-drugs, is widely dispersed across popular culture and political and scientific communities. In recent decades, fluorine has become a powerful and important tool in medicinal chemistry. In addition, fluorine-containing compounds and medicines can be found in numerous commercially successful pharmaceuticals that have gained a market share of some 5-15%. One might anticipate this trend to increase in the future. As far as fluorinated phenethylamines are concerned, much less is known about their chemistry and pharmacology. This paper provides an overview regarding the biological properties of over 60 fluorinated phenethylamines and discusses both historical and recent chemistry-related developments. It was shown that the introduction of fluorine into the phenethylamine nucleus can impact greatly on psychoactivity of these compounds, ranging from marked loss to enhancement and prolongation of effects. For example, in contrast to the psychoactive escaline (70), it was observed that its fluoroescaline (76) counterpart was almost devoid of psychoactive effects. Difluoroescaline (77), on the other hand, retained, and trifluoroescaline (78) showed increased human potency of escaline (70). Difluoromescaline (72) and trifluoromescaline (73) increasingly surpassed human potency and duration of mescaline (22) effects. Copyright © 2012 John Wiley & Sons, Ltd.

Criticality of the electron-nucleus cusp condition to local effective potential-energy theories

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pan Xiaoyin; Sahni, Viraht; Graduate School of the City University of New York, 360 Fifth Avenue, New York, New York 10016

2003-01-01

Local(multiplicative) effective potential energy-theories of electronic structure comprise the transformation of the Schroedinger equation for interacting Fermi systems to model noninteracting Fermi or Bose systems whereby the equivalent density and energy are obtained. By employing the integrated form of the Kato electron-nucleus cusp condition, we prove that the effective electron-interaction potential energy of these model fermions or bosons is finite at a nucleus. The proof is general and valid for arbitrary system whether it be atomic, molecular, or solid state, and for arbitrary state and symmetry. This then provides justification for all prior work in the literature based on themore » assumption of finiteness of this potential energy at a nucleus. We further demonstrate the criticality of the electron-nucleus cusp condition to such theories by an example of the hydrogen molecule. We show thereby that both model system effective electron-interaction potential energies, as determined from densities derived from accurate wave functions, will be singular at the nucleus unless the wave function satisfies the electron-nucleus cusp condition.« less

[Analysis of the Effect of Non-phacoemulsification Cataract Operation on Corneal Endothelial Cell Nucleus Division].

PubMed

Huang, Zufeng; Miao, Xiaoqing

2015-09-01

To investigate the effect of non-phacoemulsification cataract operation in two different patterns of nucleus delivery on the quantity and morphology of corneal endothelial cells and postoperative visual acuity. Forty patients diagnosed with cataract underwent cataract surgery and were assigned into the direct nuclear delivery and semi-nuclear delivery groups. Lens density was measured and divided into the hard and soft lenses according to Emery-little lens nucleus grading system. Non-phacoemulsification cataract operation was performed. At 3 d after surgery, the quantity and morphology of corneal endothelium were counted and observed under corneal endothelial microscope. During 3-month postoperative follow-up, the endothelial cell loss rate, morphological changes and visual acuity were compared among four groups. Corneal endothelial cell loss rate in the direct delivery of hard nucleus group significantly differed from those in the other three groups before and 3 months after operation (P < 0.01), whereas no statistical significance was found among the direct delivery of soft nucleus, semi-delivery of hard nucleus and semi-delivery soft nucleus groups (all P > 0.05). Preoperative and postoperative 2-d visual acuity did not differ between the semi-delivery of hard nucleus and direct delivery of soft nucleus groups (P = 0.49), significantly differed from those in the semi-delivery of soft nucleus (P = 0.03) and direct delivery of hard nucleus groups (P = 0.14). Visual acuity at postoperative four months did not differ among four groups (P = 0.067). During non-phacoemulsification cataract surgery, direct delivery of hard nucleus caused severe injury to corneal endothelium and semi-delivery of soft nucleus yielded mild corneal endothelial injury. Slight corneal endothelial injury exerted no apparent effect upon visual acuity and corneal endothelial morphology at three months after surgery.

In vitro and in silico investigations of disc nucleus replacement

PubMed Central

Reitmaier, Sandra; Shirazi-Adl, Aboulfazl; Bashkuev, Maxim; Wilke, Hans-Joachim; Gloria, Antonio; Schmidt, Hendrik

2012-01-01

Currently, numerous hydrogels are under examination as potential nucleus replacements. The clinical success, however, depends on how well the mechanical function of the host structure is restored. This study aimed to evaluate the extent to and mechanisms by which surgery for nucleus replacements influence the mechanical behaviour of the disc. The effects of an annulus defect with and without nucleus replacement on disc height and nucleus pressure were measured using 24 ovine motion segments. The following cases were considered: intact; annulus incision repaired by suture and glue; annulus incision with removal and re-implantation of nucleus tissue repaired by suture and glue or plug. To identify the likely mechanisms observed in vitro, a finite-element model of a human disc (L4–L5) was employed. Both studies were subjected to physiological cycles of compression and recovery. A repaired annulus defect did not influence the disc behaviour in vitro, whereas additional nucleus removal and replacement substantially decreased disc stiffness and nucleus pressure. Model predictions demonstrated the substantial effects of reductions in replaced nucleus water content, bulk modulus and osmotic potential on disc height loss and pressure, similar to measurements. In these events, the compression load transfer in the disc markedly altered by substantially increasing the load on the annulus when compared with the nucleus. The success of hydrogels for nucleus replacements is not only dependent on the implant material itself but also on the restoration of the environment perturbed during surgery. The substantial effects on the disc response of disruptions owing to nucleus replacements can be simulated by reduced nucleus water content, elastic modulus and osmotic potential. PMID:22337630

Statistical and dynamical modeling of heavy-ion fusion-fission reactions

NASA Astrophysics Data System (ADS)

Eslamizadeh, H.; Razazzadeh, H.

2018-02-01

A modified statistical model and a four dimensional dynamical model based on Langevin equations have been used to simulate the fission process of the excited compound nuclei 207At and 216Ra produced in the fusion 19F + 188Os and 19F + 197Au reactions. The evaporation residue cross section, the fission cross section, the pre-scission neutron, proton and alpha multiplicities and the anisotropy of fission fragments angular distribution have been calculated for the excited compound nuclei 207At and 216Ra. In the modified statistical model the effects of spin K about the symmetry axis and temperature have been considered in calculations of the fission widths and the potential energy surfaces. It was shown that the modified statistical model can reproduce the above mentioned experimental data by using appropriate values of the temperature coefficient of the effective potential equal to λ = 0.0180 ± 0.0055, 0.0080 ± 0.0030 MeV-2 and the scaling factor of the fission barrier height equal to rs = 1.0015 ± 0.0025, 1.0040 ± 0.0020 for the compound nuclei 207At and 216Ra, respectively. Three collective shape coordinates plus the projection of total spin of the compound nucleus on the symmetry axis, K, were considered in the four dimensional dynamical model. In the dynamical calculations, dissipation was generated through the chaos weighted wall and window friction formula. Comparison of the theoretical results with the experimental data showed that two models make it possible to reproduce satisfactorily the above mentioned experimental data for the excited compound nuclei 207At and 216Ra.

Uptake and efflux of rhenium in cells exposed to rhenium diseleno-ether and tissue distribution of rhenium and selenium after rhenium diseleno-ether treatment in mice.

PubMed

Collery, Philippe; Bastian, Gérard; Santoni, François; Mohsen, Ahmed; Wei, Ming; Collery, Thomas; Tomas, Alain; Desmaele, Didier; D'Angelo, Jean

2014-04-01

We proposed a new water-soluble rhenium diseleno-ether compound (with one atom of Re and two atoms of Se) and investigated the uptake of Re into the nucleus of malignant cells in culture exposed to the compound for 48 h and its efflux from the nucleus after a post-exposure period of 48 h, as DNA is the main target of Re. We also studied the distribution of both Re and Se in the main organs after an oral administration of 10 or 40 mg/kg Re diseleno-ether to mice for four weeks, five days-a-week. Re and Se concentrations were assayed by inductively coupled plasma mass spectrometry (ICP-MS). Statistical analysis was performed using the Wilcoxon signed-rank test, comparing two related groups. We observed that Re was well incorporated into the nucleus of malignant cells in the most sensitive cells MCF-7, derived from human breast cancer, and that there was no efflux of Re. In contrast, in MCF-7 resistant cells (MCF-7 Mdr and MCF-7 R), A549 and HeLa cells, there was significant efflux of Re from the nucleus after the wash-out period. In mice, an important and dose-dependent uptake of both Re and Se was observed in the liver, with lower concentrations in kidneys. The lowest concentrations were observed in blood, lung, spleen and bones. There was a significant increase of Re concentrations in the blood, liver and kidney in mice treated with Re diseleno-ether at the dose of 40 mg/kg/24 h versus those treated at the dose of 10 mg/kg/24 h. There was a significant increase of Se concentrations in all tissues with the dose of Re diseleno-ether of 10 mg/kg/24 h versus controls, and a significant increase in the liver in mice treated with dose of Re diseleno-ether of 40 mg/kg/24h versus those treated with 10 mg/kg/24 h. We are the first to demonstrate that a compound combining Re and Se in a single molecule, is able to deliver Re and Se to the organism via an oral route, for cancer treatment.

INHIBITION OF VASOPRESSIN RELEASE IN THE RAT SUPRAOPTIC NUCLEUS BY EXPOSRUE TO THE PBDE MIXTURE (DE-71) IN VITRO.

EPA Science Inventory

Introduction

Persistent organic pollutants (POPs) are long-lived toxic organic compounds and are of major concern for human

and ecosystem health1,2 . Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are

examples of such chemicals...

Light charged particle multiplicities in fusion and quasifission reactions

NASA Astrophysics Data System (ADS)

Kalandarov, Sh. A.; Adamian, G. G.; Antonenko, N. V.; Lacroix, D.; Wieleczko, J. P.

2018-01-01

The light charged particle evaporation from the compound nucleus and from the complex fragments in the reactions 32S+100Mo, 121Sb+27Al, 40Ar+164Dy, and 40Ar+ nat Ag is studied within the dinuclear system model. The possibility to distinguish the reaction products from different reaction mechanisms is discussed.

Analysis of the potential geochemical reactions in the Enceladus' hydrothermal environment

NASA Astrophysics Data System (ADS)

Ramirez-Cabañas, A. K.; Flandes, A.

2017-12-01

Enceladus is the sixth largest moon of Saturn and differs from its other moons, because of its cryovolcanic geysers that emanate from its south pole. The instruments of the Cassini spacecraft reveal different compounds in the gases and the dust of the geysers, such as salts (sodium chloride, sodium bicarbonate and/or sodium carbonate), as well as silica traces (Postberg et al., 2008, 2009) that could be the result of a hydrothermal environment (Hsu et al., 2014, Sekine et al., 2014). By means of a thermodynamic analysis, we propose and evaluate potential geochemical reactions that could happen from the interaction between the nucleus surface and the inner ocean of Enceladus. These reactions may well lead to the origin of the compounds found in the geysers. From this analysis, we propose that, at least, two minerals must be present in the condritic nucleus of Enceladus: olivines (fayalite and fosterite) and feldspar (orthoclase and albite). Subsequently, taking as reference the hydrothermal processes that take place on Earth, we propose the different stages of a potential hydrothermal scenario for Enceladus.

Comets: Role and importance to exobiology

NASA Technical Reports Server (NTRS)

Delsemme, Armand H.

1992-01-01

The transfer of organic compounds from interstellar space to the outskirts of a protoplanetary disk, their accretion into cometary objects, and the transport of the latter into the inner solar system by orbital diffusion throw a new light on the central problem of exobiology. It suggests the existence of a cosmic mechanism, working everywhere, that can supply prebiotic compounds to ubiquitous rocky planets, in search of the proper environment to start life in many places in the Universe. Under the heading of chemistry of the cometary nucleus, the following topics are covered: radial homogeneity of the nucleus; the dust-to-ice ratio; nature of the dust grains; origin of the dust in comets; nature of the volatile fraction; the CO distribution in comet Halley; dust contribution to the volatile fraction; elemental balance sheet of comet Halley; quantitative molecular analysis of the volatile fraction; and isotopic ratios. Under the heading of exogenous origin of carbon on terrestrial planets the following topics are covered: evidence for a high-temperature phase; from planetesimals to planets; a veneer of volatile and organic material; and cometary contribution.

Cytotoxicity, DNA binding and localisation of novel bis-naphthalimidopropyl polyamine derivatives.

PubMed

Pavlov, V; Kong Thoo Lin, P; Rodilla, V

2001-07-31

Bis-naphthalimidopropyl spermidine (BNIPSpd), spermine (BNIPSpm) and oxa-spermine (BNIPOSpm) showed high in vitro cytotoxicity against human breast cancer MCF-7 cells with IC(50) values of 1.38, 2.91 and 8.45 microM, respectively. These compounds were found to effectively displace the intercalating agent ethidium bromide bound to the calf thymus DNA using fluorimetric methods (C(50) 0.08-0.12 microM) and their apparent equilibrium binding constants (K(app)) were calculated to be in the range of 10.5-18 x 10(7) M(-1). Furthermore, strong stabilisation of calf thymus DNA duplex in the presence of bis-naphthalimidopropyl polyamine derivatives (BNIPSpd, BNIPSpm and BNIPOSpm) was observed by UV spectrophotometric analysis (T(m)=93.3-97 degrees C compared with 75 degrees C for calf thymus DNA without drug). Because of their inherent fluorescence, these compounds were localised preferentially inside the nucleus as evidenced by their direct observation under the fluorescence microscope. The results obtained suggest that the cytotoxic activity of the bis-naphthalimidopropyl polyamines may be in part, caused by their effects on DNA.

Serotonergic hallucinogens differentially modify gamma and high frequency oscillations in the rat nucleus accumbens.

PubMed

Goda, Sailaja A; Piasecka, Joanna; Olszewski, Maciej; Kasicki, Stefan; Hunt, Mark J

2013-07-01

The nucleus accumbens (NAc) is a site critical for the actions of many drugs of abuse. Psychoactive compounds, such as N-methyl-D-aspartate receptor (NMDAR) antagonists, modify gamma (40-90) and high frequency oscillations (HFO, 130-180 Hz) in local field potentials (LFPs) recorded in the NAc. Lysergic acid diethylamide (LSD) and 2,5-dimethoxy-4-iodoamphetamine (DOI) are serotonergic hallucinogens and activation of 5HT2A receptors likely underlies their hallucinogenic effects. Whether these compounds can also modulate LFP oscillations in the NAc is unclear. This study aims to examine the effect of serotonergic hallucinogens on gamma and HFO recorded in the NAc and to test whether 5HT2A receptors mediate the effects observed. LFPs were recorded from the NAc of freely moving rats. Drugs were administered intraperitoneally. LSD (0.03-0.3 mg/kg) and DOI (0.5-2.0 mg/kg) increased the power and reduced the frequency of HFO. In contrast, the hallucinogens produced a robust reduction in the power of low (40-60 Hz), but not high gamma oscillations (70-90 Hz). MDL 11939 (1.0 mg/kg), a 5HT2A receptor antagonist, fully reversed the changes induced by DOI on HFO but only partially for the low gamma band. Equivalent increases in HFO power were observed after TCB-2 (5HT2A receptor agonist, 0.1-1.5 mg/kg), but not CP 809101 (5H2C receptor agonist, 0.1-3 mg/kg). Notably, hallucinogen-induced increases in HFO power were smaller than those produced by ketamine (25 mg/kg). Serotonergic hallucinogen-induced changes in HFO and gamma are mediated, at least in part, by stimulation of 5HT2A receptors. Comparison of the oscillatory changes produced by serotonergic hallucinogens and NMDAR antagonists are also discussed.

Gene delivery by a steroid-peptide nucleic acid conjugate.

PubMed

Rebuffat, Alexandre G; Nawrocki, Andrea R; Nielsen, Peter E; Bernasconi, Alessio G; Bernal-Mendez, Eloy; Frey, Brigitte M; Frey, Felix J

2002-09-01

We previously introduced a method called steroid-mediated gene delivery (SMGD), which uses steroid receptors as shuttles to facilitate the nuclear uptake of transfected DNA. Here, we describe a SMGD strategy with peptide nucleic acids (PNAs) that allowed linkage of a steroid molecule to a defined position in a plasmid without disturbing its gene expression. We synthesized and tested several bifunctional steroid derivatives [patent in process of nationalization] and finally selected the compound named DEX-bisPNA, a molecule consisting of a dexamethasone moiety linked to a PNA clamp (bisPNA) through a 30-atom chemical spacer. Dex-bisPNA binds to the glucocorticoid receptor (GR) as well as to reporter plasmids containing the corresponding PNA binding sites, translocates the GR from the cytoplasm into the nucleus, and increases the delivery of plasmid to the nucleus, resulting in enhanced GR-dependent expression of the reporter gene. The SMGD effect was more pronounced in growth-arrested cells than in proliferating cells. The specificity for the GR was shown by the reversion of the SMGD effect in the presence of dexamethasone as well as an enhanced expression in GR-positive cells but not in GR-negative cells. Thus, SMGD with PNA is a promising strategy for nonviral gene delivery into target tissues expressing specific steroid receptors.

Advanced model for the prediction of the neutron-rich fission product yields

NASA Astrophysics Data System (ADS)

Rubchenya, V. A.; Gorelov, D.; Jokinen, A.; Penttilä, H.; Äystö, J.

2013-12-01

The consistent models for the description of the independent fission product formation cross sections in the spontaneous fission and in the neutron and proton induced fission at the energies up to 100 MeV is developed. This model is a combination of new version of the two-component exciton model and a time-dependent statistical model for fusion-fission process with inclusion of dynamical effects for accurate calculations of nucleon composition and excitation energy of the fissioning nucleus at the scission point. For each member of the compound nucleus ensemble at the scission point, the primary fission fragment characteristics: kinetic and excitation energies and their yields are calculated using the scission-point fission model with inclusion of the nuclear shell and pairing effects, and multimodal approach. The charge distribution of the primary fragment isobaric chains was considered as a result of the frozen quantal fluctuations of the isovector nuclear matter density at the scission point with the finite neck radius. Model parameters were obtained from the comparison of the predicted independent product fission yields with the experimental results and with the neutron-rich fission product data measured with a Penning trap at the Accelerator Laboratory of the University of Jyväskylä (JYFLTRAP).

GLP-1 and estrogen conjugate acts in the supramammillary nucleus to reduce food-reward and body weight.

PubMed

Vogel, Heike; Wolf, Stefanie; Rabasa, Cristina; Rodriguez-Pacheco, Francisca; Babaei, Carina S; Stöber, Franziska; Goldschmidt, Jürgen; DiMarchi, Richard D; Finan, Brian; Tschöp, Matthias H; Dickson, Suzanne L; Schürmann, Annette; Skibicka, Karolina P

2016-11-01

The obesity epidemic continues unabated and currently available pharmacological treatments are not sufficiently effective. Combining gut/brain peptide, GLP-1, with estrogen into a conjugate may represent a novel, safe and potent, strategy to treat diabesity. Here we demonstrate that the central administration of GLP-1-estrogen conjugate reduced food reward, food intake, and body weight in rats. In order to determine the brain location of the interaction of GLP-1 with estrogen, we avail of single-photon emission computed tomography imaging of regional cerebral blood flow and pinpoint a brain site unexplored for its role in feeding and reward, the supramammillary nucleus (SUM) as a potential target of the conjugated GLP-1-estrogen. We confirm that conjugated GLP-1 and estrogen directly target the SUM with site-specific microinjections. Additional microinjections of GLP-1-estrogen into classic energy balance controlling nuclei, the lateral hypothalamus (LH) and the nucleus of the solitary tract (NTS) revealed that the metabolic benefits resulting from GLP-1-estrogen injections are mediated through the LH and to some extent by the NTS. In contrast, no additional benefit of the conjugate was noted on food reward when the compound was microinjected into the LH or the NTS, identifying the SUM as the only neural substrate identified here to underlie the reward reducing benefits of GLP-1 and estrogen conjugate. Collectively we discover a surprising neural substrate underlying food intake and reward effects of GLP-1 and estrogen and uncover a new brain area capable of regulating energy balance and reward. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Effects of systemic L-tyrosine on dopamine release from rat corpus striatum and nucleus accumbens

NASA Technical Reports Server (NTRS)

During, Matthew J.; Acworth, Ian N.; Wurtman, Richard J.

1988-01-01

Intracerebral dialysis was used to monitor extracellular fluid from rat striatum and nucleus accumbens following the intraperitoneal administration of tyrosine. Dopamine concentrations in dialysates from both the striatum and the nucleus accumbens increased significantly in response to the tyrosine. The magnitude of the tyrosine effect was greater in the nucleus accumbens than in the striatum. Hence, mesolimbic dopaminergic neurons may be especially responsive to precursor availability.

Extended Glauber Model of Antiproton-Nucleus Annihilation for All Energies and Mass Numbers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Teck-Ghee; Wong, Cheuk-Yin

2014-01-01

Previous analytical formulas in the Glauber model for high-energy nucleus-nucleus collisions developed by Wong are utilized and extended to study Antiproton-nucleus annihilations for both high and low energies, after taking into account the effects of Coulomb and nuclear interactions, and the change of the antiproton momentum inside a nucleus. The extended analytical formulas capture the main features of the experimental antiproton-nucleus annihilation cross sections for all energies and mass numbers. At high antiproton energies, they exhibit the granular property for the lightest nuclei and the black-disk limit for the heavy nuclei. At low antiproton energies, they display the effect ofmore » the antiproton momentum increase due to the nuclear interaction for the light nuclei, and the effect of the magnification due to the attractive Coulomb interaction for the heavy nuclei.« less

Novel Penicillin Analogues as Potential Antimicrobial Agents; Design, Synthesis and Docking Studies.

PubMed

Ashraf, Zaman; Bais, Abdul; Manir, Md Maniruzzaman; Niazi, Umar

2015-01-01

A number of penicillin derivatives (4a-h) were synthesized by the condensation of 6-amino penicillinic acid (6-APA) with non-steroidal anti-inflammatory drugs as antimicrobial agents. In silico docking study of these analogues was performed against Penicillin Binding Protein (PDBID 1CEF) using AutoDock Tools 1.5.6 in order to investigate the antimicrobial data on structural basis. Penicillin binding proteins function as either transpeptidases or carboxypeptidases and in few cases demonstrate transglycosylase activity in bacteria. The excellent antibacterial potential was depicted by compounds 4c and 4e against Escherichia coli, Staphylococcus epidermidus and Staphylococcus aureus compared to the standard amoxicillin. The most potent penicillin derivative 4e exhibited same activity as standard amoxicillin against S. aureus. In the enzyme inhibitory assay the compound 4e inhibited E. coli MurC with an IC50 value of 12.5 μM. The docking scores of these compounds 4c and 4e also verified their greater antibacterial potential. The results verified the importance of side chain functionalities along with the presence of central penam nucleus. The binding affinities calculated from docking results expressed in the form of binding energies ranges from -7.8 to -9.2kcal/mol. The carboxylic group of penam nucleus in all these compounds is responsible for strong binding with receptor protein with the bond length ranges from 3.4 to 4.4 Ǻ. The results of present work ratify that derivatives 4c and 4e may serve as a structural template for the design and development of potent antimicrobial agents.

Novel Penicillin Analogues as Potential Antimicrobial Agents; Design, Synthesis and Docking Studies

PubMed Central

Ashraf, Zaman; Bais, Abdul; Manir, Md. Maniruzzaman; Niazi, Umar

2015-01-01

A number of penicillin derivatives (4a-h) were synthesized by the condensation of 6-amino penicillinic acid (6-APA) with non-steroidal anti-inflammatory drugs as antimicrobial agents. In silico docking study of these analogues was performed against Penicillin Binding Protein (PDBID 1CEF) using AutoDock Tools 1.5.6 in order to investigate the antimicrobial data on structural basis. Penicillin binding proteins function as either transpeptidases or carboxypeptidases and in few cases demonstrate transglycosylase activity in bacteria. The excellent antibacterial potential was depicted by compounds 4c and 4e against Escherichia coli, Staphylococcus epidermidus and Staphylococcus aureus compared to the standard amoxicillin. The most potent penicillin derivative 4e exhibited same activity as standard amoxicillin against S. aureus. In the enzyme inhibitory assay the compound 4e inhibited E. coli MurC with an IC50 value of 12.5 μM. The docking scores of these compounds 4c and 4e also verified their greater antibacterial potential. The results verified the importance of side chain functionalities along with the presence of central penam nucleus. The binding affinities calculated from docking results expressed in the form of binding energies ranges from -7.8 to -9.2kcal/mol. The carboxylic group of penam nucleus in all these compounds is responsible for strong binding with receptor protein with the bond length ranges from 3.4 to 4.4 Ǻ. The results of present work ratify that derivatives 4c and 4e may serve as a structural template for the design and development of potent antimicrobial agents. PMID:26267242

Spin distributions and cross sections of evaporation residues in the 28Si+176Yb reaction

NASA Astrophysics Data System (ADS)

Sudarshan, K.; Tripathi, R.; Sodaye, S.; Sharma, S. K.; Pujari, P. K.; Gehlot, J.; Madhavan, N.; Nath, S.; Mohanto, G.; Mukul, I.; Jhingan, A.; Mazumdar, I.

2017-02-01

Background: Non-compound-nucleus fission in the preactinide region has been an active area of investigation in the recent past. Based on the measurements of fission-fragment mass distributions in the fission of 202Po, populated by reactions with varying entrance channel mass asymmetry, the onset of non-compound-nucleus fission was proposed to be around ZpZt˜1000 [Phys. Rev. C 77, 024606 (2008), 10.1103/PhysRevC.77.024606], where Zp and Zt are the projectile and target proton numbers, respectively. Purpose: The present paper is aimed at the measurement of cross sections and spin distributions of evaporation residues in the 28Si+176Yb reaction (ZpZt=980 ) to investigate the fusion hindrance which, in turn, would give information about the contribution from non-compound-nucleus fission in this reaction. Method: Evaporation-residue cross sections were measured in the beam energy range of 129-166 MeV using the hybrid recoil mass analyzer (HYRA) operated in the gas-filled mode. Evaporation-residue cross sections were also measured by the recoil catcher technique followed by off-line γ -ray spectrometry at few intermediate energies. γ -ray multiplicities of evaporation residues were measured to infer about their spin distribution. The measurements were carried out using NaI(Tl) detector-based 4π-spin spectrometer from the Tata Institute of Fundamental Research, Mumbai, coupled to the HYRA. Results: Evaporation-residue cross sections were significantly lower compared to those calculated using the statistical model code pace2 [Phys. Rev. C 21, 230 (1980), 10.1103/PhysRevC.21.230] with the coupled-channel fusion model code ccfus [Comput. Phys. Commun. 46, 187 (1987), 10.1016/0010-4655(87)90045-2] at beam energies close to the entrance channel Coulomb barrier. At higher beam energies, experimental cross sections were close to those predicted by the model. Average γ -ray multiplicities or angular momentum values of evaporation residues were in agreement with the calculations of the code ccfus + pace2 within the experimental uncertainties at all the beam energies. Conclusions: Deviation of evaporation-residue cross sections from the "fusion + statistical model" predictions at beam energies close to the entrance channel Coulomb barrier indicates fusion hindrance at these beam energies which would lead to non-compound-nucleus fission. However, reasonable agreement of average angular momentum values of evaporation residues at these beam energies with those calculated using the coupled-channel fusion model with the statistical model codes ccfus + pace2 suggests that fusion suppression at beam energies close to the entrance channel Coulomb barrier where populated l waves are low is not l dependent.

Lowering glucose level elevates [Ca2+]i in hypothalamic arcuate nucleus NPY neurons through P/Q-type Ca2+ channel activation and GSK3β inhibition

PubMed Central

Chen, Yu; Zhou, Jun; Xie, Na; Huang, Chao; Zhang, Jun-qi; Hu, Zhuang-li; Ni, Lan; Jin, You; Wang, Fang; Chen, Jian-guo; Long, Li-hong

2012-01-01

Aim: To identify the mechanisms underlying the elevation of intracellular Ca2+ level ([Ca2+]i) induced by lowering extracellular glucose in rat hypothalamic arcuate nucleus NPY neurons. Methods: Primary cultures of hypothalamic arcuate nucleus (ARC) neurons were prepared from Sprague-Dawley rats. NPY neurons were identified with immunocytochemical method. [Ca2+]i was measured using fura-2 AM. Ca2+ current was recorded using whole-cell patch clamp recording. AMPK and GSK3β levels were measured using Western blot assay. Results: Lowering glucose level in the medium (from 10 to 1 mmol/L) induced a transient elevation of [Ca2+]i in ARC neurons, but not in hippocampal and cortical neurons. The low-glucose induced elevation of [Ca2+]i in ARC neurons depended on extracellular Ca2+, and was blocked by P/Q-type Ca2+channel blocker ω-agatoxin TK (100 nmol/L), but not by L-type Ca2+ channel blocker nifedipine (10 μmol/L) or N-type Ca2+channel blocker ω-conotoxin GVIA (300 nmol/L). Lowering glucose level increased the peak amplitude of high voltage-activated Ca2+ current in ARC neurons. The low-glucose induced elevation of [Ca2+]i in ARC neurons was blocked by the AMPK inhibitor compound C (20 μmol/L), and enhanced by the GSK3β inhibitor LiCl (10 mmol/L). Moreover, lowering glucose level induced the phosphorylation of AMPK and GSK3β, which was inhibited by compound C (20 μmol/L). Conclusion: Lowering glucose level enhances the activity of P/Q type Ca2+channels and elevates [Ca2+]i level in hypothalamic arcuate nucleus neurons via inhibition of GSK3β. PMID:22504905

Inhibition of adenovirus replication by a trisubstituted piperazin-2-one derivative.

PubMed

Sanchez-Cespedes, Javier; Moyer, Crystal L; Whitby, Landon R; Boger, Dale L; Nemerow, Glen R

2014-08-01

The number of disseminated adenovirus (Ad) infections continues to increase mostly due to the growing use of immunosuppressive treatments. Recipients of solid organ or hematopoietic stem cell transplants, mainly in pediatric units, exhibit a high morbidity and mortality due to these infections. Unfortunately, there are no Ad-specific antiviral drugs currently approved for medical use. To address this situation, we used high-throughput screening (HTS) of synthetic small molecule libraries to identify compounds that restrict Ad infection. Among the more than 25,000 compounds screened, we identified a hit compound that significantly inhibited Ad infection. The compound (15D8) is a trisubstituted piperazin-2-one derivative that showed substantial antiviral activity with little or no cytotoxicity at low micromolar concentrations. Compound 15D8 selectively inhibits Ad DNA replication in the nucleus, providing a potential candidate for the development of a new class of antiviral compounds to treat Ad infections. Copyright © 2014 Elsevier B.V. All rights reserved.

Synthesis of Some New Tetrahydropyrimidine Derivatives as Possible Antibacterial Agents.

PubMed

Foroughifar, Naser; Karimi Beromi, Somayeh; Pasdar, Hoda; Shahi, Masoumeh

2017-01-01

Heterocyclic compounds containing a pyrimidine nucleus are of special interests thanks to their applications in medicinal chemistry as they are the basic skeleton of several bioactive compounds such as antifungal, antibacterial, antitumor and antitubercular. As a part of our research in the synthesis of pyrimidine derivatives containing biological activities, some new tetrahydropyrimidine derivatives (1-10) were synthesized via Biginelli reaction using HCl or DABCO as a catalyst with good yields. All structures of products were confirmed by IR, 1 H NMR and 13 C NMR spectroscopy. The antibacterial activity of some synthesized compounds was investigated against Staphylococcus aureus (ATCC 6538), Staphylococcus epidermidis (ATCC 12228) , Bacillus cereus (ATCC14579) , Esherichia coli (ATCC 25922), Klebsiella pneumonia (ATCC 13883) and Pseudomonas aeruginosa (PAO1) bacteria. Some of these compounds such as 8 and 10 exhibited a good to significant antibacterial activity.

Synthesis of Some New Tetrahydropyrimidine Derivatives as Possible Antibacterial Agents

PubMed Central

Foroughifar, Naser; Karimi Beromi, Somayeh; Pasdar, Hoda; Shahi, Masoumeh

2017-01-01

Heterocyclic compounds containing a pyrimidine nucleus are of special interests thanks to their applications in medicinal chemistry as they are the basic skeleton of several bioactive compounds such as antifungal, antibacterial, antitumor and antitubercular. As a part of our research in the synthesis of pyrimidine derivatives containing biological activities, some new tetrahydropyrimidine derivatives (1-10) were synthesized via Biginelli reaction using HCl or DABCO as a catalyst with good yields. All structures of products were confirmed by IR, 1H NMR and 13C NMR spectroscopy. The antibacterial activity of some synthesized compounds was investigated against Staphylococcus aureus (ATCC 6538), Staphylococcus epidermidis (ATCC 12228), Bacillus cereus (ATCC14579), Esherichia coli (ATCC 25922), Klebsiella pneumonia (ATCC 13883) and Pseudomonas aeruginosa (PAO1) bacteria. Some of these compounds such as 8 and 10 exhibited a good to significant antibacterial activity. PMID:28979312

Shadowing effects on J/ψ and Υ production at energies available at the CERN Large Hadron Collider

DOE PAGES

Vogt, R.

2015-09-17

Proton-nucleus collisions have been used as a intermediate baseline for the determination of cold medium effects. They lie between proton-proton collisions in vacuum and nucleus-nucleus collisions which are expected to be dominated by hot matter effects. Modifications of the quark densities in nuclei relative to those of the proton are well established although those of the gluons in the nucleus are not well understood. We focus on the effect of these on quarkonium production in proton-lead collisions at the LHC at a center of mass energy of 5.02 TeV.

Effect of repulsive and attractive three-body forces on nucleus-nucleus elastic scattering

DOE Office of Scientific and Technical Information (OSTI.GOV)

Furumoto, T.; Sakuragi, Y.; Yamamoto, Y.

2009-10-15

The effect of the three-body force (TBF) is studied in nucleus-nucleus elastic scattering on the basis of Brueckner theory for nucleon-nucleon (NN) effective interaction (complex G matrix) in the nuclear matter. A new G matrix called CEG07 proposed recently by the present authors includes the TBF effect and reproduces a realistic saturation curve in the nuclear matter, and it is shown to well reproduce proton-nucleus elastic scattering. The microscopic optical potential for the nucleus-nucleus system is obtained by folding the G matrix with nucleon density distributions in colliding nuclei. We first analyze in detail the {sup 16}O+{sup 16}O elastic scatteringmore » at E/A=70 MeV. The observed cross sections are nicely reproduced up to the most backward scattering angles only when the TBF effect is included. The use of the frozen-density approximation (FDA) is essentially important to properly estimate the effect of the TBF in nucleus-nucleus scattering. Other prescriptions for defining the local density have also been tested, but only the FDA prescription gives a proper description of the experimental cross sections as well as the effect of the TBF. The effects of the three-body attraction and the {omega}-rearrangement term are also analyzed. The CEG07 interaction is compared with CDM3Y6, which is a reliable and successful effective density-dependent NN interaction used in the double-folding model. The CEG07 G matrix is also tested in the elastic scattering of {sup 16}O by the {sup 12}C, {sup 28}Si, and {sup 40}Ca targets at E/A=93.9 MeV, and in the elastic scattering of {sup 12}C by the {sup 12}C target at E/A=135 MeV with great success. The decisive effect of the TBF is clearly seen also in those systems. Finally, we have tested CEG07a, CEG07b, and CEG07c for the {sup 16}O+{sup 16}O system at various energies.« less

Double dissociation in the neural substrates of acute opiate dependence as measured by withdrawal-potentiated startle.

PubMed

Harris, A C; Atkinson, D M; Aase, D M; Gewirtz, J C

2006-01-01

The basolateral amygdala and portions of the "extended" amygdala (i.e. central nucleus of the amygdala, bed nucleus of the stria terminalis and shell of the nucleus accumbens) have been implicated in the aversive aspects of withdrawal from chronic opiate administration. Given that similar withdrawal signs are observed following a single opiate exposure, these structures may also play a role in "acute opiate dependence." In the current study, drug-naïve rats underwent naloxone-precipitated withdrawal from acute morphine (10 mg/kg) exposure on two successive days. On either the first or second day of testing, the basolateral amygdala, central nucleus of the amygdala, bed nucleus of the stria terminalis, or nucleus accumbens was temporarily inactivated immediately prior to naloxone injection by microinfusion of the glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo(f)quinoxaline-7-sulfonamide (3 microg/0.5 microl). On the first day, inactivation of the basolateral amygdala, central nucleus of the amygdala, or bed nucleus of the stria terminalis, but not the nucleus accumbens blocked withdrawal-potentiated startle, a behavioral measure of the anxiogenic effects of withdrawal. On the second day, inactivation of the nucleus accumbens, but not the basolateral amygdala, central nucleus of the amygdala, or bed nucleus of the stria terminalis disrupted the withdrawal effect. Effects of structural inactivations on withdrawal-potentiated startle were not influenced by differences in withdrawal severity on the two days of testing. A fear-potentiated startle procedure provided functional confirmation of correct cannulae placement in basolateral amygdale- and central nucleus of the amygdala-implanted animals. Our findings indicate a double dissociation in the neural substrates of withdrawal-potentiated startle following a first versus second morphine exposure, and may reflect a reorganization of the neural circuitry underlying the expression of withdrawal-induced negative affect during the earliest stages of opiate dependence.

Stimulation of the pedunculopontine nucleus area in Parkinson's disease: effects on speech and intelligibility.

PubMed

Pinto, Serge; Ferraye, Murielle; Espesser, Robert; Fraix, Valérie; Maillet, Audrey; Guirchoum, Jennifer; Layani-Zemour, Deborah; Ghio, Alain; Chabardès, Stéphan; Pollak, Pierre; Debû, Bettina

2014-10-01

Improvement of gait disorders following pedunculopontine nucleus area stimulation in patients with Parkinson's disease has previously been reported and led us to propose this surgical treatment to patients who progressively developed severe gait disorders and freezing despite optimal dopaminergic drug treatment and subthalamic nucleus stimulation. The outcome of our prospective study on the first six patients was somewhat mitigated, as freezing of gait and falls related to freezing were improved by low frequency electrical stimulation of the pedunculopontine nucleus area in some, but not all, patients. Here, we report the speech data prospectively collected in these patients with Parkinson's disease. Indeed, because subthalamic nucleus surgery may lead to speech impairment and a worsening of dysarthria in some patients with Parkinson's disease, we felt it was important to precisely examine any possible modulations of speech for a novel target for deep brain stimulation. Our results suggested a trend towards speech degradation related to the pedunculopontine nucleus area surgery (off stimulation) for aero-phonatory control (maximum phonation time), phono-articulatory coordination (oral diadochokinesis) and speech intelligibility. Possibly, the observed speech degradation may also be linked to the clinical characteristics of the group of patients. The influence of pedunculopontine nucleus area stimulation per se was more complex, depending on the nature of the task: it had a deleterious effect on maximum phonation time and oral diadochokinesis, and mixed effects on speech intelligibility. Whereas levodopa intake and subthalamic nucleus stimulation alone had no and positive effects on speech dimensions, respectively, a negative interaction between the two treatments was observed both before and after pedunculopontine nucleus area surgery. This combination effect did not seem to be modulated by pedunculopontine nucleus area stimulation. Although limited in our group of patients, speech impairment following pedunculopontine nucleus area stimulation is a possible outcome that should be considered before undertaking such surgery. Deleterious effects could be dependent on electrode insertion in this brainstem structure, more than on current spread to nearby structures involved in speech control. The effect of deep brain stimulation on speech in patients with Parkinson's disease remains a challenging and exploratory research area. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

In vivo neurobiological effects of ibogaine and its O-desmethyl metabolite, 12-hydroxyibogamine (noribogaine), in rats.

PubMed

Baumann, M H; Rothman, R B; Pablo, J P; Mash, D C

2001-05-01

Ibogaine is a naturally occurring compound with purported antiaddictive properties. When administered to primates, ibogaine is rapidly o-demethylated to form the metabolite 12-hydroxyibogamine (noribogaine). Peak blood levels of noribogaine exceed those of ibogaine, and noribogaine persists in the bloodstream for at least 1 day. Very few studies have systematically evaluated the neurobiological effects of noribogaine in vivo. In the present series of experiments, we compared the effects of i.v. administration of ibogaine and noribogaine (1 and 10 mg/kg) on motor behaviors, stress hormones, and extracellular levels of dopamine (DA) and serotonin (5-HT) in the nucleus accumbens of male rats. Ibogaine caused dose-related increases in tremors, whereas noribogaine did not. Both ibogaine and noribogaine produced significant elevations in plasma corticosterone and prolactin, but ibogaine was a more potent stimulator of corticosterone secretion. Neither drug altered extracellular DA levels in the nucleus accumbens. However, both drugs increased extracellular 5-HT levels, and noribogaine was more potent in this respect. Results from in vitro experiments indicated that ibogaine and noribogaine interact with 5-HT transporters to inhibit 5-HT uptake. The present findings demonstrate that noribogaine is biologically active and undoubtedly contributes to the in vivo pharmacological profile of ibogaine in rats. Noribogaine is approximately 10 times more potent than ibogaine as an indirect 5-HT agonist. More importantly, noribogaine appears less apt to produce the adverse effects associated with ibogaine, indicating the metabolite may be a safer alternative for medication development.

Antagonism of immunostimulatory CpG-oligodeoxynucleotides by quinacrine, chloroquine, and structurally related compounds.

PubMed

Macfarlane, D E; Manzel, L

1998-02-01

Phosphorothioate oligodeoxynucleotides containing CpG (CpG-ODN) activate immune responses. We report that quinacrine, chloroquine, and structurally related compounds completely inhibit the antiapoptotic effect of CpG-ODN on WEHI 231 murine B lymphoma cells and inhibit CpG-ODN-induced secretion of IL-6 by WEHI 231. They also inhibit IL-6 synthesis and thymidine uptake by human unfractionated PBMC induced by CpG-ODN. The compounds did not inhibit LPS-induced responses. Half-maximal inhibition required 10 nM quinacrine or 100 nM chloroquine. Inhibition was noncompetitive with respect to CpG-ODN. Quinine, quinidine, and primaquine were much less powerful. Quinacrine was effective even when added after the CpG-ODN. Near-toxic concentrations of ammonia plus bafilomycin A1 (used to inhibit vesicular acidification) did not reduce the efficacy of the quinacrine, but the effects of both quinacrine and chloroquine were enhanced by inhibition of the multidrug resistance efflux pump by verapamil. Agents that bind to DNA, including propidium iodide, Hoechst dye 33258, and coralyne chloride did not inhibit CpG-ODN effect, nor did 4-bromophenacyl bromide, an inhibitor of phospholipase A2. Examination of the structure-activity relationship of seventy 4-aminoquinoline and 9-aminoacridine analogues reveals that increased activity was conferred by bulky hydrophobic substituents on positions 2 and 6 of the quinoline nucleus. No correlation was found between published antimalarial activity and ability to block CpG-ODN-induced effects. These results are discussed in the light of the ability of quinacrine and chloroquine to induce remission of rheumatoid arthritis and lupus erythematosus.

Design and Synthesis of 2-Heterocyclyl-3-arylthio-1H-indoles as Potent Tubulin Polymerization and Cell Growth Inhibitors with Improved Metabolic Stability

PubMed Central

La Regina, Giuseppe; Bai, Ruoli; Rensen, Willeke; Coluccia, Antonio; Piscitelli, Francesco; Gatti, Valerio; Bolognesi, Alessio; Lavecchia, Antonio; Granata, Ilaria; Porta, Amalia; Maresca, Bruno; Soriani, Alessandra; Iannitto, Maria Luisa; Mariani, Marisa; Santoni, Angela; Brancale, Andrea; Ferlini, Cristiano; Dondio, Giulio; Varasi, Mario; Mercurio, Ciro; Hamel, Ernest; Lavia, Patrizia; Novellino, Ettore; Silvestri, Romano

2011-01-01

New arylthioindoles (ATIs) were obtained by replacing the 2-alkoxycarbonyl group with a bioisosteric 5-membered heterocycle nucleus. The new ATIs 5, 8, and 10 inhibited tubulin polymerization, reduced cell growth of a panel of human transformed cell lines, and showed higher metabolic stability than the reference ester 3. These compounds induced mitotic arrest and apoptosis at a similar level as combretastatin A-4 and vinblastine and triggered caspase-3 expression in a significant fraction of cells in both p53-proficient and p53-defective cell lines. Importantly, ATIs 5, 8, and 10 were more effective than vinorelbine, vinblastine, and paclitaxel as growth inhibitors of the P-glycoprotein-overexpressing cell line NCI/ADR-RES. Compound 5 was shown to have medium metabolic stability in both human and mouse liver microsomes, in contrast to the rapidly degraded reference ester 3, and a pharmacokinetic profile in the mouse characterized by a low systemic clearance and excellent oral bioavailability. PMID:22044164

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Qun-Yi; Zhang, Meng; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai

Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K{sub i} = 13.2 nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids formore » the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.« less

Osthole, a herbal compound, alleviates nucleus pulposus-evoked nociceptive responses through the suppression of overexpression of acid-sensing ion channel 3 (ASIC3) in rat dorsal root ganglion

PubMed Central

He, Qiu-Lan; Chen, Yuling; Qin, Jian; Mo, Sui-Lin; Wei, Ming; Zhang, Jin-Jun; Li, Mei-Na; Zou, Xue-Nong; Zhou, Shu-Feng; Chen, Xiao-Wu; Sun, Lai-Bao

2012-01-01

Summary Background Osthole (Ost), a natural coumarin derivative, has been shown to inhibit many pro-inflammatory mediators and block voltage-gated Na+ channels. During inflammation, acidosis is an important pain inducer which activates nociceptors by gating depolarizing cationic channels, such as acid-sensing ion channel 3 (ASIC3). The aim of this study was to examine the effects of Ost on nucleus pulposus-evoked nociceptive responses and ASIC3 over-expression in the rat dorsal root ganglion, and to investigate the possible mechanism. Material/Methods Radicular pain was generated with application of nucleus pulposus (NP) to nerve root. Mechanical allodynia was evaluated using von Frey filaments with logarithmically incremental rigidity to calculate the 50% probability thresholds for mechanical paw withdrawal. ASIC3 protein expression in dorsal root ganglions (DRGs) was assessed with Western blot and immunohistochemistry. Membrane potential (MP) shift of DRG neurons induced by ASIC3-sensitive acid (pH6.5) was determined by DiBAC4 (3) fluorescence intensity (F.I.). Results The NP-evoked mechanical hyperalgesia model showed allodynia for 3 weeks, and ASIC3 expression was up-regulated in DRG neurons, reaching peak on Day 7. Epidural administration of Ost induced a remarkable and prolonged antinociceptive effect, accompanied by an inhibition of over-expressed ASIC3 protein and of abnormal shift of MP. Amiloride (Ami), an antagonist of ASIC3, strengthened the antinociceptive effect of Ost. Conclusions Up-regulation of ASIC3 expression may be associated with NP-evoked mechanical hyperalgesia. A single epidural injection of Ost decreased ASIC3 expression in DGR neurons and the pain in the NP-evoked mechanical hyperalgesia model. Osthole may be of great benefit for preventing chronic pain status often seen in lumbar disc herniation (LDH). PMID:22648244

Characterization of the effects of serotonin on the release of (/sup 3/H)dopamine from rat nucleus accumbens and striatal slices

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nurse, B.; Russell, V.A.; Taljaard, J.J.

1988-05-01

The effect of serotonin agonists on the depolarization (K+)-induced, calcium-dependent, release of (/sup 3/H)dopamine (DA) from rat nucleus accumbens and striatal slices was investigated. Serotonin enhanced basal /sup 3/H overflow and reduced K+-induced release of (/sup 3/H)DA from nucleus accumbens slices. The effect of serotonin on basal /sup 3/H overflow was not altered by the serotonin antagonist, methysergide, or the serotonin re-uptake blocker, chlorimipramine, but was reversed by the DA re-uptake carrier inhibitors nomifensine and benztropine. With the effect on basal overflow blocked, serotonin did not modulate K+-induced release of (/sup 3/H)DA in the nucleus accumbens or striatum. The serotoninmore » agonists, quipazine (in the presence of nomifensine) and 5-methoxytryptamine, did not significantly affect K+-induced release of (/sup 3/H)DA in the nucleus accumbens. This study does not support suggestions that serotonin receptors inhibit the depolarization-induced release of dopamine in the nucleus accumbens or striatum of the rat brain. The present results do not preclude the possibility that serotonin may affect the mesolimbic reward system at a site which is post-synaptic to dopaminergic terminals in the nucleus accumbens.« less

Daily methylphenidate and atomoxetine treatment impacts on clock gene protein expression in the mouse brain.

PubMed

Baird, Alison L; Coogan, Andrew N; Kaufling, Jennifer; Barrot, Michel; Thome, Johannes

2013-06-04

Circadian rhythms are repeating patterns of physiological and other parameters that recur with periods of approximately 24h, and are generated by an endogenous circadian timekeeping mechanism. Such circadian rhythms, and their underlying molecular mechanisms, are known to be altered by a number of central nervous system acting pharmacological compounds, as well as becoming perturbed in a number of common psychiatric and neurological conditions. The psychostimulant methylphenidate and the non-stimulant atomoxetine are used in the pharmacotherapy of attention deficit hyperactivity disorder, a common condition in which circadian rhythms have been reported to be altered. In the present study we have examined the effects of daily methylphenidate or atomoxetine treatment across 7 days on circadian clock gene product expression across numerous brain regions in the male mouse to test the potential impact of such compounds on circadian timing. We report drug, brain region and molecular specific effects of such treatments, including alterations in expression profiles in the suprachiasmatic nucleus, the master circadian pacemaker. These results indicate that drugs used in the clinical management of attention deficit hyperactivity disorder can alter molecular factors that are believed to underpin circadian timekeeping, and such effects may be of importance in both the therapeutic and side effect profiles of such drugs. Copyright © 2013 Elsevier B.V. All rights reserved.

The Role of Nuclear Fragmentation in Particle Therapy and Space Radiation Protection.

PubMed

Zeitlin, Cary; La Tessa, Chiara

2016-01-01

The transport of the so-called HZE particles (those having high charge, Z, and energy, E) through matter is crucially important both in space radiation protection and in the clinical setting where heavy ions are used for cancer treatment. HZE particles are usually considered those having Z > 1, though sometimes Z > 2 is meant. Transport physics is governed by two types of interactions, electromagnetic (ionization energy loss) and nuclear. Models of transport, such as those used in treatment planning and space mission planning must account for both effects in detail. The theory of electromagnetic interactions is well developed, but nucleus-nucleus collisions are so complex that no fundamental physical theory currently describes them. Instead, interaction models are generally anchored to experimental data, which in some areas are far from complete. The lack of fundamental physics knowledge introduces uncertainties in the calculations of exposures and their associated risks. These uncertainties are greatly compounded by the much larger uncertainties in biological response to HZE particles. In this article, we discuss the role of nucleus-nucleus interactions in heavy charged particle therapy and in deep space, where astronauts will receive a chronic low dose from galactic cosmic rays (GCRs) and potentially higher short-term doses from sporadic, unpredictable solar energetic particles (SEPs). GCRs include HZE particles; SEPs typically do not and we, therefore, exclude them from consideration in this article. Nucleus-nucleus collisions can result in the breakup of heavy ions into lighter ions. In space, this is generally beneficial because dose and dose equivalent are, on the whole, reduced in the process. The GCRs can be considered a radiation field with a significant high-LET component; when they pass through matter, the high-LET component is attenuated, at the cost of a slight increase in the low-LET component. Not only are the standard measures of risk reduced by fragmentation, but it can be argued that fragmentation also reduces the uncertainties in risk calculations by shifting the LET distribution toward one that is more concentrated at low LET, where biological effects are better understood. We review previous work in this area, including measurements made by the Radiation Assessment Detector during its journey to Mars and while on the surface of Mars aboard the Curiosity rover. Transport of HZE is also critically important in heavy-ion therapy, as it is necessary to know the details of the radiation field at the treatment site. This field is substantially modified compared to the incident pure (or nearly pure) ion beam by the same mechanisms of energy loss and nuclear fragmentation that pertain to the transport of space radiation.

Discovery of an algicidal compound from Brevibacterium sp. BS01 and its effect on a harmful algal bloom-causing species, Alexandrium tamarense.

PubMed

An, Xinli; Zhang, Bangzhou; Zhang, Huajun; Li, Yi; Zheng, Wei; Yu, Zhiming; Fu, Lijun; Zheng, Tianling

2015-01-01

Blooms of the dinoflagellate Alexandrium tamarense have become worldwide phenomena and have detrimental impacts on aquatic ecosystems and human health. In this study, a culture supernatant of the marine actinomycete BS01 exerted a strong algicidal effect on A. tamarense (ATGD98-006). The target algicide from BS01 was separated by adsorption chromatography and identified by MALDI-TOF-MS and NMR analysis. The results suggested that the purified algicidal component corresponded to a hydrophobic compound (2-isobutoxyphenyl)amine (C10H15NO) with a molecular weight of 165 Da, which exhibited a significant algicidal effect (64.5%) on A. tamarense. After incubation in 5 μg/mL of (2-isobutoxyphenyl)amine for 24 h, the algae lost mobility and sank to the bottom of the flasks, and 56.5% of the algae cells lost vitality at a concentration of 20 μg/mL (p < 0.01) despite having intact cell profiles. Morphological analysis revealed that the cell structure of A. tamarense was altered by (2-isobutoxyphenyl)amine resulting in cytoplasm degradation and the loss of organelle integrity. The images following propidium iodide staining suggested that the algal nucleus was also severely damaged and eventually degraded due to exposure to the algicidal compound. All of the results indicate that (2-isobutoxyphenyl)amine from the actinomycete might be a candidate for the control of bloom-forming A. tamarense.

Discovery of an algicidal compound from Brevibacterium sp. BS01 and its effect on a harmful algal bloom-causing species, Alexandrium tamarense

PubMed Central

An, Xinli; Zhang, Bangzhou; Zhang, Huajun; Li, Yi; Zheng, Wei; Yu, Zhiming; Fu, Lijun; Zheng, Tianling

2015-01-01

Blooms of the dinoflagellate Alexandrium tamarense have become worldwide phenomena and have detrimental impacts on aquatic ecosystems and human health. In this study, a culture supernatant of the marine actinomycete BS01 exerted a strong algicidal effect on A. tamarense (ATGD98-006). The target algicide from BS01 was separated by adsorption chromatography and identified by MALDI-TOF-MS and NMR analysis. The results suggested that the purified algicidal component corresponded to a hydrophobic compound (2-isobutoxyphenyl)amine (C10H15NO) with a molecular weight of 165 Da, which exhibited a significant algicidal effect (64.5%) on A. tamarense. After incubation in 5 μg/mL of (2-isobutoxyphenyl)amine for 24 h, the algae lost mobility and sank to the bottom of the flasks, and 56.5% of the algae cells lost vitality at a concentration of 20 μg/mL (p < 0.01) despite having intact cell profiles. Morphological analysis revealed that the cell structure of A. tamarense was altered by (2-isobutoxyphenyl)amine resulting in cytoplasm degradation and the loss of organelle integrity. The images following propidium iodide staining suggested that the algal nucleus was also severely damaged and eventually degraded due to exposure to the algicidal compound. All of the results indicate that (2-isobutoxyphenyl)amine from the actinomycete might be a candidate for the control of bloom-forming A. tamarense. PMID:26594205

Differential effects of the new glucocorticoid receptor antagonist ORG 34517 and RU486 (mifepristone) on glucocorticoid receptor nuclear translocation in the AtT20 cell line.

PubMed

Peeters, B W M M; Ruigt, G S F; Craighead, M; Kitchener, P

2008-12-01

Glucocorticoid agonists bind to cytoplasmic glucocorticoid receptors (GRs) and subsequently translocate as an agonist-GR complex into the nucleus. In the nucleus the complex regulates the transcription of target genes. A number of GR antagonists (RU486, progesterone, RU40555) have also been shown to induce receptor translocation. These compounds should be regarded as partial agonists. For the nonselective progesterone receptor antagonists, RTI3021-012 and RTI3021-022, it was shown that GR antagonism is possible without the induction of GR translocation. In the present studies, the new GR antagonist, ORG 34517, was investigated for its potential to induce GR translocation and to antagonize corticosterone-induced GR translocation in the AtT20 (mouse pituitary) cell line. ORG 34517 was compared to RU486. In contrast to RU486, ORG 34517 (at doses up to 3 x 10(-7) M) did not induce GR translocation, but was able to block corticosterone (3 x 10(-8) M) induced GR translocation. ORG 34517 can be regarded as a true competitive GR antagonist without partial agonistic activities.

Effect of beta-phenylethylamine on extracellular concentrations of dopamine in the nucleus accumbens and prefrontal cortex.

PubMed

Murata, Mikio; Katagiri, Nobuyuki; Ishida, Kota; Abe, Kenji; Ishikawa, Masago; Utsunomiya, Iku; Hoshi, Keiko; Miyamoto, Ken-ichi; Taguchi, Kyoji

2009-05-07

It is known that psychostimulants stimulate dopamine transmission in the nucleus accumbens. In the present study, we examined the effects of systemically administered beta-phenylethylamine (beta-PEA), a psychomotor-stimulating trace amine, on dopamine concentrations in the nucleus accumbens and prefrontal cortex in freely moving rats, using an in vivo microdialysis technique. Intraperitoneal administration of beta-PEA (12.5 and 25 mg/kg) significantly increased extracellular dopamine levels in the nucleus accumbens shell. The observed increase in the dopamine concentration in nucleus accumbens shell dialysate after intraperitoneal administration of 25 mg/kg beta-PEA was inhibited by pre-treatment with a dopamine uptake inhibitor, GBR12909 (10 mg/kg, i.p.). In contrast, beta-PEA (25 mg/kg, i.p.) did not affect dopamine release in the nucleus accumbens core. Although a high dose of beta-PEA (50 mg/kg) significantly increased dopamine levels in the nucleus accumbens core, the dopamine increasing effect of beta-PEA was more potent in the nucleus accumbens shell. Systemic administration of 12.5 and 25 mg/kg beta-PEA also increased extracellular dopamine levels in the prefrontal cortex of rats. However, systemic 25 mg/kg beta-PEA-induced increases in extracellular dopamine levels were not blocked by GBR12909 within the prefrontal cortex. These results suggest that beta-PEA has a greater effect in the shell than in the core and low-dose beta-PEA stimulates dopamine release in the nucleus accumbens shell through uptake by a dopamine transporter. Similarly, beta-PEA increased extracellular dopamine levels in the prefrontal cortex. Thus, beta-PEA may increase extracellular dopamine concentrations in the mesocorticolimbic pathway.

Protective effect of cannabidiol on hydrogen peroxide‑induced apoptosis, inflammation and oxidative stress in nucleus pulposus cells.

PubMed

Chen, Jie; Hou, Chen; Chen, Xin; Wang, Dong; Yang, Pinglin; He, Xijing; Zhou, Jinsong; Li, Haopeng

2016-09-01

Cannabidiol, a major component of marijuana, protects nerves, and exerts antispasmodic, anti-inflammatory and anti‑anxiety effects. In the current study, the protective effect of cannabidiol was observed to prevent hydrogen peroxide (H2O2)‑induced apoptosis, inflammation and oxidative stress in nucleus pulposus cells. Nucleus pulposus cells were isolated from rats and cultured in vitro, and H2O2 was used to construct the nucleus pulposus cell model. Cell viability of the nucleus pulposus cells was assessed using a 3‑(4,5-dimethylthiazol-2-yl)-2,5‑diphenyltetrazolium bromide assay. The ratio of apoptotic cells, and caspase‑3 or cyclooxygenase‑2 (COX‑2) mRNA expression was analyzed by annexin V‑fluorescein isothiocyanate/propidium‑iodide staining and reverse transcription‑quantitative polymerase chain reaction, respectively. The quantities of interleukin (IL)‑1β and interleukin‑6 were measured using a series of assay kits. B-cell lymphoma 2 (Bcl‑2) and inducible nitric oxide synthase (iNOS) protein expression levels were analyzed using western blotting. The present study identified that cannabidiol enhanced cell viability and reduced apoptosis in H2O2‑treated nucleus pulposus cells in vitro using a lumbar disc herniation (LDH) model. In addition, cannabidiol reduced caspase‑3 gene expression and augmented the Bcl‑2 protein expression levels in the nucleus pulposus cells following H2O2 exposure. Pre‑treatment with cannabidiol suppressed the promotion of COX‑2, iNOS, IL‑1β and IL‑6 expression in the nucleus pulposus cells following H2O2 exposure. Taken together, these results suggest that cannabidiol potentially exerts its protective effect on LDH via the suppression of anti‑apoptosis, anti‑inflammation and anti‑oxidative activities in nucleus pulposus cells.

Synthesis and cell imaging applications of fluorescent mono/di/tri-heterocyclyl-2,6-dicyanoanilines.

PubMed

Pisal, Mahesh M; Annadate, Ritesh A; Athalye, Meghana C; Kumar, Deepak; Chavan, Subhash P; Sarkar, Dhiman; Borate, Hanumant B

2017-02-15

Synthesis of 3,4,5-triheterocyclyl-2,6-dicyanoanilines, starting from heterocyclic aldehydes and 1,2-diheterocycle-substituted ethanones, is described. 2,6-Dicyanoanilines with one or two heterocyclic substituents have also been synthesized. It was found that some of these molecules have selective cell-staining properties useful for cell imaging applications. The compounds 1g, 10f and 11 were found to stain cytoplasm of the cells in contact but not the nucleus while the compound 12 showed affinity to apoptotic cells resulting in blue fluorescence. The cell imaging results with compound 12 were similar to Annexin V-FITC, a known reagent containing recombinant Annexin V conjugated to green-fluorescent FITC dye, used for detection of apoptotic cells. These compounds were found to be non-cytotoxic and have potential application as cell imaging agents. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effects of Nicotine and Ethanol on Indices of Reward and Sensory-Motor Function in Rats: Implications for the Positive Epidemiologic Relationship Between the Use of Cigarettes and the Use of Alcohol

DTIC Science & Technology

1997-10-07

include the auditory nerve, the ventral cochlear nucleus , nuclei of the lateral lemniscus, nucleus reticularis pontis caudalis, spinal neuron, and lower...chambers. In addition, there was a significant effect of nicotine and ethanol to reduce the ratio of dopamine/DOPAC in nucleus accumbens. Because...dopaminergic activity in nucleus accumbens is known to mediate nicotine reinforcement, reductions in the ratio of dopamine/DOPAC (perhaps indicating an

L2 Milestone: Neutron Capture Cross Sections from Surrogate (p, d) Measurements: Determination of the Unknown 87Y(n, g) Cross Section and Assessment of the Method Via the 90Zr(n, g) Benchmark Case: Theory Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Escher, J. E.

Cross sections for compound-nuclear reactions involving unstable targets are important for many applications, but can often not be measured directly. Here we describe a method for extracting cross sections for neutron-capture on unstable isotopes from indirect (surrogate) measurements. The surrogate reaction, which produces the compound nucleus of interest, has to be described and the decay of the nucleus has to be modeled. We outline the approach for one-neutron pickup and report on the determination of the 90Zr(n, γ ) reaction from surrogate 92Zr(p,d) data, which is compared to the directly-measured capture cross section and thus provides a benchmark for themore » method. We then apply the method to determine the 87Y(n, γ ) cross section, which has not been measured directly. The work was carried out in the context of an LLNL L2 Milestone. This report addresses the theory aspects of the milestone. A complementary document summarizes the experimental efforts [1].« less

Dual evaluation of some novel 2-amino-substituted coumarinylthiazoles as anti-inflammatory-antimicrobial agents and their docking studies with COX-1/COX-2 active sites.

PubMed

Chandak, Navneet; Kumar, Pawan; Kaushik, Pawan; Varshney, Parul; Sharma, Chetan; Kaushik, Dhirender; Jain, Sudha; Aneja, Kamal R; Sharma, Pawan K

2014-08-01

Synthesis of total eighteen 2-amino-substituted 4-coumarinylthiazoles including sixteen new compounds (3a-o and 5b) bearing the benzenesulfonamide moiety is described in the present report. All the synthesized target compounds were examined for their in vivo anti-inflammatory (AI) activity and in vitro antimicrobial activity. Results revealed that six compounds (3 d, 3 f, 3 g, 3 h, 3 j and 3 n) exhibited pronounced anti-inflammatory activity comparable to the standard drug indomethacin. AI results were further confirmed by the docking studies of the most active (3n) and the least active compound (3a) with COX-1 and COX-2 active sites. In addition, most of the compounds exhibited moderate antimicrobial activity against Gram-positive bacteria as well as fungal yeast, S. cervisiae. Comparison between 3 and 5 indicated that incorporation of additional substituted pyrazole nucleus into the scaffold significantly enhanced AI activity.

Distinct effect of orphanin FQ in nucleus raphe magnus and nucleus reticularis gigantocellularis on the rat tail flick reflex.

PubMed

Yang, Z; Zhang, Y; Wu, G

2001-06-22

The aim of the present study is to investigate the effects of orphanin FQ (OFQ) microinjected into the nucleus raphe magnus (NRM) and the nucleus reticularis gigantocellularis (NGC) on pain modulation. The tail-flick latency (TFL) was used as a behavioral index of nociceptive responsiveness. The result showed microinjection of OFQ into the NRM significantly increased the TFL, whereas microinjection of OFQ into the NGC decreased the TFL, suggesting the analgesic effect of OFQ in the NRM and the hyperalgesic effect of OFQ in the NGC. As there are three classes of putative pain modulating neurons in the rostral ventromedial medulla (RVM), the hyperalgesic or analgesic effect of OFQ in the RVM might depend upon the different class of the neurons being acted.

Effects of ampicillin, cefazolin and cefoperazone treatments on GLT-1 expressions in the mesocorticolimbic system and ethanol intake in alcohol-preferring rats.

PubMed

Rao, P S S; Goodwani, S; Bell, R L; Wei, Y; Boddu, S H S; Sari, Y

2015-06-04

Chronic ethanol consumption is known to downregulate expression of the major glutamate transporter 1 (GLT-1), which increases extracellular glutamate concentrations in subregions of the mesocorticolimbic reward pathway. While β-lactam antibiotics were initially identified as potent upregulators of GLT-1 expression, only ceftriaxone has been extensively studied in various drug addiction models. Therefore, in this study, adult male alcohol-preferring (P) rats exposed chronically to ethanol were treated with other β-lactam antibiotics, ampicillin, cefazolin or cefoperazone (100mg/kg) once daily for five consecutive days to assess their effects on ethanol consumption. The results demonstrated that each compound significantly reduced ethanol intake compared to the saline-treated control group. Importantly, each compound significantly upregulated both GLT-1 and pAKT expressions in the nucleus accumbens and prefrontal cortex compared to saline-treated control group. In addition, only cefoperazone significantly inhibited hepatic aldehyde dehydrogenase-2 enzyme activity. Moreover, these β-lactams exerted only a transient effect on sucrose drinking, suggesting specificity for chronically inhibiting ethanol reward in adult male P rats. Cerebrospinal fluid concentrations of ampicillin, cefazolin or cefoperazone have been confirmed using high-performance liquid chromatography. These findings demonstrate that multiple β-lactam antibiotics demonstrate efficacy in reducing alcohol consumption and appear to be potential therapeutic compounds for treating alcohol abuse and/or dependence. In addition, these results suggest that pAKT may be an important player in this effect, possibly through increased transcription of GLT-1. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Lamb shift of electronic states in neutral muonic helium, an electron-muon-nucleus system

NASA Astrophysics Data System (ADS)

Karshenboim, Savely G.; Ivanov, Vladimir G.; Amusia, Miron

2015-03-01

Neutral muonic helium is an exotic atomic system consisting of an electron, a muon, and a nucleus. Being a three-body system, it possesses a clear hierarchy. This allows us to consider it as a hydrogenlike atom with a compound nucleus, which is, in turn, another hydrogenlike system. There are a number of corrections to the Bohr energy levels, all of which can be treated as contributions of generic hydrogenlike theory. While the form of those contributions is the same for all hydrogenlike atoms, their relative numerical importance differs from atom to atom. Here, the leading contribution to the (electronic) Lamb shift in neutral muonic helium is found in a closed analytic form together with the most important corrections. We believe that the Lamb shift in neutral muonic hydrogen is measurable, at least through a measurement of the (electronic) 1 s -2 s transition. We present a theoretical prediction for the 1 s -2 s transitions with an uncertainty of 3 ppm (9 GHz ), as well as for the 2 s -2 p Lamb shift with an uncertainty of 1.3 GHz .

Antagonism at the NR2B subunit of NMDA receptors induces increased connectivity of the prefrontal and subcortical regions regulating reward behavior.

PubMed

Gass, Natalia; Becker, Robert; Sack, Markus; Schwarz, Adam J; Reinwald, Jonathan; Cosa-Linan, Alejandro; Zheng, Lei; von Hohenberg, Christian Clemm; Inta, Dragos; Meyer-Lindenberg, Andreas; Weber-Fahr, Wolfgang; Gass, Peter; Sartorius, Alexander

2018-04-01

Evidence indicates that ketamine's rapid antidepressant efficacy likely results from its antagonism of NR2B-subunit-containing NMDA receptors (NMDAR). Since ketamine equally blocks NR2A- and NR2B-containing NMDAR, and has affinity to other receptors, NR2B-selective drugs might have improved therapeutic efficiency and side effect profile. We aimed to compare the effects of (S)-ketamine and two different types of NR2B-selective antagonists on functional brain networks in rats, in order to find common circuits, where their effects intersect, and that might explain their antidepressant action. The experimental design comprised four parallel groups of rats (N = 37), each receiving (S)-Ketamine, CP-101,606, Ro 25-6981 or saline. After compound injection, we acquired resting-state functional magnetic resonance imaging time series. We used graph theoretical approach to calculate brain network properties. Ketamine and CP-101,606 diminished the global clustering coefficient and small-worldness index. At the nodal level, all compounds induced increased connectivity of the regions mediating reward and cognitive aspects of emotional processing, such as ventromedial prefrontal cortex, septal nuclei, and nucleus accumbens. The dorsal hippocampus and regions involved in sensory processing and aversion, such as superior and inferior colliculi, exhibited an opposite effect. The effects common to ketamine and NR2B-selective compounds were localized to the same brain regions as those reported in depression, but in the opposite direction. The upregulation of the reward circuitry might partially underlie the antidepressant and anti-anhedonic effects of the antagonists and could potentially serve as a translational imaging phenotype for testing putative antidepressants, especially those targeting the NR2B receptor subtype.

Identification of B. anthracis N(5)-carboxyaminoimidazole ribonucleotide mutase (PurE) active site binding compounds via fragment library screening.

PubMed

Lei, Hao; Jones, Christopher; Zhu, Tian; Patel, Kavankumar; Wolf, Nina M; Fung, Leslie W-M; Lee, Hyun; Johnson, Michael E

2016-02-15

The de novo purine biosynthesis pathway is an attractive target for antibacterial drug design, and PurE from this pathway has been identified to be crucial for Bacillus anthracis survival in serum. In this study we adopted a fragment-based hit discovery approach, using three screening methods-saturation transfer difference nucleus magnetic resonance (STD-NMR), water-ligand observed via gradient spectroscopy (WaterLOGSY) NMR, and surface plasmon resonance (SPR), against B. anthracis PurE (BaPurE) to identify active site binding fragments by initially testing 352 compounds in a Zenobia fragment library. Competition STD NMR with the BaPurE product effectively eliminated non-active site binding hits from the primary hits, selecting active site binders only. Binding affinities (dissociation constant, KD) of these compounds varied between 234 and 301μM. Based on test results from the Zenobia compounds, we subsequently developed and applied a streamlined fragment screening strategy to screen a much larger library consisting of 3000 computationally pre-selected fragments. Thirteen final fragment hits were confirmed to exhibit binding affinities varying from 14μM to 700μM, which were categorized into five different basic scaffolds. All thirteen fragment hits have ligand efficiencies higher than 0.30. We demonstrated that at least two fragments from two different scaffolds exhibit inhibitory activity against the BaPurE enzyme. Published by Elsevier Ltd.

Identification of Novel Activators of Constitutive Androstane Receptor from FDA-approved Drugs by Integrated Computational and Biological Approaches

PubMed Central

Lynch, Caitlin; Pan, Yongmei; Li, Linhao; Ferguson, Stephen S.; Xia, Menghang; Swaan, Peter W.; Wang, Hongbing

2012-01-01

Purpose The constitutive androstane receptor (CAR, NR1I3) is a xenobiotic sensor governing the transcription of numerous hepatic genes associated with drug metabolism and clearance. Recent evidence suggests that CAR also modulates energy homeostasis and cancer development. Thus, identification of novel human (h) CAR activators is of both clinical importance and scientific interest. Methods Docking and ligand-based structure-activity models were used for virtual screening of a database containing over 2000 FDA-approved drugs. Identified lead compounds were evaluated in cell-based reporter assays to determine hCAR activation. Potential activators were further tested in human primary hepatocytes (HPHs) for the expression of the prototypical hCAR target gene CYP2B6. Results Nineteen lead compounds with optimal modeling parameters were selected for biological evaluation. Seven of the 19 leads exhibited moderate to potent activation of hCAR. Five out of the seven compounds translocated hCAR from the cytoplasm to the nucleus of HPHs in a concentration-dependent manner. These compounds also induce the expression of CYP2B6 in HPHs with rank-order of efficacies closely resembling that of hCAR activation. Conclusion These results indicate that our strategically integrated approaches are effective in the identification of novel hCAR modulators, which may function as valuable research tools or potential therapeutic molecules. PMID:23090669

Role of amygdala central nucleus in feature negative discriminations

PubMed Central

Holland, Peter C.

2012-01-01

Consistent with a popular theory of associative learning, the Pearce-Hall (1980) model, the surprising omission of expected events enhances cue associability (the ease with which a cue may enter into new associations), across a wide variety of behavioral training procedures. Furthermore, previous experiments from this laboratory showed that these enhancements are absent in rats with impaired function of the amygdala central nucleus (CeA). A notable exception to these assertions is found in feature negative (FN) discrimination learning, in which a “target” stimulus is reinforced when it is presented alone but nonreinforced when it is presented in compound with another, “feature” stimulus. According to the Pearce-Hall model, reinforcer omission on compound trials should enhance the associability of the feature relative to control training conditions. However, prior experiments have shown no evidence that CeA lesions affect FN discrimination learning. Here we explored this apparent contradiction by evaluating the hypothesis that the surprising omission of an event confers enhanced associability on a cue only if that cue itself generates the disconfirmed prediction. Thus, in a FN discrimination, the surprising omission of the reinforcer on compound trials would enhance the associability of the target stimulus but not that of the feature. Our data confirmed this hypothesis, and showed this enhancement to depend on intact CeA function, as in other procedures. The results are consistent with modern reformulations of both cue and reward processing theories that assign roles for both individual and aggregate error terms in associative learning. PMID:22889308

[Construction of injectable tissue engineered nucleus pulposus in vitro].

PubMed

Tian, Huake; Wang, Jian; Chen, Chao; Liu, Jie; Zhou, Yue

2009-02-01

To investigate the feasibility of using thermo-sensitive chitosan hydrogen as a scaffold to construct tissue engineered injectable nucleus pulposus (NP). Three-month-old neonatal New Zealand rabbits (male or female) weighing 150-200 g were selected to isolate and culture NP cells. The thermo-sensitive chitosan hydrogel scaffold was made of chitosan, disodium beta-glycerophosphate and hydroxyethyl cellulose. Its physical properties and gross condition were observed. The tissue engineered NP was constructed by compounding the scaffold and rabbit NP cells. Then, the viability of NP cells in the chitosan hydrogel was observed 2 days after compound culture and the growth condition of NP cells on the scaffold was observed by SEM 7 days after compound culture. NP cells went through histology and immunohistochemistry detection and their secretion of aggrecan and expression of Col II mRNA were analyzed by RT-PCR 21 days after compound culture. The thermo-sensitive chitosan hydrogel was liquid at room temperature and solidified into gel at 37 degrees C (15 minutes) due to crosslinking reaction. Acridine orange-propidium iodide staining showed that the viability rate of NP cells in chitosan hydrogel was above 90%. Scanning electron microscope observation demonstrated that the NP cells were distributed in the reticulate scaffold, with ECM on their surfaces. The results of HE, toluidine blue, safranin O and histology and immunohistochemistry staining confirmed that the NP cells in chitosan hydrogel were capable of producing ECM. RT-PCR results showed that the secretion of Col II and aggrecan mRNA in NP cells cultured three-dimensionally by chitosan hydrogen scaffold were 0.631 +/- 0.064 and 0.832 +/- 0.052, respectively, showing more strengths of producing matrix than that of monolayer culture (0.528 +/- 0.039, 0.773 +/- 0.046) with a significant difference (P < 0.05). With good cellular compatibilities, the thermo-sensitive chitosan hydrogel makes it possible for NP cells to maintain their normal morphology and secretion after compound culture, and may be a potential NP cells carrier for tissue engineered NP.

Reproductive responses of male Brandt's voles ( Lasiopodomys brandtii) to 6-methoxybenzoxazolinone (6-MBOA) under short photoperiod

NASA Astrophysics Data System (ADS)

Dai, Xin; Jiang, Lian Yu; Han, Mei; Ye, Man Hong; Wang, Ai Qin; Wei, Wan Hong; Yang, Sheng Mei

2016-04-01

The plant secondary metabolite 6-methoxybenzoxazolinone (6-MBOA) can stimulate and enhance animal reproduction. This compound has been successfully detected in Leymus chinensis, which is the main diet of Brandt's voles. The aim of this study was to investigate the effect of different 6-MBOA doses on the reproductive physiology of male Brandt's voles under a short photoperiod. The results showed that 6-MBOA administration increased relative testis weight, regardless of the dose, but it had little effect on the body mass. Low and middle doses of 6-MBOA increased the concentrations of luteinizing hormone and testosterone in the serum and the mRNA levels of StAR and CYP11a1 in the testes. However, 6-MBOA did not cause any significant increase in the mRNA levels of KiSS-1, GPR54, and GnRH compared to those in the control group. The mRNA level of KiSS-1 in the arcuate nucleus (ARC) was higher than that in the anteroventral periventricular nucleus (AVPV). Collectively, our results demonstrated that the number of KiSS-1-expressing neurons located in the ARC was the highest, and that 6-MBOA, which might modulate the reproductive activity along the hypothalamic-pituitary-gonadal axis, had a dose-dependent stimulatory effect on the reproductive activity of Brandt's voles under a short photoperiod. Our study provided insights into the mechanism of 6-MBOA action and the factors influencing the onset of reproduction in Brandt's voles.

Reproductive responses of male Brandt's voles (Lasiopodomys brandtii) to 6-methoxybenzoxazolinone (6-MBOA) under short photoperiod.

PubMed

Dai, Xin; Jiang, Lian Yu; Han, Mei; Ye, Man Hong; Wang, Ai Qin; Wei, Wan Hong; Yang, Sheng Mei

2016-04-01

The plant secondary metabolite 6-methoxybenzoxazolinone (6-MBOA) can stimulate and enhance animal reproduction. This compound has been successfully detected in Leymus chinensis, which is the main diet of Brandt's voles. The aim of this study was to investigate the effect of different 6-MBOA doses on the reproductive physiology of male Brandt's voles under a short photoperiod. The results showed that 6-MBOA administration increased relative testis weight, regardless of the dose, but it had little effect on the body mass. Low and middle doses of 6-MBOA increased the concentrations of luteinizing hormone and testosterone in the serum and the mRNA levels of StAR and CYP11a1 in the testes. However, 6-MBOA did not cause any significant increase in the mRNA levels of KiSS-1, GPR54, and GnRH compared to those in the control group. The mRNA level of KiSS-1 in the arcuate nucleus (ARC) was higher than that in the anteroventral periventricular nucleus (AVPV). Collectively, our results demonstrated that the number of KiSS-1-expressing neurons located in the ARC was the highest, and that 6-MBOA, which might modulate the reproductive activity along the hypothalamic-pituitary-gonadal axis, had a dose-dependent stimulatory effect on the reproductive activity of Brandt's voles under a short photoperiod. Our study provided insights into the mechanism of 6-MBOA action and the factors influencing the onset of reproduction in Brandt's voles.

Preliminary study on the inhibition of nuclear internalization of Tat peptides by conjugation with a receptor-specific peptide and fluorescent dyes

NASA Astrophysics Data System (ADS)

Shen, Duanwen; Liang, Kexiang; Ye, Yunpeng; Tetteh, Elizabeth; Achilefu, Samuel

2006-02-01

Numerous studies have shown that basic Tat peptide (48-57) internalized non-specifically in cells and localized in the nucleus. However, localization of imaging agents in cellular nucleus is not desirable because of the potential mutagenesis. When conjugated to the peptides that undergo receptor-mediated endocytosis, Tat peptide could target specific cells or pathologic tissue. We tested this hypothesis by incorporating a somatostatin receptor-avid peptide (octreotate, Oct) and two different fluorescent dyes, Cypate 2 (Cy2) and fluorescein 5'-carboxlic acid (5-FAM), into the Tat-peptide sequence. In addition to the Cy2 or 5-FAM-labeled Oct conjugated to Tat peptide (Tat) to produce Tat-Oct-Cypate2 or Tat-Oct-5-FAM, we also labeled the Tat the Tat peptide with these dyes (Tat-Cy2 and Tat-5-FAM) to serve as positive control. A somatostatin receptor-positive pancreatic tumor cell line, AR42J, was used to assess cell internalization. The results show that Tat-5-FAM and Tat-Cypate2 localized in both nucleus and cytoplasm of the cells. In contrast to Tat-Oct-Cypate2, which localized in both the cytoplasm and nucleus, Tat-Oct-5-FAM internalized in the cytoplasm but not in the nucleus of AR42J cells. The internalizations were inhibited by adding non-labeled corresponding peptides, suggesting that the endocytoses of each group of labeled and the corresponding unlabeled compounds occurred through a common pathway. Thus, fluorescent probes and endocytosis complex between octreotate and somatostatin receptors in cytoplasm could control nuclear internalization of Tat peptides.

Acoustic Effects in Classical Nucleation Theory

NASA Technical Reports Server (NTRS)

Baird, J. K.; Su, C.-H.

2017-01-01

The effect of sound wave oscillations on the rate of nucleation in a parent phase can be calculated by expanding the free energy of formation of a nucleus of the second phase in powers of the acoustic pressure. Since the period of sound wave oscillation is much shorter than the time scale for nucleation, the acoustic effect can be calculated as a time average of the free energy of formation of the nucleus. The leading non-zero term in the time average of the free energy is proportional to the square of the acoustic pressure. The Young-Laplace equation for the surface tension of the nucleus can be used to link the time average of the square of the pressure in the parent phase to its time average in the nucleus of the second phase. Due to the surface tension, the pressure in the nuclear phase is higher than the pressure in the parent phase. The effect is to lower the free energy of formation of the nucleus and increase the rate of nucleation.

A Retrospect Study on Thiazole Derivatives as the Potential Antidiabetic Agents in Drug Discovery & Developments.

PubMed

Khatik, Gopal L; Datusalia, Ashok Kumar; Ahsan, Waquar; Kaur, Paranjeet; Vyas, Manish; Mittal, Amit; Nayak, Surendra Kumar

2017-09-15

Heterocycles containing thiazole, a moiety with sulfur and nitrogen is a core structure which found in a number of biologically active compounds. The thiazole ring is notable as a component of the certain natural products, such as vitamin B1 (thiamine) and penicillins. Thiazole is also known as wonder nucleus and has versatile in different biological fields. A number of new compounds contain heterocycle thiazole moieties, thus it is one of the important areas of research. We searched the scientific database using relevant keywords. Among the searched literature only peer-reviewed papers were collected which addresses our questions. The retrieved quality research articles were screened and analyzed critically. The key findings of these studies were included along with their importance. The quality research articles included in this review, were selected for the life-threatening diseases i.e. diabetes, which is one of the serious issues all over the globe with an estimated worldwide prevalence in 2016 of 422 million people, which is expected to rise double by 2030. Since 1995, there has been an explosion of the introduction of new classes of pharmacological agents having thiazole moieties. However, most of the drugs can cause noncompliance, hypoglycemia, and obesity. Thus new antidiabetic drugs with thiazole moieties came up with improved compliance and reduced side effects such as pioglitazone (Actos), rosiglitazone (Avandia), netoglitazone, DRF-2189, PHT46, PMT13, DRF-2519. With such a great importance, research in thiazole is part of many academic and industrial laboratories worldwide. The present review describes the importance of thiazole nucleus and its derivatives as antidiabetic agents with an emphasis on the past as well as recent developments. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Biotransformation of the citrus flavone tangeretin in rats. Identification of metabolites with intact flavane nucleus.

PubMed

Nielsen, S E; Breinholt, V; Cornett, C; Dragsted, L O

2000-09-01

The present study was carried out in order to investigate the in vivo biotransformation and excretion of the flavone, tangeretin, found in citrus fruits, by analysing urine and faeces samples from rats after repeated administration of 100 mg/kg body weight/day tangeretin. The formed metabolites were separated and identified by HPLC and the structures elucidated by LC/MS and 1H NMR. Ten new, major metabolites with intact flavonoid structure were identified. The metabolites identified were either demethylated or hydroxylated derivatives of the parent compound and metabolic changes were found primarily to occur in the 4' position of the B-ring. The total urinary excretion of tangeretin metabolites with intact flavan nucleus was about 11% of the administered daily dose.

Characterization of Mg/Al butt joints welded by gas tungsten arc filling with Zn–29.5Al–0.5Ti filler metal

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Fei; Wang, Hongyang; Liu, Liming, E-mail: liulm@dlut.edu.cn

2014-04-01

The multivariate alloying design of a welding joint is used in the Mg to Al welding process. A Zn–29.5Al–0.5Ti alloy is added as filler metal in gas tungsten arc welding of Mg and Al alloy joint based on the analysis of Al and Mg alloy characteristics. The tensile strength, microstructure, and phase constitution of the weld seam are analyzed. The formation of brittle and hard Mg–Al intermetallic compounds is avoided because of the effects of Zn, Al, and Ti. The average tensile strength of the joint is 148 MPa. Al{sub 3}Ti is first precipitated and functions as the nucleus ofmore » heterogeneous nucleation during solidification. Moreover, the precipitated Al–MgZn{sub 2} hypoeutectic phase exhibited a feather-like structure, which enhances the property of the Mg–Al dissimilar joint. - Highlights: • Mg alloy AZ31B and Al alloy 6061 are butt welded by fusion welding. • The effect of Ti in filler metal is investigated. • The formation of Mg–Al intermetallic compounds is avoided.« less

The Nonpeptide Oxytocin Receptor Agonist WAY 267,464: Receptor-Binding Profile, Prosocial Effects and Distribution of c-Fos Expression in Adolescent Rats

PubMed Central

Hicks, C.; Jorgensen, W.; Brown, C.; Fardell, J.; Koehbach, J.; Gruber, C. W.; Kassiou, M.; Hunt, G. E.; McGregor, I. S.

2012-01-01

Previous research suggests that the nonpeptide oxytocin receptor (OTR) agonist WAY 267,464 may only partly mimic the effects of oxytocin in rodents. The present study further explored these differences and related them to OTR and vasopressin 1a receptor (V1aR) pharmacology and regional patterns of c-Fos expression. Binding data for WAY 267,464 and oxytocin were obtained by displacement binding assays on cellular membranes, while functional receptor data were generated by luciferase reporter assays. For behavioural testing, adolescent rats were tested in a social preference paradigm, the elevated plus-maze (EPM) and for locomotor activity changes following WAY 267,464 (10 and 100 mg/kg, i.p.) or oxytocin (0.1 and 1 mg/kg, i.p.). The higher doses were also examined for their effects on regional c-Fos expression. Results showed that WAY 267,464 had higher affinity (Ki) at the V1aR than the OTR (113 versus 978 nm). However, it had no functional response at the V1aR and only a weak functional effect (EC50) at the OTR (881 nm). This suggests WAY 267,464 is an OTR agonist with weak affinity and a possible V1aR antagonist. Oxytocin showed high binding at the OTR (1.0 nm) and V1aR (503 nm), with a functional EC50 of 9.0 and 59.7 nm, respectively, indicating it is a potent OTR agonist and full V1aR agonist. WAY 267,464 (100 mg/kg), but not oxytocin, significantly increased the proportion of time spent with a live rat, over a dummy rat, in the social preference test. Neither compound affected EPM behaviour, whereas the higher doses of WAY 267,464 and oxytocin suppressed locomotor activity. WAY 267,464 and oxytocin produced similar c-Fos expression in the paraventricular hypothalamic nucleus, central amygdala, lateral parabrachial nucleus and nucleus of the solitary tract, suggesting a commonality of action at the OTR with the differential doses employed. However, WAY 267,464 caused greater c-Fos expression in the medial amygdala and the supraoptic nucleus than oxytocin, and lesser effects in the locus coeruleus. Overall, our results confirm the differential effects of WAY 267,464 and oxytocin and suggest that this may reflect contrasting actions of WAY 267,464 and oxytocin at the V1aR. Antagonism of the V1aR by WAY 267,464 could underlie some of the prosocial effects of this drug either through a direct action or through disinhibition of oxytocin circuitry that is subject to vasopressin inhibitory influences. PMID:22420322

Comets - Chemistry and chemical evolution

NASA Technical Reports Server (NTRS)

Donn, B.

1982-01-01

Research on the chemical composition and conditions in comets and their possible role in the origin of life on earth is surveyed. The inorganic and organic compounds and ions indicated in the ultraviolet and visible spectra of comets are noted, and evidence for the existence of at least a small proportion of complex organic molecules in comets is presented. It is then pointed out that while cometary material could have reached the earth and provided volatile elements from which biochemical compounds could have formed, it is unlikely that a cometary nucleus could have withstood the temperatures and pressures necessary to sustain an environment in which life could have originated.

Prenylfuranocoumarin-HMGA-flavonol glucoside conjugates and other constituents of the fruit peels of Citrus hystrix and their anticholinesterase activity.

PubMed

Seeka, Chonticha; Sutthivaiyakit, Pakawadee; Youkwan, Juthamanee; Hertkorn, Norbert; Harir, Mourad; Schmitt-Kopplin, Philippe; Sutthivaiyakit, Somyote

2016-07-01

Sixteen compounds including dihydroxy prenylfuranocoumarins/3-hydroxy-3-methylglutaric acid conjugates and dihydroxy prenylfuranocoumarins/3-hydroxy-3-methylglutaric acid/1-O-flavonyl-β-d-glucopyranoside conjugates, together with other dihydroxyprenylfuranocoumarins conjugates, were isolated from the ethyl acetate extract of the fruit peels of Citrus hystrix. Some of the isolates were evaluated for their cholinesterase inhibitory activity, but only one compound possessing a 3-O-β-d-glucopyranosyl-3,5,7,4'-tetrahydroxy-6,8,3'-trimethoxyflavonol nucleus in the prenylfuranocoumarin-HMGA conjugate showed strong activity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Relationship between chemical structure and rat repellency

USGS Publications Warehouse

Bellack, E.; DeWitt, J.B.; Treichler, R.

1953-01-01

Repellent activity is defined as the activity of a compound in preventing consumption of, or gnawing attacks upon, foodstuffs or articles containing or treated with the candidate substance. Data are presented on repellency indices of 2700 compounds, and it is shown that repellency is associated with specific functional groups attached to alkyl, aryl, or heterocyclic nuclei. Functional groups containing nitrogen, sulfur or halogens are most active, with amines, imides, thiocyanates and thiocarbamates forming some of the most active classes. Activity of any functional group may be affected by molecular weight, unsaturation, or spatial configuration of the nucleus, or by the presence of additional substituent groups.

Electrical coupling: novel mechanism for sleep-wake control.

PubMed

Garcia-Rill, Edgar; Heister, David S; Ye, Meijun; Charlesworth, Amanda; Hayar, Abdallah

2007-11-01

Recent evidence suggests that certain anesthetic agents decrease electrical coupling, whereas the stimulant modafinil appears to increase electrical coupling. We investigated the potential role of electrical coupling in 2 reticular activating system sites, the subcoeruleus nucleus and in the pedunculopontine nucleus, which has been implicated in the modulation of arousal via ascending cholinergic activation of intralaminar thalamus and descending activation of the subcoeruleus nucleus to generate some of the signs of rapid eye movement sleep. We used 6- to 30-day-old rat pups to obtain brainstem slices to perform whole-cell patch-clamp recordings. Recordings from single cells revealed the presence of spikelets, manifestations of action potentials in coupled cells, and of dye coupling of neurons in the pedunculopontine nucleus. Recordings in pairs of pedunculopontine nucleus and subcoeruleus nucleus neurons revealed that some of these were electrically coupled with coupling coefficients of approximately 2%. After blockade of fast synaptic transmission, the cholinergic agonist carbachol was found to induce rhythmic activity in pedunculopontine nucleus and subcoeruleus nucleus neurons, an effect eliminated by the gap junction blockers carbenoxolone or mefloquine. The stimulant modafinil was found to decrease resistance in neurons in the pedunculopontine nucleus and subcoeruleus nucleus after fast synaptic blockade, indicating that the effect may be due to increased coupling. The finding of electrical coupling in specific reticular activating system cell groups supports the concept that this underlying process behind specific neurotransmitter interactions modulates ensemble activity across cell populations to promote changes in sleep-wake state.

Stopping powers and cross sections due to two-photon processes in relativistic nucleus-nucleus collisions

NASA Technical Reports Server (NTRS)

Cheung, Wang K.; Norbury, John W.

1994-01-01

The effects of electromagnetic-production processes due to two-photon exchange in nucleus-nucleus collisions are discussed. Feynman diagrams for two-photon exchange are evaluated using quantum electrodynamics. The total cross section and stopping power for projectile and target nuclei of identical charge are found to be significant for heavy nuclei above a few GeV per nucleon-incident energy.

Parkin disease: a clinicopathologic entity?

PubMed

Doherty, Karen M; Silveira-Moriyama, Laura; Parkkinen, Laura; Healy, Daniel G; Farrell, Michael; Mencacci, Niccolo E; Ahmed, Zeshan; Brett, Francesca M; Hardy, John; Quinn, Niall; Counihan, Timothy J; Lynch, Timothy; Fox, Zoe V; Revesz, Tamas; Lees, Andrew J; Holton, Janice L

2013-05-01

Mutations in the gene encoding parkin (PARK2) are the most common cause of autosomal recessive juvenile-onset and young-onset parkinsonism. The few available detailed neuropathologic reports suggest that homozygous and compound heterozygous parkin mutations are characterized by severe substantia nigra pars compacta neuronal loss. To investigate whether parkin-linked parkinsonism is a different clinicopathologic entity to Parkinson disease (PD). We describe the clinical, genetic, and neuropathologic findings of 5 unrelated cases of parkin disease and compare them with 5 pathologically confirmed PD cases and 4 control subjects. The PD control cases and normal control subjects were matched first for age at death then disease duration (PD only) for comparison. Presenting signs in the parkin disease cases were hand or leg tremor often combined with dystonia. Mean age at onset was 34 years; all cases were compound heterozygous for mutations of parkin. Freezing of gait, postural deformity, and motor fluctuations were common late features. No patients had any evidence of cognitive impairment or dementia. Neuronal counts in the substantia nigra pars compacta revealed that neuronal loss in the parkin cases was as severe as that seen in PD, but relative preservation of the dorsal tier was seen in comparison with PD (P = .04). Mild neuronal loss was identified in the locus coeruleus and dorsal motor nucleus of the vagus, but not in the nucleus basalis of Meynert, raphe nucleus, or other brain regions. Sparse Lewy bodies were identified in 2 cases (brainstem and cortex). These findings support the notion that parkin disease is characterized by a more restricted morphologic abnormality than is found in PD, with predominantly ventral nigral degeneration and absent or rare Lewy bodies.

Systematic study of probable projectile-target combinations for the synthesis of the superheavy nucleus 302120

NASA Astrophysics Data System (ADS)

Santhosh, K. P.; Safoora, V.

2016-08-01

Probable projectile-target combinations for the synthesis of the superheavy element 302120 have been studied taking the Coulomb and proximity potential as the interaction barrier. The probabilities of the compound nucleus formation PCN for the projectile-target combinations found in the cold reaction valley of 302120 are estimated. At energies near and above the Coulomb barrier, we have calculated the capture, fusion, and evaporation residue cross sections for the reactions of all probable projectile-target combinations so as to predict the most promising projectile-target combinations for the synthesis of the superheavy element 302120 in heavy-ion fusion reactions. The calculated fusion and evaporation cross sections for the more asymmetric ("hotter") projectile-target combination is found to be higher than the less asymmetric ("colder") combination. It can be seen from the nature of the quasifission barrier height, mass asymmetry, the probability of compound nucleus formation, survival probability, and excitation energy, the systems 44Ar+258No , 46Ar+256No , 48Ca+254Fm , 50Ca+252Fm , 54Ti+248Cf , and 58Cr+244Cm in deep region I of the cold reaction valley and the systems 62Fe+240Pu , 64Fe+238Pu , 68Ni+234U , 70Ni+232U , 72Ni+230U , and 74Zn+228Th in the other cold valleys are identified as the better projectile-target combinations for the synthesis of 302120. Our predictions on the synthesis of 302120 superheavy nuclei using the combinations 54Cr+248Cm , 58Fe+244Pu , 64Ni+238U , and 50Ti+249Cf are compared with available experimental data and other theoretical predictions.

Dynamical Cluster-decay Model (DCM) applied to 9Li+208Pb reaction

NASA Astrophysics Data System (ADS)

Kaur, Arshdeep; Hemdeep; Kaushal, Pooja; Behera, Bivash R.; Gupta, Raj K.

2017-10-01

The decay mechanism of 217At* formed in 9Li+208Pb reaction is studied within the dynamical cluster-decay model (DCM) at various center-of-mass energies. The aim is to see the behavior of a light neutron-rich radioactive beam on a doubly-magic target nucleus for the (total) fusion cross section σfus and the individual decay channel cross sections. Experimentally, only the isotopic yield of heavy mass residues * 211- 214At [equivalently, the light-particles (LPs) evaporation residue cross sections σxn for x = 3- 6 neutrons emission] are measured, with the fusion-fission (ff) component σff taken zero. For a fixed neck-length parameter ΔR, the only parameter in the DCM, we are able to fit σfus =∑x=16σxn almost exactly for 9Li on 208Pb at all E c . m .'s. However, the observed individual decay channels (3n-6n) are very poorly fitted, with unobserved channels (1n, 2n) and σff strongly over-estimated. Different ΔR values, meaning thereby different reaction time scales, are required to fit individually both the observed and unobserved evaporation residue channels (1n-6n) and σff, but then the compound nucleus (CN) contribution σCN is very small (< 1%), and the non-compound nucleus (nCN) decay cross section σnCN contributes the most towards total σfus (=σCN +σnCN). Thus, the 9Li induced reaction on doubly-magic 208Pb is more of a quasi-fission-like nCN decay, which is further analyzed in terms of the statistical CN formation probability PCN and CN survival probability Psurv. For the reaction under study, PCN < < 1 and Psurv → 1, in particular at above barrier energies.

Paradoxical augmented relapse in alcohol-dependent rats during deep-brain stimulation in the nucleus accumbens

PubMed Central

Hadar, R; Vengeliene, V; Barroeta Hlusicke, E; Canals, S; Noori, H R; Wieske, F; Rummel, J; Harnack, D; Heinz, A; Spanagel, R; Winter, C

2016-01-01

Case reports indicate that deep-brain stimulation in the nucleus accumbens may be beneficial to alcohol-dependent patients. The lack of clinical trials and our limited knowledge of deep-brain stimulation call for translational experiments to validate these reports. To mimic the human situation, we used a chronic-continuous brain-stimulation paradigm targeting the nucleus accumbens and other brain sites in alcohol-dependent rats. To determine the network effects of deep-brain stimulation in alcohol-dependent rats, we combined electrical stimulation of the nucleus accumbens with functional magnetic resonance imaging (fMRI), and studied neurotransmitter levels in nucleus accumbens-stimulated versus sham-stimulated rats. Surprisingly, we report here that electrical stimulation of the nucleus accumbens led to augmented relapse behavior in alcohol-dependent rats. Our associated fMRI data revealed some activated areas, including the medial prefrontal cortex and caudate putamen. However, when we applied stimulation to these areas, relapse behavior was not affected, confirming that the nucleus accumbens is critical for generating this paradoxical effect. Neurochemical analysis of the major activated brain sites of the network revealed that the effect of stimulation may depend on accumbal dopamine levels. This was supported by the finding that brain-stimulation-treated rats exhibited augmented alcohol-induced dopamine release compared with sham-stimulated animals. Our data suggest that deep-brain stimulation in the nucleus accumbens enhances alcohol-liking probably via augmented dopamine release and can thereby promote relapse. PMID:27327255

A study of the nucleus-nucleus total reaction cross section of stable systems at intermediate energies: An application to 12C

NASA Astrophysics Data System (ADS)

Hu, Liyuan; Song, Yushou; Hou, Yingwei; Liu, Huilan; Li, Hui

2018-07-01

A semi-microscopic analytical expression of the nucleus-nucleus total reaction cross section (σR) was proposed based on the strong absorption model. It is suitable for stable nuclei at intermediate energies. The matter density distributions of nuclei and the nucleon-nucleon total cross section were both considered. Particularly, the Fermi motion effect of the nucleons in a nucleus was also taken into account. The parametrization of σR was applied to the colliding systems including 12C. The experimental data at energies from 30 to 1000 MeV/nucleon were well reproduced, according to which an approach of deriving σR without adjustable parameters was developed. The necessity of considering the Fermi motion effect in the parametrization was discussed.

Effect of energy transfer from atomic electron shell to an α particle emitted by decaying nucleus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Igashov, S. Yu., E-mail: igashov@theor.mephi.ru; Tchuvil’sky, Yu. M.

2016-12-15

The process of energy transfer from the electron shell of an atom to an α particle propagating through the shell is formulated mathematically. Using the decay of the {sup 226}Ra nucleus as an example, it is demonstrated that this phenomenon increases the α-decay intensity in contrast with other known effects of similar type. Moreover, the α decay of the nucleus is more strongly affected by the energy transfer than by all other effects taken together.

Cytotoxicity and genotoxicity of nano - and microparticulate copper oxide: role of solubility and intracellular bioavailability.

PubMed

Semisch, Annetta; Ohle, Julia; Witt, Barbara; Hartwig, Andrea

2014-02-13

Nano- or microscale copper oxide particles (CuO NP, CuO MP) are increasingly applied as catalysts or antimicrobial additives. This increases the risk of adverse health effects, since copper ions are cytotoxic under overload conditions. The extra- and intracellular bioavailability of CuO NP and CuO MP were explored. In addition, different endpoints related to cytotoxicity as well as direct and indirect genotoxicity of the copper oxides and copper chloride (CuCl2) were compared. Comprehensively characterized CuO NP and CuO MP were analysed regarding their copper ion release in model fluids. In all media investigated, CuO NP released far more copper ions than CuO MP, with most pronounced dissolution in artificial lysosomal fluid. CuO NP and CuCl2 caused a pronounced and dose dependent decrease of colony forming ability (CFA) in A549 and HeLa S3 cells, whereas CuO MP exerted no cytotoxicity at concentrations up to 50 μg/mL. Cell death induced by CuO NP was at least in part due to apoptosis, as determined by subdiploid DNA as well as via translocation of the apoptosis inducing factor (AIF) into the cell nucleus. Similarly, only CuO NP induced significant amounts of DNA strand breaks in HeLa S3 cells, whereas all three compounds elevated the level of H2O2-induced DNA strand breaks. Finally, all copper compounds diminished the H2O2-induced poly(ADP-ribosyl)ation, catalysed predominantly by poly(ADP-ribose)polymerase-1 (PARP-1); here, again, CuO NP exerted the strongest effect. Copper derived from CuO NP, CuO MP and CuCl2 accumulated in the soluble cytoplasmic and nuclear fractions of A549 cells, yielding similar concentrations in the cytoplasm but highest concentrations in the nucleus in case of CuO NP. The results support the high cytotoxicity of CuO NP and CuCl2 and the missing cytotoxicity of CuO MP under the conditions applied. For these differences in cytotoxicity, extracellular copper ion levels due to dissolution of particles as well as differences in physicochemical properties of the particles like surface area may be of major relevance. Regarding direct and indirect genotoxicity, especially the high copper content in the cell nucleus derived after cell treatment with CuO NP appears to be decisive.

Cytotoxicity and genotoxicity of nano - and microparticulate copper oxide: role of solubility and intracellular bioavailability

PubMed Central

2014-01-01

Background Nano- or microscale copper oxide particles (CuO NP, CuO MP) are increasingly applied as catalysts or antimicrobial additives. This increases the risk of adverse health effects, since copper ions are cytotoxic under overload conditions. Methods The extra- and intracellular bioavailability of CuO NP and CuO MP were explored. In addition, different endpoints related to cytotoxicity as well as direct and indirect genotoxicity of the copper oxides and copper chloride (CuCl2) were compared. Results Comprehensively characterized CuO NP and CuO MP were analysed regarding their copper ion release in model fluids. In all media investigated, CuO NP released far more copper ions than CuO MP, with most pronounced dissolution in artificial lysosomal fluid. CuO NP and CuCl2 caused a pronounced and dose dependent decrease of colony forming ability (CFA) in A549 and HeLa S3 cells, whereas CuO MP exerted no cytotoxicity at concentrations up to 50 μg/mL. Cell death induced by CuO NP was at least in part due to apoptosis, as determined by subdiploid DNA as well as via translocation of the apoptosis inducing factor (AIF) into the cell nucleus. Similarly, only CuO NP induced significant amounts of DNA strand breaks in HeLa S3 cells, whereas all three compounds elevated the level of H2O2-induced DNA strand breaks. Finally, all copper compounds diminished the H2O2-induced poly(ADP-ribosyl)ation, catalysed predominantly by poly(ADP-ribose)polymerase-1 (PARP-1); here, again, CuO NP exerted the strongest effect. Copper derived from CuO NP, CuO MP and CuCl2 accumulated in the soluble cytoplasmic and nuclear fractions of A549 cells, yielding similar concentrations in the cytoplasm but highest concentrations in the nucleus in case of CuO NP. Conclusions The results support the high cytotoxicity of CuO NP and CuCl2 and the missing cytotoxicity of CuO MP under the conditions applied. For these differences in cytotoxicity, extracellular copper ion levels due to dissolution of particles as well as differences in physicochemical properties of the particles like surface area may be of major relevance. Regarding direct and indirect genotoxicity, especially the high copper content in the cell nucleus derived after cell treatment with CuO NP appears to be decisive. PMID:24520990

Cytotoxic and clastogenic effects of soluble and insoluble compounds containing hexavalent and trivalent chromium.

PubMed Central

Levis, A. G.; Majone, F.

1981-01-01

Cr(III) and Cr(VI) compounds of varying solubilities have been tested in vitro for their ability to inhibit cell growth and nucleic acid and protein syntheses in BHK cells, to induce alterations in the mitotic cycle in HEp cells, and to increase the frequency of chromosomal aberrations and sister chromatid exchanges (SCE) in CHO cells. All Cr(VI) compounds, and particularly those containing soluble Cr(VI), such as potassium dichromate and zinc yellow, differentially inhibit macromolecular syntheses in BKH cells, that of DNA being always the most affected. Among Cr(III) compounds, which generally have very low cytotoxicity, chromite is particularly active, and inhibits cell growth and DNA synthesis even more than the poorly soluble Cr(VI) compounds. Preincubation in growth medium, with or without metabolizing cell cultures, solubilizes considerable amounts of Cr(VI) from zinc yellow and chromite, but significant amounts are also obtained from the most insoluble Cr(VI) pigments. When BHK cells are treated with such preincubated solutions, reduction of soluble Cr(VI) to Cr(III) by cell metabolites is seen with all Cr(VI) compounds, accompanied by decreased cytotoxicity. The same differences between Cr(VI) and Cr(III) compounds apply to the cytotoxic effects on mitosis of HEp cells and the clastogenic effects on CHO cells. The activity of chromite, the only Cr(III) pigment capable of significantly increasing the frequency of SCE, is due to contamination with soluble Cr(VI). In contrast to the very low cytotoxicity of Cr(III), much higher chromium levels are detected in the cells incubated with soluble Cr(III) than with the same concentrations of soluble Cr(VI). 50% and 75% of chromium accumulated in the cells during treatments with Cr(VI) and Cr(III) respectively remains firmly bound to the cells, even when they are incubated for up to 48 h in normal growth medium. Chromium accumulated in the cells after treatment with Cr(III) is most probably bound to the cell membrane, whereas some of the Cr(VI) is transported through the cell membrane and reduced in the cell nucleus. The results of the present investigation are in agreement with those obtained with the same Cr(VI) and Cr(III) compounds in mutagenicity assays in bacteria and carcinogenicity tests in rodents. A re-evaluation of the mechanisms of chromium carcinogenisis is proposed. PMID:7272188

Uncertainties of α-particle optical potential assessment around and below the Coulomb barrier

NASA Astrophysics Data System (ADS)

Avrigeanu, V.; Avrigeanu, M.; Mǎnǎilescu, C.

2017-06-01

A competition of the low-energy Coulomb excitation (CE) with the compound nucleus (CN) formation in α-induced reactions below the Coulomb barrier has recently been assumed in order to make possible the description of the latter as well as the α-particle emission by the same optical model (OM) potential. However, we show in the present work that the corresponding partial waves and integration radii provide evidence for the distinct account of the CE cross section and OM total-reaction cross section σR. Thus the largest contribution to CE cross section comes by far from partial waves larger than the ones contributing to the σR values. Finally, effects of statistical model parameters are comparatively discussed.

Effects of cocaine combined with a social cue on conditioned place preference and nucleus accumbens monoamines after isolation rearing in rats

PubMed Central

Grotewold, Susan K.; Wall, Vanessa L.; Goodell, Dayton J.; Hayter, Cassandra

2015-01-01

Rationale Social interaction during drug exposure can potentiate cocaine reward. Isolation rearing (ISO) during adolescence increases social interaction and may amplify this potentiation. Objectives The objectives of this study are to determine whether ISO alters conditioned place preference (CPP) for cocaine when combined with a social cue and to determine whether ISO alters the effects of cocaine when combined with social cue on nucleus accumbens shell (NAcS) dopamine (DA) and serotonin (5-HT). Methods Male and female rats were either ISO or group (GRP) reared for 4 weeks during adolescence. CPP was performed using a low dose of cocaine (2 mg/kg or saline) with or without exposure to a novel same-sex conspecific during conditioning. In vivo microdialysis was performed using the same parameters. Results ISO rats engaged in more social and aggressive behaviors during conditioning relative to GRP. Cocaine reduced social and aggressive behaviors in all rats. CPP was not influenced by rearing condition. Cocaine produced significant CPP, and a social cue produced CPP only in males. In contrast, the interaction of cocaine and a social cue on NAcS DA and 5-HT differed depending upon rearing condition. In isolates, cocaine-induced DA was attenuated, while cocaine plus a social cue produced potentiated DA and 5-HT. Conclusions Exposure to a low dose of cocaine in the presence of a social cue produced additive effects on CPP while producing synergistic effects on DA and 5-HT in the NAcS of ISO rats. The aversive effects of this compound stimulus may negate the rewarding effects in isolates. PMID:24553577

Deep brain stimulation modulates synchrony within spatially and spectrally distinct resting state networks in Parkinson's disease.

PubMed

Oswal, Ashwini; Beudel, Martijn; Zrinzo, Ludvic; Limousin, Patricia; Hariz, Marwan; Foltynie, Tom; Litvak, Vladimir; Brown, Peter

2016-05-01

Chronic dopamine depletion in Parkinson's disease leads to progressive motor and cognitive impairment, which is associated with the emergence of characteristic patterns of synchronous oscillatory activity within cortico-basal-ganglia circuits. Deep brain stimulation of the subthalamic nucleus is an effective treatment for Parkinson's disease, but its influence on synchronous activity in cortico-basal-ganglia loops remains to be fully characterized. Here, we demonstrate that deep brain stimulation selectively suppresses certain spatially and spectrally segregated resting state subthalamic nucleus-cortical networks. To this end we used a validated and novel approach for performing simultaneous recordings of the subthalamic nucleus and cortex using magnetoencephalography (during concurrent subthalamic nucleus deep brain stimulation). Our results highlight that clinically effective subthalamic nucleus deep brain stimulation suppresses synchrony locally within the subthalamic nucleus in the low beta oscillatory range and furthermore that the degree of this suppression correlates with clinical motor improvement. Moreover, deep brain stimulation relatively selectively suppressed synchronization of activity between the subthalamic nucleus and mesial premotor regions, including the supplementary motor areas. These mesial premotor regions were predominantly coupled to the subthalamic nucleus in the high beta frequency range, but the degree of deep brain stimulation-associated suppression in their coupling to the subthalamic nucleus was not found to correlate with motor improvement. Beta band coupling between the subthalamic nucleus and lateral motor areas was not influenced by deep brain stimulation. Motor cortical coupling with subthalamic nucleus predominantly involved driving of the subthalamic nucleus, with those drives in the higher beta frequency band having much shorter net delays to subthalamic nucleus than those in the lower beta band. These observations raise the possibility that cortical connectivity with the subthalamic nucleus in the high and low beta bands may reflect coupling mediated predominantly by the hyperdirect and indirect pathways to subthalamic nucleus, respectively, and that subthalamic nucleus deep brain stimulation predominantly suppresses the former. Yet only the change in strength of local subthalamic nucleus oscillations correlates with the degree of improvement during deep brain stimulation, compatible with the current view that a strengthened hyperdirect pathway is a prerequisite for locally generated beta activity but that it is the severity of the latter that may determine or index motor impairment. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.

First Search for the EMC Effect and Nuclear Shadowing in Neutrino Nucleus Deep Inelastic Scattering at MINERvA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mousseau, Joel A.

2015-01-01

Decades of research in electron-nucleus deep inelastic scattering (DIS) have provided a clear picture of nuclear physics at high momentum transfer. While these effects have been clearly demonstrated by experiment, the theoretical explanation of their origin in some kinematic regions has been lacking. Particularly, the effects in the intermediate regions of Bjorken-x, anti-shadowing and the EMC effect have no universally accepted quantum mechanical explanation. In addition, these effects have not been measured systematically with neutrino-nucleus deep inelastic scattering, due to experiments lacking multiple heavy targets.

Modeling the surface and interior structure of comet nuclei using a multidisciplinary approach

NASA Technical Reports Server (NTRS)

Odell, C. R.; Dakoulas, Panos C.; Pharr, George M.

1991-01-01

The goal was to investigate the structural properties of the surface of comet nucleus and how the surface should change with time under effect of solar radiation. The basic model that was adopted was that the nucleus is an aggregate of frosty particles loosely bound together, so that it is essentially a soil. The nucleus must mostly be composed of dust particles. The observed mass ratios of dust to gas in the coma is never much greater than unity, but this ratio is probably a much lower limit than that of the nucleus because it is vastly easier to remove the gaseous component by sublimation than by carrying off the dust. Therefore the described models assumed that the particles in the soil were frost covered grains of submicron basic size, closely resembling the interstellar grains. The surface properties of such a nucleus under the effects of heating and cooling as the nucleus approaches and recedes from the Sun generally characterized.

Morphine-induced changes in acetylcholine release in the interpeduncular nucleus and relationship to changes in motor behavior in rats

PubMed Central

Taraschenko, Olga D.; Rubbinaccio, Heather Y.; Shulan, Joseph M.; Glick, Stanley D.; Maisonneuve, Isabelle M.

2007-01-01

Owing to multiple anatomical connections and functional interactions between the habenulo-interpeduncular and the mesolimbic pathways, it has been proposed that these systems could together mediate the reinforcing properties of addictive drugs. 18-Methoxycoronaridine, an agent that reduces morphine self-administration and attenuates dopamine sensitization in the nucleus accumbens in response to repeated morphine, has been shown to produce these effects by acting in the medial habenula and interpeduncular nucleus. Acetylcholine, one of the predominant neurotransmitters in the interpeduncular nucleus, may be a major determinant of these interactions. To determine if and how morphine acts in the interpeduncular nucleus, the effects of acute and repeated administration of morphine on extracellular acetylcholine levels in this brain area were assessed. In addition, the motor behavior of rats receiving repeated morphine administration was monitored during microdialysis sessions. Acutely, morphine produced a biphasic effect on extracellular acetylcholine levels in the interpeduncular nucleus such that low and high doses of morphine (i.e., 5 and 20 mg/kg i.p.) significantly increased and decreased acetylcholine levels, respectively. Repeated administration of the same doses of morphine resulted in tolerance to the inhibitory but not to the stimulatory effects; tolerance was accompanied by sensitization to morphine-induced changes in locomotor activity and stereotypic behavior. The latter results suggest that tolerance to morphine's effect on the cholinergic habenulo-interpeduncular pathway is related to its sensitizing effects on the mesostriatal dopaminergic pathways. PMID:17544456

Mechanical behavior of the human lumbar intervertebral disc with polymeric hydrogel nucleus implant: An experimental and finite element study

NASA Astrophysics Data System (ADS)

Joshi, Abhijeet Bhaskar

The origin of the lower back pain is often the degenerated lumbar intervertebral disc (IVD). We are proposing replacement of the degenerated nucleus by a PVA/PVP polymeric hydrogel implant. We hypothesize that a polymeric hydrogel nucleus implant can restore the normal biomechanics of the denucleated IVD by mimicking the natural load transfer phenomenon as in case of the intact IVD. Lumbar IVDs (n = 15) were harvested from human cadavers. In the first part, specimens were tested in four different conditions for compression: Intact, bone in plug, denucleated and Implanted. Hydrogel nucleus implants were chosen to have line-to-line fit in the created nuclear cavity. In the second part, nucleus implant material (modulus) and geometric (height and diameter) parameters were varied and specimens (n = 9) were tested. Nucleus implants with line-to-line fit significantly restored (88%) the compressive stiffness of the denucleated IVD. The synergistic effect between the implant and the intact annulus resulted in the nonlinear increase in implanted IVD stiffness, where Poisson effect of the hydrogel played major role. Nucleus implant parameters were observed to have a significant effect on the compressive stiffness. All implants with modulus in the tested range restored the compressive stiffness. The undersize implants resulted in incomplete restoration while oversize implants resulted in complete restoration compared to the BI condition. Finite element models (FEM) were developed to simulate the actual test conditions and validated against the experimental results for all conditions. The annulus (defined as hyperelastic, isotropic) mainly determined the nonlinear response of the IVD. Validated FEMs predicted 120--3000 kPa as a feasible range for nucleus implant modulus. FEMs also predicted that overdiameter implant would be more effective than overheight implant in terms of stiffness restoration. Underdiameter implants, initially allowed inward deformation of the annulus and hence were less effective compared to underheight implants. This research successfully proved the feasibility of PVA/PVP polymeric hydrogel as a replacement for degenerated nucleus. This approach may reduce the abnormal stresses on the annulus and thus, prevent/postpone the degeneration of the annulus. A validated FEM can be used as a design tool for optimization of hydrogel nucleus implants design and related feasibility studies.

EMPIRE: Nuclear Reaction Model Code System for Data Evaluation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Herman, M.; Capote, R.; Carlson, B.V.

EMPIRE is a modular system of nuclear reaction codes, comprising various nuclear models, and designed for calculations over a broad range of energies and incident particles. A projectile can be a neutron, proton, any ion (including heavy-ions) or a photon. The energy range extends from the beginning of the unresolved resonance region for neutron-induced reactions ({approx} keV) and goes up to several hundred MeV for heavy-ion induced reactions. The code accounts for the major nuclear reaction mechanisms, including direct, pre-equilibrium and compound nucleus ones. Direct reactions are described by a generalized optical model (ECIS03) or by the simplified coupled-channels approachmore » (CCFUS). The pre-equilibrium mechanism can be treated by a deformation dependent multi-step direct (ORION + TRISTAN) model, by a NVWY multi-step compound one or by either a pre-equilibrium exciton model with cluster emission (PCROSS) or by another with full angular momentum coupling (DEGAS). Finally, the compound nucleus decay is described by the full featured Hauser-Feshbach model with {gamma}-cascade and width-fluctuations. Advanced treatment of the fission channel takes into account transmission through a multiple-humped fission barrier with absorption in the wells. The fission probability is derived in the WKB approximation within the optical model of fission. Several options for nuclear level densities include the EMPIRE-specific approach, which accounts for the effects of the dynamic deformation of a fast rotating nucleus, the classical Gilbert-Cameron approach and pre-calculated tables obtained with a microscopic model based on HFB single-particle level schemes with collective enhancement. A comprehensive library of input parameters covers nuclear masses, optical model parameters, ground state deformations, discrete levels and decay schemes, level densities, fission barriers, moments of inertia and {gamma}-ray strength functions. The results can be converted into ENDF-6 formatted files using the accompanying code EMPEND and completed with neutron resonances extracted from the existing evaluations. The package contains the full EXFOR (CSISRS) library of experimental reaction data that are automatically retrieved during the calculations. Publication quality graphs can be obtained using the powerful and flexible plotting package ZVView. The graphic user interface, written in Tcl/Tk, provides for easy operation of the system. This paper describes the capabilities of the code, outlines physical models and indicates parameter libraries used by EMPIRE to predict reaction cross sections and spectra, mainly for nucleon-induced reactions. Selected applications of EMPIRE are discussed, the most important being an extensive use of the code in evaluations of neutron reactions for the new US library ENDF/B-VII.0. Future extensions of the system are outlined, including neutron resonance module as well as capabilities of generating covariances, using both KALMAN and Monte-Carlo methods, that are still being advanced and refined.« less

Analgesia induced by morphine microinjected into the nucleus raphe magnus: effects on tonic pain.

PubMed

Dualé, Christian; Sierralta, Fernando; Dallel, Radhouane

2007-07-01

One of the possible sites of action of the analgesic effect of morphine is the Nucleus Raphe Magnus, as morphine injected into this structure induces analgesia in transient pain models. In order to test if morphine in the Nucleus Raphe Magnus is also analgesic in a tonic pain model, 5 microg of morphine or saline (control) were microinjected into the Nucleus Raphe Magnus of the rat. Analgesic effects were assessed following nociceptive stimulation using transient heating of the tail (phasic pain) and subcutaneous orofacial injection of 1.5 % formalin (tonic pain). While morphine was strongly analgesic for the tail-flick response (p <0.0001 compared to control), analgesia on the response to formalin was also observed for both early (p = 0.007) and late responses (p = 0.02). However, the response to formalin was not completely blunted. These results suggest that the Nucleus Raphe Magnus is not the exclusive site of action of morphine-induced analgesia in clinical conditions.

Deep brain stimulation modulates synchrony within spatially and spectrally distinct resting state networks in Parkinson’s disease

PubMed Central

Oswal, Ashwini; Beudel, Martijn; Zrinzo, Ludvic; Limousin, Patricia; Hariz, Marwan; Foltynie, Tom; Litvak, Vladimir

2016-01-01

Abstract Chronic dopamine depletion in Parkinson’s disease leads to progressive motor and cognitive impairment, which is associated with the emergence of characteristic patterns of synchronous oscillatory activity within cortico-basal-ganglia circuits. Deep brain stimulation of the subthalamic nucleus is an effective treatment for Parkinson’s disease, but its influence on synchronous activity in cortico-basal-ganglia loops remains to be fully characterized. Here, we demonstrate that deep brain stimulation selectively suppresses certain spatially and spectrally segregated resting state subthalamic nucleus–cortical networks. To this end we used a validated and novel approach for performing simultaneous recordings of the subthalamic nucleus and cortex using magnetoencephalography (during concurrent subthalamic nucleus deep brain stimulation). Our results highlight that clinically effective subthalamic nucleus deep brain stimulation suppresses synchrony locally within the subthalamic nucleus in the low beta oscillatory range and furthermore that the degree of this suppression correlates with clinical motor improvement. Moreover, deep brain stimulation relatively selectively suppressed synchronization of activity between the subthalamic nucleus and mesial premotor regions, including the supplementary motor areas. These mesial premotor regions were predominantly coupled to the subthalamic nucleus in the high beta frequency range, but the degree of deep brain stimulation-associated suppression in their coupling to the subthalamic nucleus was not found to correlate with motor improvement. Beta band coupling between the subthalamic nucleus and lateral motor areas was not influenced by deep brain stimulation. Motor cortical coupling with subthalamic nucleus predominantly involved driving of the subthalamic nucleus, with those drives in the higher beta frequency band having much shorter net delays to subthalamic nucleus than those in the lower beta band. These observations raise the possibility that cortical connectivity with the subthalamic nucleus in the high and low beta bands may reflect coupling mediated predominantly by the hyperdirect and indirect pathways to subthalamic nucleus, respectively, and that subthalamic nucleus deep brain stimulation predominantly suppresses the former. Yet only the change in strength of local subthalamic nucleus oscillations correlates with the degree of improvement during deep brain stimulation, compatible with the current view that a strengthened hyperdirect pathway is a prerequisite for locally generated beta activity but that it is the severity of the latter that may determine or index motor impairment. PMID:27017189

The hadronic interaction model EPOS

NASA Astrophysics Data System (ADS)

Werner, Klaus

2008-01-01

EPOS is a sophisticated multiple scattering approach based on partons and Pomerons (parton ladders), with special emphasis on high parton densities. The latter aspect, particularly important in proton-nucleus or nucleus-nucleus collisions, is taken care of via an effective treatment of Pomeron-Pomeron interactions, referred to as parton ladder splitting. In addition, collective effects are introduced after separating the high density central core from the peripheral corona. EPOS is the successor of the NEXUS model.

Toxic Effects of Prodigiosin Secreted by Hahella sp. KA22 on Harmful Alga Phaeocystis globosa

PubMed Central

Zhang, Huajun; Wang, Hui; Zheng, Wei; Yao, Zhiyuan; Peng, Yun; Zhang, Su; Hu, Zhong; Tao, Zhen; Zheng, Tianling

2017-01-01

Application of algicidal compounds secreted by bacteria is a promising and environmentally friendly strategy to control harmful algal blooms (HABs). Years ago prodigiosin was described as an efficient algicidal compound, but the details about the effect of prodigiosin on algal cells are still elusive. Prodigiosin shows high algicidal activity on Phaeocystis globosa, making it a potential algicide in HAB control. When P. globosa were treated with prodigiosin at 5 μg/mL, algae cells showed cytoplasmic hypervacuolization, chloroplast and nucleus rupture, flagella missing, and cell fracture, when observed by scanning electron microscope and transmission electron microscopy. Prodigiosin induced a reactive oxygen species (ROS) burst in P. globosa at 2 h, which could result in severe oxidative damage to algal cells. Chlorophyll a (Chl a) fluorescence decreased significantly after prodigiosin treatment; about 45.3 and 90.0% of algal cells lost Chl a fluorescence at 24 and 48 h. The Fv/Fm value, reflecting the status of the photosystem II electron flow also decreased after prodigiosin treatment. Quantitative polymerase chain reaction (PCR) analysis psbA and rbcS expression indicated that photosynthesis process was remarkably inhibited by prodigiosin. The results indicated that the inhibition of photosynthesis may produce excessive ROS causing cell necrosis. This study is the first report about algal lysis mechanism of prodigiosin on harmful algae. Our results could increase our knowledge on the interaction between algicidal compounds and harmful algae, which could lead to further studies in the microcosm. PMID:28634473

A morphine/heroin vaccine with new hapten design attenuates behavioral effects in rats.

PubMed

Li, Qian-Qian; Luo, Yi-Xiao; Sun, Cheng-Yu; Xue, Yan-Xue; Zhu, Wei-Li; Shi, Hai-Shui; Zhai, Hai-Feng; Shi, Jie; Lu, Lin

2011-12-01

Heroin use has seriously threatened public heath in many countries, but the existing therapies continue to have many limitations. Recently, immunotherapy has shown efficacy in some clinical studies, including vaccines against nicotine and cocaine, but no opioid vaccines have been introduced in clinical studies. The development of a novel opioid antigen designed specifically for the prevention of heroin addiction is necessary. A morphine-keyhole limpet hemocyanin conjugate was prepared and administered subcutaneously in rats. Antibody titers in plasma were measured using an enzyme-linked immunosorbent assay (ELISA). Competitive ELISA was used to assess the selectivity of the antibodies. Dopamine concentrations in the nucleus accumbens in rats after vaccine administration were determined by high-performance liquid chromatography with electrochemical detection. The effects of the vaccine on the heroin-primed restatement of self-administration and locomotor sensitization were evaluated. A novel hapten, 6-glutarylmorphine, was produced, and the vaccine generated a high antibody titer response. This vaccine displayed specificity for both morphine and heroin, but the anti-morphine antibodies could not recognize dissimilar therapeutic opioid compounds, such as buprenorphine, methadone, naloxone, naltrexone, codeine, and nalorphine. The morphine antibody significantly decreased morphine-induced locomotor activity in rats after immunization. Importantly, rats immunized with this vaccine did not exhibit heroin-primed reinstatement of heroin seeking when antibody levels were sufficiently high. The vaccine reduced dopamine levels in the nucleus accumbens after morphine administration, which is consistent with its behavioral effects. These results suggest that immunization with a novel vaccine is an effective means of inducing a morphine-specific antibody response that is able to attenuate the behavioral and psychoactive effects of heroin. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

N/Z effect on reaction mechanisms cross sections in the 78Kr + 40Ca and 86Kr + 48Ca collisions at 10A MeV

NASA Astrophysics Data System (ADS)

Gnoffo, B.; Pirrone, S.; Politi, G.; La Commara, M.; Wieleczko, J. P.; De Filippo, E.; Russotto, P.; Trimarchi, M.; Vigilante, M.; Ademard, G.; Auditore, L.; Beck, C.; Bercenau, I.; Bonnet, E.; Borderie, B.; Cardella, G.; Chibihi, A.; Colonna, M.; De Luca, S.; Dell'Aquila, D.; D'Onofrio, A.; Frankland, J. D.; Lanzalone, G.; Lautesse, P.; Lebhertz, D.; Le Neidre, N.; Lombardo, I.; Martorana, N. S.; Mazurek, N.; Norella, S.; Pagano, A.; Pagano, E. V.; Papa, M.; Piasecki, E.; Porto, F.; Quattrocchi, L.; Rizzo, F.; Spadaccini, G.; Trifirò, A.; Verde, G.

2017-11-01

Nuclear reactions between medium-mass nuclei at low bombarding energy are characterized by the competition between binary and evaporation processes in the compound nucleus decay. A study of the influence of the neutron richness of the entrance channel on the decay paths of the compound nuclei formed in the 78Kr + 40Ca and 86Kr + 48Ca at 10MeV/A is presented. The experiment has been performed at Laboratori Nazionali del Sud by using the CHIMERA 4 π multidetector for charged particles. The kinematical characteristics of the two reactions support the conclusion of a production of the IMFs via long-lived system and the global features suggest a different competition among the various reaction channels. The cross sections of the mechanisms responsible for the fragments production have been extracted. Besides the results relative to the n-poor system are compared to those obtained at GANIL, performed at 5.5A MeV, in order to study the energy influence on the mechanisms.

Design, synthesis, and biological evaluation of combretabenzodiazepines: a novel class of anti-tubulin agents.

PubMed

Galli, Ubaldina; Travelli, Cristina; Aprile, Silvio; Arrigoni, Elena; Torretta, Simone; Grosa, Giorgio; Massarotti, Alberto; Sorba, Giovanni; Canonico, Pier Luigi; Genazzani, Armando A; Tron, Gian Cesare

2015-02-12

In the present manuscript, starting from the 1,4-benzodiazepin-2-one nucleus, a privileged structure in medicinal chemistry, we have synthesized a novel class of cis-locked combretastatins named combreatabenzodiazepines. They show similar cytotoxic and antitubulin activity compared to combretastatin A-4 in neuroblastoma cells, showing a better pharmacokinetic profile. This class of compounds has therefore the potential for further development as antitubulin agents.

Investigation of the heavy nuclei fission with anomalously high values of the fission fragments total kinetic energy

NASA Astrophysics Data System (ADS)

Khryachkov, Vitaly; Goverdovskii, Andrei; Ketlerov, Vladimir; Mitrofanov, Vecheslav; Sergachev, Alexei

2018-03-01

Binary fission of 232Th and 238U induced by fast neutrons were under intent investigation in the IPPE during recent years. These measurements were performed with a twin ionization chamber with Frisch grids. Signals from the detector were digitized for further processing with a specially developed software. It results in information of kinetic energies, masses, directions and Bragg curves of registered fission fragments. Total statistics of a few million fission events were collected during each experiment. It was discovered that for several combinations of fission fragment masses their total kinetic energy was very close to total free energy of the fissioning system. The probability of such fission events for the fast neutron induced fission was found to be much higher than for spontaneous fission of 252Cf and thermal neutron induced fission of 235U. For experiments with 238U target the energy of incident neutrons were 5 MeV and 6.5 MeV. Close analysis of dependence of fission fragment distribution on compound nucleus excitation energy gave us some explanation of the phenomenon. It could be a process in highly excited compound nucleus which leads the fissioning system from the scission point into the fusion valley with high probability.

Maruhn-Greiner Maximum of Uranium Fission for Confirmation of Low Energy Nuclear Reactions LENR via a Compound Nucleus with Double Magic Numbers

NASA Astrophysics Data System (ADS)

Hora, H.; Miley, G. H.

2007-12-01

One of the most convincing facts about LENR due to deuterons of very high concentration in host metals as palladium is the measurement of the large scale minimum of the reaction probability depending on the nucleon number A of generated elements at A = 153 where a local maximum was measured. This is similar to the fission of uranium at A = 119 where the local maximum follows from the Maruhn-Greiner theory if the splitting nuclei are excited to about MeV energy. The LENR generated elements can be documented any time after the reaction by SIMS or K-shell X-ray excitation to show the very unique distribution with the local maximum. An explanation is based on the strong Debye screening of the Maxwellian deuterons within the degenerate rigid electron background especially within the swimming electron layer at the metal surface or at interfaces. The deuterons behave like neutrals at distances of about 2 picometers. They may form clusters due to soft attraction in the range above thermal energy. Clusters of 10 pm diameter may react over long time probabilities (megaseconds) with Pd nuclei leading to a double magic number compound nucleus which splits like in fission to the A = 153 element distribution.

Recent advances of pyrrolopyridines derivatives: a patent and literature review.

PubMed

El-Gamal, Mohammed I; Anbar, Hanan S

2017-05-01

Several pyrrolopyridines or azaindoles have been reported in the literature as biologically-active molecules. Most of them are anticancer agents, and few possess other therapeutic effects. Areas covered: The most recent biologically-active pyrrolopyridine derivatives have been reviewed from the patents and research articles published from 2010 to the mid of 2016. Their structural and biological features have been explained. In general, the pyrrolopyridine scaffold mimics the purine ring of the ATP molecule. So the well-designed pyrrolopyridine analogues can successfully act as kinase inhibitors for treatment of cancer and/or other diseases. The most successful pyrrolopyridine derivative that is currently used in the market is vemurafenib, which is used for treatment of melanoma. Its chemical and biological features have been reviewed and explained. Expert opinion: The heterocyclic pyrrolopyridine nucleus mimics the purine ring of ATP. So they can work as inhibitors of the kinase at hinge region. Due to the structural similarity with ATP, these pyrrolopyridine derivatives are estimated to be non-selective kinase inhibitors. The selectivity is conferred mainly from the different substituents attached to the azaindole nucleus. More details are presented in the 'Expert Opinion' section at the end of this article. This section covers the chemistry and the biological properties of therapeutically-efficient pyrrolopyridine-possessing compounds.

Fragmentation analysis of α-induced reactions using clusterization approach

NASA Astrophysics Data System (ADS)

Kaur, Amandeep; Sharma, Manoj K.

2018-01-01

The dynamics of α-induced reactions are worked out over an incident beam energy Eα ∼ 10- 15 MeV using targets of different masses. The decay patterns of odd mass compound systems 117Sb*, 145Pm* and 191Ir* formed in α +113In, α +141Pr and α +187Re reactions are investigated in view of n-evaporation data. The methodology of collective clusterization is applied by optimizing the neck-length parameter ΔR and the DCM calculated cross-sections find nice agreement with the experimental data. The resulting compound systems with ACN = 117- 191 cover a wide range of compound nucleus mass, and hence give an opportunity to explore various aspects related to the dynamics involved. Moreover the neutron-proton asymmetry dependence is explored in terms of the Bulk constant (α) (in the liquid drop binding energy expression) and radius term Ri and its consequent influence on the fragmentation structure of these compound systems is investigated.

AgRP and MC3/4 receptor agonists both inhibit excitatory hypothalamic ventromedial nucleus neurons

PubMed Central

Fu, Li-Ying; van den Pol, Anthony N.

2009-01-01

Anorexigenic melanocortins decrease food intake by activating MC3/MC4 receptors (MC3/4R); the prevailing view is that the orexigenic neuropeptide AgRP exerts the opposite action by acting as an antagonist at MC3/MC4 receptors. 370 VMH glutamatergic neurons were studied using whole-cell recording in hypothalamic slices from a novel mouse expressing GFP under control of the vGluT2 promoter. Massive numbers of GFP-expressing VMH dendrites extended out of the core of the nucleus into the surrounding cell-poor shell. VMH dendrites received frequent appositions from AgRP immunoreactive axons in the shell of the nucleus, but not the core, suggesting that AgRP may influence target VMH neurons. Alpha-MSH, MTII, and selective MC3R or MC4R agonists were all inhibitory, reducing the spontaneous firing rate and hyperpolarizing vGluT2 neurons. The MC3/4R antagonist SHU9119 was excitatory. Unexpectedly, AgRP did not attenuate MTII actions on these neurons; instead these two compounds showed an additive inhibitory effect. In the absence of synaptic activity, no hyperpolarization or change in input resistance was evoked by either MTII or AgRP, suggesting indirect actions. Consistent with this view, MTII increased the frequency of spontaneous and miniature IPSCs. In contrast, the mechanism of AgRP inhibition was dependent on presynaptic inhibition of EPSCs mediated by Gi/Go proteins, and was attenuated by pertussis toxin and NF023, inconsistent with mediation by Gs proteins associated with MC receptors. Together, our data suggest that the mechanism of AgRP actions on these excitatory VMH cells appears to be independent of the actions of melanocortins on MC receptors. PMID:18495877

[Effects of stimulation of dorso-medial area of nucleus facialis on respiration related units in ventro-lateral region of nucleus tractus solitaris in rabbits].

PubMed

Gao, J X; Liu, L

1990-10-01

In urethane-anesthetized, vagotomized and paralyzed rabbits, effects of electrical stimulation of the dorso-medial area of the nucleus facialis (DMNF) on the respiration-related units (RRUs) in ventro-lateral region of nucleus tractus solitaris (VLNTS) were observed. The experimental results showed that during electrical stimulation of DMNF the majority of the inspiratory (I) neurons (64.4%) were increased in frequency and duration of discharge, some to a marked extent. During electrical stimulation of DMNF the expiratory neurons (35%) were decreased in their frequency and duration of discharge, some to a marked extent too. The responses of RRUs in ipsilateral and contralateral VLNTS to stimulation of DMNF was not statistically significant (P greater than 0.05). It is suggested that DMNF may have a facilitating effect on the inspiratory neurons and an inhibiting effect on the expiratory neurons in VLNTS.

Electrical Coupling: Novel Mechanism for Sleep-Wake Control

PubMed Central

Garcia-Rill, Edgar; Heister, David S.; Ye, Meijun; Charlesworth, Amanda; Hayar, Abdallah

2007-01-01

Study Objectives: Recent evidence suggests that certain anesthetic agents decrease electrical coupling, whereas the stimulant modafinil appears to increase electrical coupling. We investigated the potential role of electrical coupling in 2 reticular activating system sites, the subcoeruleus nucleus and in the pedunculopontine nucleus, which has been implicated in the modulation of arousal via ascending cholinergic activation of intralaminar thalamus and descending activation of the subcoeruleus nucleus to generate some of the signs of rapid eye movement sleep. Design: We used 6- to 30-day-old rat pups to obtain brainstem slices to perform whole-cell patch-clamp recordings. Measurements and Results: Recordings from single cells revealed the presence of spikelets, manifestations of action potentials in coupled cells, and of dye coupling of neurons in the pedunculopontine nucleus. Recordings in pairs of pedunculopontine nucleus and subcoeruleus nucleus neurons revealed that some of these were electrically coupled with coupling coefficients of approximately 2%. After blockade of fast synaptic transmission, the cholinergic agonist carbachol was found to induce rhythmic activity in pedunculopontine nucleus and subcoeruleus nucleus neurons, an effect eliminated by the gap junction blockers carbenoxolone or mefloquine. The stimulant modafinil was found to decrease resistance in neurons in the pedunculopontine nucleus and subcoeruleus nucleus after fast synaptic blockade, indicating that the effect may be due to increased coupling. Conclusions: The finding of electrical coupling in specific reticular activating system cell groups supports the concept that this underlying process behind specific neurotransmitter interactions modulates ensemble activity across cell populations to promote changes in sleep-wake state. Citation: Garcia-Rill E; Heister DS; Ye M; Charlesworth A; Hayar A. Electrical coupling: novel mechanism for sleep-wake control. SLEEP 2007;30(11):1405-1414. PMID:18041475

A thalamic input to the nucleus accumbens mediates opiate dependence.

PubMed

Zhu, Yingjie; Wienecke, Carl F R; Nachtrab, Gregory; Chen, Xiaoke

2016-02-11

Chronic opiate use induces opiate dependence, which is characterized by extremely unpleasant physical and emotional feelings after drug use is terminated. Both the rewarding effects of a drug and the desire to avoid withdrawal symptoms motivate continued drug use, and the nucleus accumbens is important for orchestrating both processes. While multiple inputs to the nucleus accumbens regulate reward, little is known about the nucleus accumbens circuitry underlying withdrawal. Here we identify the paraventricular nucleus of the thalamus as a prominent input to the nucleus accumbens mediating the expression of opiate-withdrawal-induced physical signs and aversive memory. Activity in the paraventricular nucleus of the thalamus to nucleus accumbens pathway is necessary and sufficient to mediate behavioural aversion. Selectively silencing this pathway abolishes aversive symptoms in two different mouse models of opiate withdrawal. Chronic morphine exposure selectively potentiates excitatory transmission between the paraventricular nucleus of the thalamus and D2-receptor-expressing medium spiny neurons via synaptic insertion of GluA2-lacking AMPA receptors. Notably, in vivo optogenetic depotentiation restores normal transmission at these synapses and robustly suppresses morphine withdrawal symptoms. This links morphine-evoked pathway- and cell-type-specific plasticity in the paraventricular nucleus of the thalamus to nucleus accumbens circuit to opiate dependence, and suggests that reprogramming this circuit holds promise for treating opiate addiction.

The central nucleus of the amygdala modulates gut-related neurons in the dorsal vagal complex in rats

PubMed Central

Zhang, Xueguo; Cui, Jinjuan; Tan, Zhenjun; Jiang, Chunhui; Fogel, Ronald

2003-01-01

Using retrograde tract-tracing and electrophysiological methods, we characterized the anatomical and functional relationship between the central nucleus of the amygdala and the dorsal vagal complex. Retrograde tract-tracing techniques revealed that the central nucleus of the amygdala projects to the dorsal vagal complex with a topographic distribution. Following injection of retrograde tracer into the vagal complex, retrogradely labelled neurons in the central nucleus of the amygdala were clustered in the central portion at the rostral level and in the medial part at the middle level of the nucleus. Few labelled neurons were seen at the caudal level. Electrical stimulation of the central nucleus of the amygdala altered the basal firing rates of 65 % of gut-related neurons in the nucleus of the solitary tract and in the dorsal motor nucleus of the vagus. Eighty-one percent of the neurons in the nucleus of the solitary tract and 47 % of the neurons in the dorsal motor nucleus were inhibited. Electrical stimulation of the central nucleus of the amygdala also modulated the response of neurons in the dorsal vagal complex to gastrointestinal stimuli. The predominant effect on the neurons of the nucleus of the solitary tract was inhibition. These results suggest that the central nucleus of the amygdala influences gut-related neurons in the dorsal vagal complex and provides a neuronal circuitry that explains the regulation of gastrointestinal activity by the amygdala. PMID:14555729

Regional Differential Effects of the Novel Histamine H3 Receptor Antagonist 6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) on Histamine Release in the Central Nervous System of Freely Moving Rats

PubMed Central

Giannoni, Patrizia; Medhurst, Andrew D.; Passani, Maria Beatrice; Giovannini, Maria Grazia; Ballini, Chiara; Corte, Laura Della

2010-01-01

After oral administration, the nonimidazole histamine H3 receptor antagonist, 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254), increased histamine release from the tuberomammillary nucleus, where all histaminergic somata are localized, and from where their axons project to the entire brain. To further understand functional histaminergic circuitry in the brain, dual-probe microdialysis was used to pharmacologically block H3 receptors in the tuberomammillary nucleus, and monitor histamine release in projection areas. Perfusion of the tuberomammillary nucleus with GSK189254 increased histamine release from the tuberomammillary nucleus, nucleus basalis magnocellularis, and cortex, but not from the striatum or nucleus accumbens. Cortical acetylcholine (ACh) release was also increased, but striatal dopamine release was not affected. When administered locally, GSK189254 increased histamine release from the nucleus basalis magnocellularis, but not from the striatum. Thus, defined by their sensitivity to GSK189254, histaminergic neurons establish distinct pathways according to their terminal projections, and can differentially modulate neurotransmitter release in a brain region-specific manner. Consistent with its effects on cortical ACh release, systemic administration of GSK189254 antagonized the amnesic effects of scopolamine in the rat object recognition test, a cognition paradigm with important cortical components. PMID:19815811

Mechanical stability of the cell nucleus: roles played by the cytoskeleton in nuclear deformation and strain recovery.

PubMed

Wang, Xian; Liu, Haijiao; Zhu, Min; Cao, Changhong; Xu, Zhensong; Tsatskis, Yonit; Lau, Kimberly; Kuok, Chikin; Filleter, Tobin; McNeill, Helen; Simmons, Craig A; Hopyan, Sevan; Sun, Yu

2018-05-18

Extracellular forces transmitted through the cytoskeleton can deform the cell nucleus. Large nuclear deformation increases the risk of disrupting the nuclear envelope's integrity and causing DNA damage. Mechanical stability of the nucleus defines its capability of maintaining nuclear shape by minimizing nuclear deformation and recovering strain when deformed. Understanding the deformation and recovery behavior of the nucleus requires characterization of nuclear viscoelastic properties. Here, we quantified the decoupled viscoelastic parameters of the cell membrane, cytoskeleton, and the nucleus. The results indicate that the cytoskeleton enhances nuclear mechanical stability by lowering the effective deformability of the nucleus while maintaining nuclear sensitivity to mechanical stimuli. Additionally, the cytoskeleton decreases the strain energy release rate of the nucleus and might thus prevent shape change-induced structural damage to chromatin. © 2018. Published by The Company of Biologists Ltd.

HIV-1 Nef protein in the nucleus influences adipogenesis as well as viral transcription through the peroxisome proliferator-activated receptors.

PubMed

Otake, Kaori; Omoto, Shinya; Yamamoto, Takuya; Okuyama, Harumi; Okada, Hidechika; Okada, Noriko; Kawai, Masahiro; Saksena, Nitin K; Fujii, Yoichi R

2004-01-23

Although the HIV-1 Nef protein (27 kDa) localizes primarily in cytoplasm, there is considerable evidence suggesting its occasional localization in the nucleus. Nef is known to play an important role in transcriptional events and viral replication, but the actual target of Nef in the nucleus remains to be identified. To examine the functional roles of Nef in the nucleus and its possible interactions with other unknown factors in the nucleus. High-density microarray analysis was used to screen directly the unique functions of Nef on host gene transcription. The nuclear localization of Nef and its effects on the expression of peroxisome proliferator-activated receptors (PPAR) was examined using PPAR promoter/reporter assay and immunoblotting. A long terminal repeat/reporter assay was used to investigated the effects of Nef and PPAR on viral transcription. Nef in the nucleus suppressed PPAR gamma expression and reduced fatty acid levels in human T and macrophage cell lines. Expression of Nef or PPAR suppressed viral replication; the effect of PPAR gamma or retinoid X receptor-alpha on viral replication were reduced by coexpression of Nef in MT(-)4 T cells. Nef may be involved in both viral replication and the wasting syndrome associated with AIDS.

Observation of direct hadronic pairs in nucleus-nucleus collisions in JACEE emulsion chambers

NASA Technical Reports Server (NTRS)

Burnett, T. H.; Dake, S.; Fuki, M.; Gregory, J. C.; Hayashi, T.; Hayashi, T.; Holynski, R.; Iwai, J.; Jones, W. V.; Jurak, A.

1985-01-01

In a number of high energy ( or = 1 TeV/amu) nucleus-nucleus collisions observed in Japanese-American Cooperative Emulsion Experiment (JACEE) emulsion chambers, nonrandom spatial association of produced charged particles, mostly hadronic pairs, are observed. Similar narrow pairs are observed in about 100 events at much low energy (20 to 60 GeV/amu). Analysis shows that 30 to 50% of Pair abundances are understood by the Hambury-Brown-Twiss effect, and the remainder seems to require other explanations.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Munro, S.L.; Andrews, P.R.; Craik, D.J.

The solution dynamics of a series of clinically potent antidepressants have been investigated by measuring /sup 13/C NMR relaxation parameters. Correlation times and internal motional rates were calculated from spin-lattice relaxation times and nuclear Overhauser effects for the protonated carbons in mianserin, imipramine-like antidepressants, and amitriptyline-like antidepressants. These data were interpreted in terms of overall molecular tumbling, internal rotations, and inherent flexibility of these structures. Of particular interest was the conformational variability of the tricyclic nucleus of the tricyclic antidepressants, where the data indicated a fivefold difference in mobility of the dimethylene bridge of imipramine-like antidepressants relative to amitriptyline-like compounds.more » The implications of such a difference in internal motions is discussed in relation to previous NMR studies and to the reported differences in pharmacological activity of these antidepressants.« less

Pharmacological AMP-kinase activators have compartment-specific effects on cell physiology.

PubMed

Kodiha, Mohamed; Ho-Wo-Cheong, Dennis; Stochaj, Ursula

2011-12-01

5'-AMP-activated kinase (AMPK) regulates numerous biological events and is an essential target for the treatment of type 2 diabetes. The objectives of the present study were first to determine the compartment-specific effects of three established AMPK activators on Thr172 phosphorylation of the α-subunit, an indicator of AMPK activation. Second, we examined how cytoplasmic and nuclear processes are modulated by pharmacological AMPK activators. Specifically, the impact of phenformin, resveratrol, and 5-aminoimidazole-4-carboxamide riboside (AICAR) on Thr172 phosphorylation in the cytoplasm and nucleus was quantified by different methods. To analyze how these activators change cell physiology, we measured the inactivation of acetyl-CoA-carboxylase 1, a predominantly cytoplasmic enzyme that is crucial for lipid metabolism. As a criterion for activities associated with the nucleus, de novo RNA synthesis in nucleoli was quantified. Our studies demonstrate that pharmacological activators of AMPK can alter the balance between nuclear and cytoplasmic AMPK pools. Thus, phenformin and resveratrol caused a strong activation of AMPK in the cytoplasm, whereas the effect was less pronounced in nuclei. By contrast, AICAR elicited a comparable rise in Thr172 phosphorylation in both compartments. Notably, these activators differed drastically in their effects on physiological processes that are located in distinct subcellular compartments. All compounds led to a substantial inactivation of acetyl-CoA-carboxylase 1 in the cytoplasm, with only minor changes to the nuclear enzyme. In the nucleolus, transcription was strongly inhibited by resveratrol, while a moderate inhibition was observed with phenformin and AICAR. Taken together, the compartment-specific phosphorylation of AMPK and downstream events are determined by the activator.

Short-term effects of cardiac steroids on intracellular membrane traffic in neuronal NT2 cells.

PubMed

Rosen, H; Glukmann, V; Feldmann, T; Fridman, E; Lichtstein, D

2006-12-30

Cardiac steroids (CS) are specific inhibitors of Na+, K+-ATPase activity. Although the presence of CS-like compounds in animal tissues has been established, their physiological role is not clear. In a previous study we showed that in pulse-chase membrane-labeling experiments, long term (hours) interaction of CS at physiological concentrations (nM) with Na+, K+-ATPase, caused changes in endocytosed membrane traffic in human NT2 cells. This was associated with the accumulation of large vesicles adjacent to the nucleus. For this sequence of events to function in the physiological setting, however, CS would be expected to modify membrane traffic upon short term (min) exposure and membrane labeling. We now demonstrate that CS affects membrane traffic also following a short exposure. This was reflected by the CS-induced accumulation of FM1-43 and transferrin in the cells, as well as by changes in their colocalization with Na+, K+-ATPase. We also show that the CS-induced changes in membrane traffic following up to 2 hrs exposure are reversible, whereas longer treatment induces irreversible effects. Based on these observations, we propose that endogenous CS-like compounds are physiological regulators of the recycling of endocytosed membrane proteins and cargo in neuronal cells, and may affect basic mechanisms such as neurotransmitter release and reuptake.

Mass spectra of heavy ions near comet Halley

NASA Astrophysics Data System (ADS)

Korth, A.; Richter, A. K.; Loidl, A.; Anderson, K. A.; Carlson, C. W.; Curtis, D. W.; Lin, R. P.; Reme, H.; Sauvaud, J. A.; D'Uston, C.; Cotin, F.; Cros, A.; Mendis, D. A.

1986-05-01

The heavy-ion analyser aboard the Giotto spacecraft, detected the first cometary ions at a distance of ≡1.05x106km from the nucleus of comet Halley. In the inner coma the major ions identified are associated with the H2O, CO and CO2 groups. Ions of larger atomic mass unit are also present, corresponding possibly to various hydrocarbons, heavy metals of the iron-group or to sulphur compounds.

Mass spectra of heavy ions near comet Halley

NASA Technical Reports Server (NTRS)

Korth, A.; Richter, A. K.; Loidl, A.; Anderson, K. A.; Carlson, C. W.

1986-01-01

The heavy-ion analyzer, RPA2-PICCA, aboard the Giotto spacecraft, detected the first cometary ions at a distance of about 1.05 million km from the nucleus of comet Halley. In the inner coma the major ions identified are associated with the H2O, CO and CO2 groups. Ions of larger atomic mass unit are also present, corresponding possibly to various hydrocarbons, heavy metals of the iron-group or to sulphur compounds.

Level Densities of Residual Nuclei from particle evaporation of 64Cu

NASA Astrophysics Data System (ADS)

Oginni, B. M.; Grimes, S. M.; Voinov, A. V.; Adekola, A. S.; Brune, C. R.; Carter, D.; Heinen, Z.; Jacobs, D.; Massey, T. N.; O'Donnell, J.

2009-07-01

The reactions of 6Li on 58Fe and 7Li on 57Fe have been studied at beam energy 15 MeV. These two reactions produce the same compound nucleus, 64Cu. The neutron, proton, and alpha spectra were measured at backward angles. The data obtained have been compared with Hauser Fesh-bach model calculations. The level density parameters of the residual nuclei have been obtained from the particle evaporation spectra.

/sup 18/O + /sup 12/C fusion-evaporation reaction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Heusch, B; Beck, C; Coffin, J P

1980-01-01

A study of the /sup 18/O + /sup 12/C fusion evaporation reaction has been undertaken for 2 reasons: to make a systematic study of the formation cross section for each individual evaporation residue over a broad excitation energy region in the compound nucleus /sup 30/Si:30 to 62 MeV; and to compare all results to fusion-evaporation calculations done in the framework of the Hauser-Feschbach statistical model.

Palladium-catalyzed Br/D exchange of arenes: Selective deuterium incorporation with versatile functional group tolerance and high efficiency

DOE PAGES

Zhang, Honghai -Hai; Bonnesen, Peter V.; Hong, Kunlun

2015-07-13

There is a facile method for introducing one or more deuterium atoms onto an aromatic nucleus via Br/D exchange with high functional group tolerance and high incorporation efficiency is disclosed. Deuterium-labeled aryl chlorides and aryl borates which could be used as substrates in cross-coupling reactions to construct more complicated deuterium-labeled compounds can also be synthesized by this method.

Comparative study of the neuroprotective and nootropic activities of the carboxylate and amide forms of the HLDF-6 peptide in animal models of Alzheimer's disease.

PubMed

Bogachouk, Anna P; Storozheva, Zinaida I; Solovjeva, Olga A; Sherstnev, Vyacheslav V; Zolotarev, Yury A; Azev, Vyacheslav N; Rodionov, Igor L; Surina, Elena A; Lipkin, Valery M

2016-01-01

A comparative study of the neuroprotective and nootropic activities of two pharmaceutical substances, the HLDF-6 peptide (HLDF-6-OH) and its amide form (HLDF-6-NH2), was conducted. The study was performed in male rats using two models of a neurodegenerative disorder. Cognitive deficit in rats was induced by injection of the beta-amyloid fragment 25-35 (βA 25-35) into the giant-cell nucleus basalis of Meynert or by coinjection of βA 25-35 and ibotenic acid into the hippocampus. To evaluate cognitive functions in animals, three tests were used: the novel object recognition test, the conditioned passive avoidance task and the Morris maze. Comparative analysis of the data demonstrated that the neuroprotective activity of HLDF-6-NH2, evaluated by improvement of cognitive functions in animals, surpassed that of the native HLDF-6-OH peptide. The greater cognitive/ behavioral effects can be attributed to improved kinetic properties of the amide form of the peptide, such as the character of biodegradation and the half-life time. The effects of HLDF-6-NH2 are comparable to, or exceed, those of the reference compounds. Importantly, HLDF-6-NH2 exerts its effects at much lower doses than the reference compounds. © The Author(s) 2015.

Recent Development of Benzimidazole-Containing Antibacterial Agents.

PubMed

Song, Di; Ma, Shutao

2016-04-05

Clinically significant antibiotic resistance is one of the greatest challenges of the twenty-first century. However, new antibacterial agents are currently being developed at a much slower pace than our growing need for such drugs. Given their diverse biological activities and clinical applications, many bioactive heterocyclic compounds containing a benzimidazole nucleus have been the focus of interest for many researchers. The benzimidazole nucleus is a structural isostere of naturally occurring nucleotides. This advantage allows benzimidazoles to readily interact with the various biopolymers found in living systems. In view of this situation, much attention has been given to the exploration of benzimidazole-based antibacterial agents, leading to the discovery of many new chemical entities with intriguing profiles. In this minireview we summarize novel benzimidazole derivatives active against various bacterial strains. In particular, we outline the relationship between the structures of variously modified benzimidazoles and their antibacterial activity. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Histone deacetylase 3 indirectly modulates tubulin acetylation.

PubMed

Bacon, Travis; Seiler, Caroline; Wolny, Marcin; Hughes, Ruth; Watson, Peter; Schwabe, John; Grigg, Ronald; Peckham, Michelle

2015-12-15

Histone deacetylase 3 (HDAC3), a member of the Class I subfamily of HDACs, is found in both the nucleus and the cytoplasm. Its roles in the nucleus have been well characterized, but its cytoplasmic roles are still not elucidated fully. We found that blocking HDAC3 activity using MI192, a compound specific for HDAC3, modulated tubulin acetylation in the human prostate cancer cell line PC3. A brief 1 h treatment of PC3 cells with MI192 significantly increased levels of tubulin acetylation and ablated the dynamic behaviour of microtubules in live cells. siRNA-mediated knockdown (KD) of HDAC3 in PC3 cells, significantly increased levels of tubulin acetylation, and overexpression reduced it. However, the active HDAC3-silencing mediator of retinoic and thyroid receptors (SMRT)-deacetylase-activating domain (DAD) complex did not directly deacetylate tubulin in vitro. These data suggest that HDAC3 indirectly modulates tubulin acetylation. © 2015 Authors.

Excitatory innervation of caudal hypoglossal nucleus from nucleus reticularis gigantocellularis in the rat.

PubMed

Yang, C C; Chan, J Y; Chan, S H

1995-03-01

We examined the possible innervation of the caudal hypoglossal nucleus by the nucleus reticularis gigantocellularis of the medulla oblongata, based on single-neuron recording and retrograde tracing experiments in Sprague-Dawley rats. Under pentobarbital sodium (50 mg/kg, i.p.) anesthesia, electrical stimulation of the caudal portion of the nucleus reticularis gigantocellularis with repetitive 0.5-ms rectangular pulses increased (46 of 51 neurons) the basal discharge frequency of spontaneously active cells, or evoked spike activity in silent, hypoglossal neurons located at the level of the obex. This excitatory effect was related to the intensity (25-100 microA) and/or frequency (0.5-20 Hz) of the stimulating pulses to the nucleus reticularis gigantocellularis. Perikaryal activation of neurons by microinjection of L-glutamate (0.5 nmol, 25 nl) into the caudal portion of the nucleus reticularis gigantocellularis similarly produced an excitatory action on eight of 14 hypoglossal neurons. Retrogradely labeled neurons were found bilaterally within the confines of the nucleus reticularis gigantocellularis following unilateral microinjection of wheatgerm agglutinin-conjugated horseradish peroxidase or Fast Blue into the corresponding hypoglossal recording sites. Furthermore, the distribution of labeled neurons in the nucleus reticularis gigantocellularis substantially overlapped with the loci of electrical or chemical stimulation. These complementary electrophysiological and neuroanatomical results support the conclusion that an excitatory link exists between the nucleus reticularis gigantocellularis and at least the caudal portion of the hypoglossal nucleus in the rat.

Azimuthal correlation and collective behavior in nucleus-nucleus collisions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mali, P.; Mukhopadhyay, A., E-mail: amitabha-62@rediffmail.com; Sarkar, S.

2015-03-15

Various flow effects of nuclear and hadronic origin are investigated in nucleus-nucleus collisions. Nuclear emulsion data collected from {sup 84}Kr + Ag/Br interaction at an incident energy of 1.52 GeV per nucleon and from {sup 28}Si + Ag/Br interaction at an incident energy of 14.5 GeV per nucleon are used in the investigation. The transverse momentum distribution and the flow angle analysis show that collective behavior, like a bounce-off effect of the projectile spectators and a sidesplash effect of the target spectators, are present in our event samples. From an azimuthal angle analysis of the data we also see amore » direct flow of the projectile fragments and of the produced charged particles. On the other hand, for both data samples the target fragments exhibit a reverse flow, while the projectile fragments exhibit an elliptic flow. Relevant flow parameters are measured.« less

Diffusion of beta-lactam antibiotics through the porin channels of Escherichia coli K-12.

PubMed Central

Yoshimura, F; Nikaido, H

1985-01-01

Diffusion rates of various beta-lactam antibiotics through the OmpF and OmpC porin channels of Escherichia coli K-12 were measured by the use of reconstituted proteoliposomes. The results can be interpreted on the basis of the gross physicochemical properties of the antibiotics along the following lines. (i) As noted previously (Nikaido et al., J. Bacteriol., 153:232-240, 1983), there was a monotonous dependence of the penetration rate on the hydrophobicity of the molecule among the classical monoanionic beta-lactams, and a 10-fold increase in the octanol-water partition coefficient of the uncharged molecule decreased the penetration rate by a factor of 5 to 6. (ii) Compounds with exceptionally bulky side chains, such as mezlocillin, piperacillin, and cefoperazone, showed much slower penetration rates than expected from their hydrophobicity. (iii) The substituted oxime side chain on the alpha-carbon of the substituent group at position 7 of the cephem nucleus decreased the penetration rate almost by an order of magnitude; this appears to be largely due to the steric effect. (iv) The presence of a methoxy group at position 7 of the cephalosporins also reduced the penetration rate by 20%, probably also due to the steric hindrance. (v) Zwitterionic compounds penetrated very rapidly, and the correlation between the rate and hydrophobicity appeared to be much weaker than with the monoanionic compounds. Imipenem showed the highest permeability among the compounds tested, presumably due, at least in part, to its compact molecular structure. (vi) Compounds with two negative charges penetrated more slowly than did analogs with only one negatively charged group. Among them, only moxalactam, ceftriaxone, and azthreonam showed penetration rates corresponding to, or higher than, 10% of that of imipenem. PMID:2580479

Organotin Dyes Bearing Anionic Boron Clusters as Cell-Staining Fluorescent Probes.

PubMed

Muñoz-Flores, Blanca M; Cabrera-González, Justo; Viñas, Clara; Chávez-Reyes, Arturo; Dias, H V Rasika; Jiménez-Pérez, Víctor M; Núñez, Rosario

2018-04-11

Within the cell nucleus, in the nucleoli, ribosomal RNAs are synthesized and participate in several biological processes. To better understand nucleoli-related processes, their visualization is often required, for which specific markers are needed. Herein, we report the design of novel fluorescent organotin compounds derived from 4-hydroxy-N'-((2-hydroxynaphthalen-1-yl)methylene)benzohydrazide and their cytoplasm and nucleoli staining of B16F10 cells in vitro. Tin compounds bearing an aliphatic carbon chain (-C 12 H 25 ) and an electron-donating group (-OH) were prepared, and the latter could be derivatized to bear the boron cluster anions [B 12 H 12 ] 2- and [3,3'-Co(1,2-C 2 B 9 H 11 ) 2 ] - (COSAN). All of the conjugates have been fully characterized and their luminescence properties have been assessed. In general, they show good quantum yields in solution (24-49 %), those for the COSAN derivatives being lower. Remarkably, the linking of [B 12 H 12 ] 2- and COSAN to the complexes made them more soluble, without being detrimental to their luminescence properties. Living B16F10 cells were treated with all of the compounds to determine their fluorescence staining properties; the compounds bearing the aliphatic chain showed a reduced staining capacity due to the formation of aggregates. Notably, the complexes bearing different boron clusters showed different staining effects; those bearing [B 12 H 12 ] 2- showed extraordinary staining of the nucleoli and cytoplasm, whereas those bearing COSAN were only detected in the cytoplasm. The remarkable fluorescence staining properties shown by these organotin compounds make them excellent candidates for fluorescence bioimaging in vitro. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Evaporation residue cross-section measurements for 48Ti-induced reactions

NASA Astrophysics Data System (ADS)

Sharma, Priya; Behera, B. R.; Mahajan, Ruchi; Thakur, Meenu; Kaur, Gurpreet; Kapoor, Kushal; Rani, Kavita; Madhavan, N.; Nath, S.; Gehlot, J.; Dubey, R.; Mazumdar, I.; Patel, S. M.; Dhibar, M.; Hosamani, M. M.; Khushboo, Kumar, Neeraj; Shamlath, A.; Mohanto, G.; Pal, Santanu

2017-09-01

Background: A significant research effort is currently aimed at understanding the synthesis of heavy elements. For this purpose, heavy ion induced fusion reactions are used and various experimental observations have indicated the influence of shell and deformation effects in the compound nucleus (CN) formation. There is a need to understand these two effects. Purpose: To investigate the effect of proton shell closure and deformation through the comparison of evaporation residue (ER) cross sections for the systems involving heavy compound nuclei around the ZCN=82 region. Methods: A systematic study of ER cross-section measurements was carried out for the 48Ti+Nd,150142 , 144Sm systems in the energy range of 140 -205 MeV . The measurement has been performed using the gas-filled mode of the hybrid recoil mass analyzer present at the Inter University Accelerator Centre (IUAC), New Delhi. Theoretical calculations based on a statistical model were carried out incorporating an adjustable barrier scaling factor to fit the experimental ER cross section. Coupled-channel calculations were also performed using the ccfull code to obtain the spin distribution of the CN, which was used as an input in the calculations. Results: Experimental ER cross sections for 48Ti+Nd,150142 were found to be considerably smaller than the statistical model predictions whereas experimental and statistical model predictions for 48Ti+144Sm were of comparable magnitudes. Conclusion: Though comparison of experimental ER cross sections with statistical model predictions indicate considerable non-compound-nuclear processes for 48Ti+Nd,150142 reactions, no such evidence is found for the 48Ti+144Sm system. Further investigations are required to understand the difference in fusion probabilities of 48Ti+142Nd and 48Ti+144Sm systems.

α-Dihydroxychalcone-glycoside (α-DHC) isolated from the heartwood of Pterocarpus marsupium inhibits LPS induced MAPK activation and up regulates HO-1 expression in murine RAW 264.7 macrophage.

PubMed

Chakraborty, Prarthana; Saraswat, Ghungroo; Kabir, Syed N

2014-05-15

Three phenolic glycosides isolated from the heartwood of Pterocarpus marsupium showed significant free radical and superoxide ion scavenging activity and antioxidant potential that were comparable to, or several folds higher than those of standard antioxidants, trolox and ascorbic acid. The effective concentrations of these compounds were far below their cytotoxic levels. Compound 3, which was characterized to be α-dihydroxychalcone-glycoside (α-DHC), was the most potent one. Subsequent studies demonstrated that α-DHC effectively reduced nitric oxide and cytokine production by the LPS stimulated RAW 264.7 mouse macrophage cell line. The compound effectively attenuated the expression of inflammation-mediating enzymes COX-2 and iNOS at the mRNA as well as protein levels in a concentration dependent manner. It prevented phosphorylation of all the three MAPKs (JNK, ERK, p38) and eventually blocked the activation of downstream elements contributing to inflammation. Phosphorylation of IκB-α and subsequent translocation of NF-κB into the nucleus were restricted, while the expression of stress responsive gene HO-1 was up-regulated. α-DHC targeted Keap-1 by modifying its cysteine thiols, dissociating it from Nrf-2 and facilitating nuclear entry of the latter; and this in turn induced HO-1 expression. Thus α-DHC exerts its anti-inflammatory activity in a dual manner: by down regulating MAPKs and restricting nuclear stabilization of NF-κB at one end, and by disrupting Nrf-2-Keap-1 complex on the other. In conclusion, the anti-inflammatory potential together with its high therapeutic index envisages α-DHC as a prospective candidate molecule for the development of therapeutic strategy against inflammatory disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

Intracellular Physiology of the Rat Suprachiasmatic Nucleus: Electrical Properties, Neurotransmission, and Effects of Neuromodulators

DTIC Science & Technology

1992-01-10

Physiology of the Rat Suprachiasmatic Nucleus: Electrical Properties, Neurotransmission, and Effects of Neuromodulators . I-f 12. PERSONAL AUTHOR(S) F...interplay between intrinsic electrophysiological properties, amino-acid-mediated synaptic transmission, and neuromodulation . We have continued to study the

Regulation of estrogen receptor beta mRNA in the brain: opposite effects of 17beta-estradiol and the phytoestrogen, coumestrol.

PubMed

Patisaul, H B; Whitten, P L; Young, L J

1999-04-06

Estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) are differentially distributed in the brain and likely mediate different estrogen-dependent processes. ERbeta is abundant in the bed nucleus of the stria terminalis, medial preoptic nucleus, paraventricular nucleus of the hypothalamus and the amygdala of the rat. In the paraventricular nucleus, which is devoid of ERalpha, ERbeta is colocalized with the neuropeptides, oxytocin and vasopressin, suggesting a potential functional role for ERbeta in the regulation of these peptides. We examined the regulation of ERbeta mRNA expression in the rat brain by 17beta-estradiol and the phytoestrogen, coumestrol. 17beta-Estradiol treatment decreased ERbeta mRNA in situ hybridization signal by 44.5% in the paraventricular nucleus of the hypothalamus (PVN), but had no effect in the bed nucleus of the stria terminalis (BnST) or the medial preoptic nucleus (MPA). In contrast, dietary exposure to coumestrol increased ERbeta mRNA signal by 47.5% in the PVN but had no effect in the BnST or the MPA. These data demonstrate that like ERalpha, ERbeta is down regulated by estrogen in a region specific manner in the rat brain. Furthermore, exposure to coumestrol may modulate ERbeta-dependent processes by acting as an anti-estrogen at ERbeta. This data contradicts results from cell transfection assays which suggest an estrogenic activity of coumestrol on ERbeta, indicating that the mode of action may be tissue specific, or that metabolism of dietary coumestrol may alter its effects. Because the highest concentrations of phytoestrogens are found in legumes, vegetables and grains, they are most prevalent in vegetarian and traditional Asian diets. Understanding the neuroendocrine effects of phytoestrogens is particularly important now that they are being marketed as a natural alternative to estrogen replacement therapy and sold in highly concentrated pills and powders. Copyright 1999 Elsevier Science B.V.

Nigral stimulation for resistant axial motor impairment in Parkinson's disease? A randomized controlled trial.

PubMed

Weiss, Daniel; Walach, Margarete; Meisner, Christoph; Fritz, Melanie; Scholten, Marlieke; Breit, Sorin; Plewnia, Christian; Bender, Benjamin; Gharabaghi, Alireza; Wächter, Tobias; Krüger, Rejko

2013-07-01

Gait and balance disturbances typically emerge in advanced Parkinson's disease with generally limited response to dopaminergic medication and subthalamic nucleus deep brain stimulation. Therefore, advanced programming with interleaved pulses was put forward to introduce concomittant nigral stimulation on caudal contacts of a subthalamic lead. Here, we hypothesized that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata improves axial symptoms compared with standard subthalamic nucleus stimulation. Twelve patients were enrolled in this 2 × 2 cross-over double-blind randomized controlled clinical trial and both the safety and efficacy of combined subthalamic nucleus and substantia nigra pars reticulata stimulation were evaluated compared with standard subthalamic nucleus stimulation. The primary outcome measure was the change of a broad-scaled cumulative axial Unified Parkinson's Disease Rating Scale score (Scale II items 13-15, Scale III items 27-31) at '3-week follow-up'. Secondary outcome measures specifically addressed freezing of gait, balance, quality of life, non-motor symptoms and neuropsychiatric symptoms. For the primary outcome measure no statistically significant improvement was observed for combined subthalamic nucleus and substantia nigra pars reticulata stimulation at the '3-week follow-up'. The secondary endpoints, however, revealed that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata might specifically improve freezing of gait, whereas balance impairment remained unchanged. The combined stimulation of subthalamic nucleus and substantia nigra pars reticulata was safe, and of note, no clinically relevant neuropsychiatric adverse effect was observed. Patients treated with subthalamic nucleus and substantia nigra pars reticulata stimulation revealed no 'global' effect on axial motor domains. However, this study opens the perspective that concomittant stimulation of the substantia nigra pars reticulata possibly improves otherwise resistant freezing of gait and, therefore, highly warrants a subsequent phase III randomized controlled trial.

GABAA receptor positive allosteric modulators modify the abuse-related behavioral and neurochemical effects of methamphetamine in rhesus monkeys.

PubMed

Berro, Laís F; Andersen, Monica L; Tufik, Sergio; Howell, Leonard L

2017-09-01

GABA A receptor positive allosteric modulators (GABA A receptor modulators) are commonly used for the treatment of insomnia. Nevertheless, the effects of these compounds on psychostimulant-induced sleep impairment are poorly understood. Because GABA A receptor modulators have been shown to decrease the abuse-related effects of psychostimulants, the aim of the present study was to evaluate the effects of temazepam (0.3, 1.0 or 3.0 mg/kg) and eszopiclone (0.3, 1.0 or 3.0 mg/kg), two GABA A receptor modulators, on the behavioral neuropharmacology of methamphetamine in adult rhesus macaques (n = 5). Sleep-like measures and general daytime activity were evaluated with Actiwatch monitors. Methamphetamine self-administration (0.03 mg/kg/inf) was evaluated during morning sessions. Methamphetamine-induced dopamine overflow was assessed through in vivo microdialysis targeting the nucleus accumbens. Nighttime treatment with either temazepam or eszopiclone was ineffective in improving sleep-like measures disrupted by methamphetamine self-administration. Acute pretreatment with a low dose of temazepam before self-administration sessions increased methamphetamine self-administration without affecting normal daytime home-cage activity. At a high dose, acute temazepam pretreatment decreased methamphetamine self-administration and attenuated methamphetamine-induced increases in dopamine in the nucleus accumbens, without decreasing general daytime activity. Acute eszopiclone treatment exerted no effects on methamphetamine intake or drug-induced increases in dopamine. Our study suggests that treatments based on GABA A receptor modulators are not effective for the treatment of sleep disruption in the context of psychostimulant use. In addition, distinct GABA A receptor modulators differentially modulated the abuse-related effects of methamphetamine, with acute treatment with the high efficacy GABA A receptor modulator temazepam decreasing the behavioral and neurochemical effects of methamphetamine. Copyright © 2017 Elsevier Ltd. All rights reserved.

Virtual photon polarization and dilepton anisotropy in relativistic nucleus-nucleus collisions

NASA Astrophysics Data System (ADS)

Speranza, Enrico; Jaiswal, Amaresh; Friman, Bengt

2018-07-01

The polarization of virtual photons produced in relativistic nucleus-nucleus collisions provides information on the conditions in the emitting medium. In a hydrodynamic framework, the resulting angular anisotropy of the dilepton final state depends on the flow as well as on the transverse momentum and invariant mass of the photon. We illustrate these effects in dilepton production from quark-antiquark annihilation in the QGP phase and π+π- annihilation in the hadronic phase for a static medium in global equilibrium and for a longitudinally expanding system.

Comparison of torsional and longitudinal modes using phacoemulsification parameters.

PubMed

Rekas, Marek; Montés-Micó, Robert; Krix-Jachym, Karolina; Kluś, Adam; Stankiewicz, Andrzej; Ferrer-Blasco, Teresa

2009-10-01

To compare phacoemulsification parameters of torsional and longitudinal ultrasound modes. Ophthalmology Department, Military Health Service Institute, Warsaw, Poland. This prospective study evaluated eyes 1, 7, and 30 days after phacoemulsification with an Infiniti Vision System using the torsional or longitudinal ultrasound (US) mode. Cataract classification was according to the Lens Opacities Classification System II. Nucleus fragmentation was by the phaco-chop and quick-chop methods. Primary outcome measures were phaco time, mean phaco power, mean torsional amplitude, and aspiration time. Total energy, defined as cumulative dissipated energy (CDE) x aspiration time, and the effective coefficient, defined as aspiration time/phaco time, were also calculated. Four hundred eyes were evaluated. The CDE was statistically significantly lower in the torsional mode for nucleus grades I, II, and III (P<.001) but not for grade IV (P>.05). Aspiration time was statistically significantly shorter in the torsional mode than in the longitudinal mode for nucleus grades III and IV (P<.05). Total energy was significantly lower in the torsional mode for all nucleus densities (P<.05). The effective coefficient was significantly lower in the longitudinal mode except for nucleus grade I (P<.05). Torsional phacoemulsification was more effective than longitudinal phacoemulsification in the amount of applied fluid and the quantity of US energy expended. With the torsional method, it was possible to maintain a constant ratio of amount of fluid flow to quantity of US energy used, regardless of nucleus density.

The nucleus parvocellularis reticularis regulates submandibular-sublingual salivary secretion in the rat: a pharmacological study.

PubMed

Ramos, J M; Puerto, A

1988-09-01

This experiment shows that activation of the nucleus parvocellularis reticularis in the rat brainstem provokes salivary hypersecretion by the submandibular-sublingual glands. The secretory effect is mediated by cholinergic mechanisms, as the administration of atropine blocked the flow of saliva evoked by stimulation of the nucleus parvocellularis. In contrast, injection of dihydroergotamine (an alpha-blocker) and/or propranolol (a beta-blocker) failed to significantly reduce submandibular and sublingual salivary secretion when compared to a control group injected with distilled water. The cholinergic nature of the salivary response suggests that the nucleus parvocellularis reticularis exerts its secretory effect on the salivary glands parasympathetically rather than through mechanisms associated with sympathetic pathways. The area of the brainstem activated in the present study closely overlaps the region in which cell bodies of superior salivatory neurons have recently been identified with retrograde transport of peroxidase. The data presented herein represent functional proof in support of the location of the superior salivatory nucleus within the parvocellularis reticular formation.

Synthesis of omeprazole analogues and evaluation of these as potential inhibitors of the multidrug efflux pump NorA of Staphylococcus aureus.

PubMed

Vidaillac, Céline; Guillon, Jean; Arpin, Corinne; Forfar-Bares, Isabelle; Ba, Boubakar B; Grellet, Jean; Moreau, Stéphane; Caignard, Daniel-Henri; Jarry, Christian; Quentin, Claudine

2007-03-01

A series of 11 pyrrolo[1,2-a]quinoxaline derivatives, 1a to 1k, sharing structural analogies with omeprazole, a eukaryotic efflux pump inhibitor (EPI) used as an antiulcer agent, was synthesized. Their inhibitory effect was evaluated using Staphylococcus aureus strain SA-1199B overexpressing NorA. By determinations of the MIC of norfloxacin in the presence of these EPIs devoid of intrinsic antibacterial activity and used at 128 microg/ml, and by the checkerboard method, compound 1e (MIC decrease, 16-fold; fractional inhibitory concentration index [SigmaFIC], 0.18) appeared to be more active than compounds 1b to 1d, reserpine, and omeprazole (MIC decrease, eightfold; SigmaFIC, 0.31), followed by compounds 1a and 1f (MIC decrease, fourfold; SigmaFIC, 0.37) and 1g to 1k (MIC decrease, twofold; SigmaFIC, 0.50 to 0.56). By time-kill curves combining norfloxacin (1/4 MIC) and the most efficient EPIs (128 microg/ml), compound 1e persistently restored the bactericidal activity of norfloxacin (inoculum reduction, 3 log(10) CFU/ml at 8 and 24 h), compound 1f led to a delayed but progressive decrease in the number of viable cells, and compounds 1b to 1d and omeprazole acted synergistically (inoculum reduction, 3 log(10) CFU/ml at 8 h but further regrowth), while compound 1a and reserpine slightly enhanced norfloxacin activity. The bacterial uptake of norfloxacin monitored by high-performance liquid chromatography confirmed that compounds 1a to 1f increased antibiotic accumulation, as did reserpine and omeprazole. Since these EPIs did not disturb the Deltapsi and DeltapH, they might directly interact with the pump. A structure-activity relationships study identified the benzimidazole nucleus of omeprazole as the main structural element involved in efflux pump inhibition and highlighted the critical role of the chlorine substituents in the stability and efficiency of compounds 1e to 1f. However, further pharmacomodulation is required to obtain therapeutically applicable derivatives.

Synthesis, DNA Binding, and Antiproliferative Activity of Novel Acridine-Thiosemicarbazone Derivatives

PubMed Central

de Almeida, Sinara Mônica Vitalino; Lafayette, Elizabeth Almeida; Gomes da Silva, Lúcia Patrícia Bezerra; Amorim, Cézar Augusto da Cruz; de Oliveira, Tiago Bento; Gois Ruiz, Ana Lucia Tasca; de Carvalho, João Ernesto; de Moura, Ricardo Olímpio; Beltrão, Eduardo Isidoro Carneiro; de Lima, Maria do Carmo Alves; de Carvalho Júnior, Luiz Bezerra

2015-01-01

In this work, the acridine nucleus was used as a lead-compound for structural modification by adding different substituted thiosemicarbazide moieties. Eight new (Z)-2-(acridin-9-ylmethylene)-N-phenylhydrazinecarbothioamide derivatives (3a–h) were synthesized, their antiproliferative activities were evaluated, and DNA binding properties were performed with calf thymus DNA (ctDNA) by electronic absorption and fluorescence spectroscopies. Both hyperchromic and hypochromic effects, as well as red or blue shifts were demonstrated by addition of ctDNA to the derivatives. The calculated binding constants ranged from 1.74 × 104 to 1.0 × 106 M−1 and quenching constants from −0.2 × 104 to 2.18 × 104 M−1 indicating high affinity to ctDNA base pairs. The most efficient compound in binding to ctDNA in vitro was (Z)-2-(acridin-9-ylmethylene)-N-(4-chlorophenyl) hydrazinecarbothioamide (3f), while the most active compound in antiproliferative assay was (Z)-2-(acridin-9-ylmethylene)-N-phenylhydrazinecarbothioamide (3a). There was no correlation between DNA-binding and in vitro antiproliferative activity, but the results suggest that DNA binding can be involved in the biological activity mechanism. This study may guide the choice of the size and shape of the intercalating part of the ligand and the strategic selection of substituents that increase DNA-binding or antiproliferative properties. PMID:26068233

Demonstration of mechanical connections between integrins, cytoskeletal filaments, and nucleoplasm that stabilize nuclear structure

NASA Technical Reports Server (NTRS)

Maniotis, A. J.; Chen, C. S.; Ingber, D. E.

1997-01-01

We report here that living cells and nuclei are hard-wired such that a mechanical tug on cell surface receptors can immediately change the organization of molecular assemblies in the cytoplasm and nucleus. When integrins were pulled by micromanipulating bound microbeads or micropipettes, cytoskeletal filaments reoriented, nuclei distorted, and nucleoli redistributed along the axis of the applied tension field. These effects were specific for integrins, independent of cortical membrane distortion, and were mediated by direct linkages between the cytoskeleton and nucleus. Actin microfilaments mediated force transfer to the nucleus at low strain; however, tearing of the actin gel resulted with greater distortion. In contrast, intermediate filaments effectively mediated force transfer to the nucleus under both conditions. These filament systems also acted as molecular guy wires to mechanically stiffen the nucleus and anchor it in place, whereas microtubules acted to hold open the intermediate filament lattice and to stabilize the nucleus against lateral compression. Molecular connections between integrins, cytoskeletal filaments, and nuclear scaffolds may therefore provide a discrete path for mechanical signal transfer through cells as well as a mechanism for producing integrated changes in cell and nuclear structure in response to changes in extracellular matrix adhesivity or mechanics.

Actions of Agonists and Antagonists of the ghrelin/GHS-R Pathway on GH Secretion, Appetite, and cFos Activity

PubMed Central

Hassouna, Rim; Labarthe, Alexandra; Zizzari, Philippe; Videau, Catherine; Culler, Michael; Epelbaum, Jacques; Tolle, Virginie

2012-01-01

The stimulatory effects of ghrelin, a 28-AA acylated peptide originally isolated from stomach, on growth hormone (GH) secretion and feeding are exclusively mediated through the growth hormone secretagogue 1a receptor (GHS-R1a), the only ghrelin receptor described so far. Several GHS-R1a agonists and antagonists have been developed to treat metabolic or nutritional disorders but their mechanisms of action in the central nervous system remain poorly understood. In the present study, we compared the activity of BIM-28163, a GHS-R1a antagonist, and of several agonists, including native ghrelin and the potent synthetic agonist, BIM-28131, to modulate food intake, GH secretion, and cFos activity in arcuate nucleus (ArcN), nucleus tractus solitarius (NTS), and area postrema (AP) in wild-type and NPY-GFP mice. BIM-28131 was as effective as ghrelin in stimulating GH secretion, but more active than ghrelin in inducing feeding. It stimulated cFos activity similarly to ghrelin in the NTS and AP but was more powerful in the ArcN, suggesting that the super-agonist activity of BIM-28131 is mostly mediated in the ArcN. BIM-28163 antagonized ghrelin-induced GH secretion but not ghrelin-induced food consumption and cFos activation, rather it stimulated food intake and cFos activity without affecting GH secretion. The level of cFos activation was dependent on the region considered: BIM-28163 was as active as ghrelin in the NTS, but less active in the ArcN and AP. All compounds also induced cFos immunoreactivity in ArcN NPY neurons but BIM-28131 was the most active. In conclusion, these data demonstrate that two peptide analogs of ghrelin, BIM-28163, and BIM-28131, are powerful stimulators of appetite in mice, acting through pathways and key brain regions involved in the control of appetite that are only partially superimposable from those activated by ghrelin. A better understanding of the molecular pathways activated by these compounds could be useful in devising future therapeutic applications, such as for cachexia and anorexia. PMID:23515849

Electron paramagnetic resonance and FT-IR spectroscopic studies of glycine anhydride and betaine hydrochloride

NASA Astrophysics Data System (ADS)

Halim Başkan, M.; Kartal, Zeki; Aydın, Murat

2015-12-01

Gamma irradiated powders of glycine anhydride and betaine hydrochloride have been investigated at room temperature by electron paramagnetic resonance (EPR). In these compounds, the observed paramagnetic species were attributed to the R1 and R2 radicals, respectively. It was determined that the free electron interacted with environmental protons and 14N nucleus in both radicals. The EPR spectra of gamma irradiated powder samples remained unchanged at room temperature for two weeks after irradiation. Also, the Fourier Transform Infrared (FT-IR), FT-Raman and thermal analyses of both compounds were investigated. The functional groups in the molecular structures of glycine anhydride and betaine hydrochloride were identified by vibrational spectroscopies (FT-IR and FT-Raman).

Nucleus Z=126 with magic neutron number N=184 may be related to the measured Maruhn-Greiner maximum at A/2=155 from compound nuclei at low energy nuclear reactions

NASA Astrophysics Data System (ADS)

Prelas, M. A.; Hora, H.; Miley, G. H.

2014-07-01

Evaluation of nuclear binding energies from theory close to available measurements of a very high number of superheavy elements (SHE) based on α-decay energies Qα, arrived at a closing shell with a significant neutron number 184. Within the option of several discussed magic numbers for protons of around 120, Bagge's numbers 126 and 184 fit well and are supported by the element generation measurements by low energy nuclear reactions (LENR) discovered in deuterium loaded host metals. These measurements were showing a Maruhn-Greiner maximum from fission of compound nuclei in an excited state with double magic numbers for mutual confirmation.

Synthesis, characterization and antimicrobial evaluation of some new schiff, mannich and acetylenic Mannich bases incorporating a 1,2,4-triazole nucleus.

PubMed

Aouad, Mohamed R

2014-11-18

A series of Schiff and Mannich bases derived from 4-amino-5-(3-fluoro-phenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione were synthesized. The alkylation of 4-phenyl-5-(3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione with propargyl bromide afforded the corresponding thiopropargylated derivative which upon treatment with the appropriate secondary amines in the presence of CuCl2 furnished the desired acetylenic Mannich bases. The synthesized compounds were characterized on the basis of their spectral (IR, 1H- and 13C-NMR) data and evaluated for their biological activities. Some of the compounds were found to exhibit significant antimicrobial activity.

Restoration of isospin symmetry in highly excited nuclei

NASA Astrophysics Data System (ADS)

Sagawa, H.; Bortignon, P. F.; Colò, G.

1998-12-01

Explicit relations between the isospin mixing probability, the spreading width ΓIAS↓ of the Isobaric Analog State (IAS) and the statistical decay width Γc of the compound nucleus at finite excitation energy, are derived by using the Feshbach projection formalism. The temperature dependence of the isospin mixing probability is discussed quantitatively for the first time by using the values of ΓIAS↓ and of Γc calculated by means of microscopic models. It is shown that the mixing probability remains essentially constant up to a temperature of the order of 1 MeV and then decreases to about 1/4 of its zero temperature value, at higher temperature than ~3 MeV, due to the short decay time of the compound system.

Foam model of planetary formation

NASA Astrophysics Data System (ADS)

Andreev, Y.; Potashko, O.

The Analysis of 2637 terrestrial minerals shows presence of characteristic element and isotope structure for each ore irrespective of its site. The model of processes geo-nuclear syntheses elements is offered due to avalanche merge of nucleus which simply explains these laws. Main assumption: nucleus, atoms, connections, ores and minerals were formed in volume of the modern Earth at an early stage of its evolution from uniform proto-substance. Substantive provisions of the model: 1)The most part of nucleus of atoms of all chemical elements of the Earth's crust were formed on the mechanism of avalanche chain merge practically in one stage (in geological scales) in a course of correlated(in scales of a planet) process with allocation of a plenty of heat. 2) Atoms of chemical elements were generated during cooling a planet with preservation of a relative spatial arrangement of nucleus. 3) Chemical compounds have arisen at cooling a surface of a planet and were accompanied by reorganizations (hashing) macro- and geo-scale. 4) Mineral formations are consequence of correlated behaviour of chemical compounds on microscopic scales during phase transition from gaseous or liquid to a firm condition. 5) Synthesis of chemical elements in deep layers of the Earth occurs till now. "Foaming'' instead of "Big Bang" The physical space is continual gas-fluid environment consist of super fluid foam. The continuity, keeping and uniqueness of proto-substance are postulated. Scenario: primary singularity-> droplets(proto-galaxies) droplets(proto-stars)-> droplets(proto-planets)-> droplets(proto- satellites)-> droplets. Proto-planet substance->proton+electron as 1st generation disintegration result of primary foam. Nuclei or nucleonic crystals are the 2nd generation in result of cascade merge of protons into conglomerates. The theory has applied to the analysis of samples of native copper deposit from Rafalovka's ore deposit in Ukraine. The abundance of elements by use of the roentgen fluorescent microanalysis has been made. Changes of a parity of elements are described by nuclear synthesis reactions: 16O+47Ti, 23Na+40Ca, 24Mg+39K, 31P+32S-> 63Cu; 16O+49Ti, 23Na+42Ca, 26Mg+39K, 31P+34S-> 65Cu Dramatical change of isotope parities of 56Fe and 57Fe in the sites of space carried on 3 millimetres. The content of 57Fe is greater then 56Fe in Cu granule.

[The relationships among raphe magnus nucleus, locus coeruleus and dorsal motor nucleus of vagus in the descending regulation of gastric motility].

PubMed

Qiao, Hui; An, Shu-Cheng; Xu, Chang

2011-02-01

To explore the interrelationship among dorsal motor nucleus of the vagus (DMV), locus coeruleus (LC) and raphe magnus nucleus (NRM) in the mechanism of the descending regulation on gastric motility, which may constitute a parasympathetic local circuit, work as a neural center of gastric modulation in brainstem. Using nucleus location, electric stimulation and lesion, together with microinjection, and recording the inter-gastric pressure. (1) LC stimulation could inhibit the gastric motility significantly (P < 0.01), DMV lesion weaken this effect, while blocking the a receptor on DMV could reverse the effect. (2) NRM stimulation reduced the amplitude of gastric constriction (P < 0.01), DMV lesion could abolish the effect, but blocking the 5-HT2A receptor on DMV depressed the gastric motility heavily (P < 0.01) like NRM stimulation. While LC lesion could abolish the effect of NRM stimulation, and microinjection of ritanserin into LC could likewise abolish it. (1) LC inhibit the gastric motility via a receptor in DMV, and meanwhile may excite it through 5-HT2A receptor in DMV, these two ways work together to keeping the gastric motility amplitude normally. (2) NRM inhibit the gastric motility via 5-HT2A receptor in LC.

The endocrine disruptor nonylphenol induces sublethal toxicity in vascular plant development at environmental concentrations: A risk for riparian plants and irrigated crops?

PubMed

Esteban, S; Llamas, P M; García-Cortés, H; Catalá, M

2016-09-01

In recent years, there is a growing concern among the scientific community about the presence of the so-called emergent pollutants in waters of different countries, especially endocrine-disrupting compounds (EDCs) that have the ability to alter the hormonal system. One of the substances found almost ubiquitously and in higher concentrations is the alkylphenol nonylphenol. Albeit this compound is included in priority lists as a probable risk for human health and the environment, little is known about its effects on developing plants. The aim of this work is to assess the acute and sub-chronic toxicity of environmental concentrations of nonylphenol in riparian vascular plant development using spores of the fern Polystichum setiferum and a biomarker-based approach: mitochondrial activity (cell viability), chlorophyll (plant physiology) and DNA content (growth). Mitochondrial activity and DNA content show that nonylphenol induces acute and sub-chronic toxicity at 48 h and after 1 week, respectively. Significant effects are observed in both parameters in fern spores at ng L(-1) but chlorophyll autofluorescence shows little changes. The inhibition of germination by natural allelochemicals has been reported to be related with the active hydroxyl group of phenolic compounds and largely independent of the structural nucleus to which it is attached. Results presented in this study suggest that environmental concentrations of nonylphenol could interfere with higher plant germination development by mimicking natural allelochemicals and/or phytohormones acting as a "phytoendocrine disruptor" likely posing ecophysiological risks. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effects of low dose treatment of tributyltin on the regulation of estrogen receptor functions in MCF-7 cells.

PubMed

Sharan, Shruti; Nikhil, Kumar; Roy, Partha

2013-06-01

Endocrine disrupting chemicals are the natural/synthetic compounds which mimic or inhibit the actions of endogenous hormones. Organotin compounds, such as tributyltin (TBT) are typical environmental contaminants and suspected endocrine-disrupting chemical. The present study evaluates the estrogenic potential of this compound in vitro in ER (+) breast adenocarcinoma, MCF-7 cell line. Our data showed that tributyltin chloride (TBTCl) had agonistic activities for estrogen receptor-α (ER-α). Its estrogenic potential was checked using cell proliferation assay, aromatase assay, transactivation assay, and protein expression analysis. Low dose treatment of TBTCl had a proliferative effect on MCF-7 cells and resulted in up-regulation of aromatase enzyme activity and enhanced estradiol production in MCF-7 cells. Immunofluorescence staining showed translocation of ER-α from cytoplasm to nucleus and increased expression of ER-α, 3β-HSD and aromatase on treatment with increasing doses of TBTCl. Further, to decipher the probable signaling pathways involved in its action, the MCF-7 cells were transfected with different pathway dependent luciferase reporter plasmids (CRE, SRE, NF-κB and AP1). A significant increase in CRE and SRE and decrease in NF-κB regulated pathway were observed (p<0.05). Our results thus showed that the activation of SRE by TBTCl may be due to ligand dependent ER-α activation of the MAPK pathway and increased phosphorylation of ERK. In summary, the present data suggests that low dose of tributyltin genomically and non-genomically augmented estrogen dependent signaling by targeting various pathways. Copyright © 2013 Elsevier Inc. All rights reserved.

Effect of timing of the removal of oocyte chromosomes before or after injection of somatic nucleus on development of NT embryos.

PubMed

Wakayama, Sayaka; Cibelli, Jose B; Wakayama, Teruhiko

2003-01-01

Cloning methods are now well described and becoming routine. Yet the frequency at which live cloned offspring are produced (as a percentage of starting one-cell embryos) remains below 5% irrespective of nucleus donor species or cell type. In considering the cause(s) of this universally low efficiency, features common to all cloning protocols are strong candidates. One such shared feature is enucleation; the donor nucleus is inserted into an enucleated cytoplast (ooplast). However, it is not known whether a nucleus-free metaphase II oocyte is developmentally impaired other than by virtue of lacking chromosomes, or if in nuclear transfer protocols, enucleation removes factors necessary to reprogram the incoming nucleus. We have here investigated the role of enucleation in nuclear transfer. Three hours after the injection of cumulus cell nuclei into non-enucleated oocytes, 65% contained two distinct metaphase spindles, with the remainder exhibiting a single spindle in which oocyte-derived and nucleus donor chromosomes were mixed. However, staining only one hour after donor nucleus insertion revealed that most had two discrete spindles. In the absence of staining, the donor nucleus spindle was not visible. This provided a straightforward way to identify and select the oocyte-derived metaphase chromosomes 1 h after donor nucleus microinjection, and 34-41% cloned embryo developed to the morulla-blastocyst stage following Sr(2+)-induced activation. Of these, two (1% of starting one-cell embryos) developed to term, an efficiency which is comparable to that obtained for controls (6 clone; 1-2%) in which enucleation preceded nuclear transfer. In conclusion, the timing of the removal of oocyte chromosomes before or after injection of somatic nucleus had no effect on cloned embryo development. These findings argue that neither oocyte chromosome depletion per se, nor the potential removal of "reprogramming" factors during enucleation explain the low efficiency of nuclear transfer cloning.

Decreased expression of GST pi is correlated with a poor prognosis in human esophageal squamous carcinoma

PubMed Central

2010-01-01

Background Glutathione S-transferase pi (GST pi) is a subgroup of GST family, which provides cellular protection against free radical and carcinogenic compounds due to its detoxifying function. Expression patterns of GST pi have been studied in several carcinomas and its down-regulation was implicated to be involved in malignant transformation in patients with Barrett's esophagus. However, neither the exact role of GST pi in the pathogenesis nor its prognostic impact in squamous esophageal carcinoma is fully characterized. Methods Immunohistochemistry was used to investigate GST pi expression on 153 archival squamous esophageal carcinoma specimens with a GST pi monoclonal antibody. Statistic analyses were performed to explore its association with clinicopathological factors and clinical outcome. Results The GST pi expression was greatly reduced in tissues of esophageal carcinomas compared to adjacent normal tissues and residual benign tissues. Absent of GST pi protein expression in cytoplasm, nuclear and cytoplasm/nucleus was found in 51%, 64.7% and 48% of all the carcinoma cases, respectively. GST pi deficiency in cytoplasm, nucleus and cytoplasm/nucleus was significantly correlated to poor differentiation (p < 0.001, p < 0.001 and p < 0.001, respectively). UICC stage and T stage were found significantly correlated to negative expression of GST pi in cytoplasm (p < 0.001 and p = 0.004, respectively) and cytoplasm/nucleus (p = 0.017 and p = 0.031, respectively). In univariate analysis, absent of GST pi protein expression in cytoplasm, nucleus and cytoplasm/nucleus was significantly associated with a shorter overall survival (p < 0.001, p < 0.001 and p < 0.001, respectively), whereas only GST pi cytoplasmic staining retained an independent prognostic significance (p < 0.001) in multivariate analysis. Conclusions Our results show that GST pi expression is down regulated in the squamous esophageal carcinoma, and that the lack of GST pi expression is associated with poor prognosis. Therefore, deficiency of GST pi protein expression may be an important mechanism involved in the carcinogenesis and progression of the squamous esophageal carcinoma, and the underlying mechanisms leading to decreased GST pi expression deserve further investigation. PMID:20602752

Skyrme forces and decay of the Rf266*104 nucleus synthesized via different incoming channels

NASA Astrophysics Data System (ADS)

Niyti, Deep, Aman; Kharab, Rajesh; Chopra, Sahila; Gupta, Raj K.

2017-03-01

The excitation functions for the production of 262Rf, 261Rf, and 260Rf isotopes via 4 n -, 5 n -, and 6 n -decay channels from the *266Rf compound nucleus are studied within the dynamical cluster-decay model (DCM), including deformations β2 i and so-called hot-optimum orientations θi which support symmetric fission, in agreement with experiments. The data are available for 18O+248Cm and 22Ne+244Pu reactions, respectively, at the energy ranges of Elab=88.2 to 101.3 and 109.0 to 124.8 MeV. For the nuclear interaction potentials, we use the Skyrme energy density functional (SEDF) based on semiclassical extended Thomas Fermi (ETF) approach, which means an extension of the earlier study of excitation functions of *266Rf formed in 18O+248Cm reaction, based on the DCM using the pocket formula for nuclear proximity potential, showing interaction dependence. The Skyrme forces used here are the old SIII and SIV and new GSkI and KDE0(v1) given for both normal and isospin-rich nuclei, with densities added in frozen density approximation. Interestingly, the DCM gives an excellent fit to the measured data on fusion evaporation residue (ER) for both the incoming channels (18O+248Cm and 22Ne+244Pu ) at the energy range Elab=88.2 to 124.8 MeV, independent of the entrance channel and Skyrme force used. The possible fusion-fission (ff) and quasifission (qf) mass regions of fragments on DCM are also predicted. The DCM with Skyrme forces is further used to look for all the possible target-projectile (t-p) combinations forming the cold compound nucleus (CN) *266Rf at the CN excitation energy of Elab for hot compact configurations. The fusion evaporation residue cross sections, for the proposed new reactions in synthesizing the CN *266Rf, are also estimated for the future experiments, and role of mass asymmetry of nuclei is indicated.

Blockade of arginine vasotocin signaling reduces aggressive behavior and c-Fos expression in the preoptic area and periventricular nucleus of the posterior tuberculum in male Amphiprion ocellaris.

PubMed

Yaeger, C; Ros, A M; Cross, V; Deangelis, R S; Stobaugh, D J; Rhodes, J S

2014-05-16

Many marine fishes change sex in response to social cues when the dominance hierarchy is perturbed. Arginine-vasotocin (AVT) and the mammalian homolog arginine vasopressin are neuropeptides involved in social and reproductive behaviors across vertebrate taxa. The goal of this study was to determine whether AVT signaling influences aggression and expression of c-Fos, a marker of neuroplasticity, in key brain regions of the social decision circuit in Amphiprion ocellaris clownfish, a species where behavioral dominance precedes gonadal sex change from male to female. In experiment 1, juvenile clownfish (average mass 2.5g) were paired together in a tank (a total of 24 pairs), matched approximately for size with one fish randomly receiving either an intraperitoneal injection of the arginine vasopressin V1a receptor antagonist (Manning compound) or saline vehicle, and evaluated for aggressive and submissive behaviors over a 10-min period. The second experiment was a repeat of the first using five pairs of mature, reproductive males, except the animals interacted for 90-min immediately followed by euthanasia for immunohistochemical detection of c-Fos protein. Numbers of c-Fos-positive cells were quantified in the preoptic area of the hypothalamus (POA), the anterior tuberal nucleus (aTn), and periventricular nucleus of the posterior tuberculum (TPp). Manning compound significantly reduced aggression and the probability of winning the contest relative to saline (vehicle) controls. In experiment 2, saline-treated fish displayed approximately twice as many c-Fos-positive cells in the POA and 25% more in the TPp than the Manning-treated fish, no differences were observed in the aTn. Taken together, results suggest AVT signaling is necessary for aggressive behavior and expression of neuroplasticity in the POA and TPp that likely contributes to behavioral dominance and hence, sex change in A. ocellaris. Published by Elsevier Ltd.

Synthesis and Biological Evaluation of 2-Methyl-4,5-Disubstituted Oxazoles as a Novel Class of Highly Potent Antitubulin Agents

NASA Astrophysics Data System (ADS)

Romagnoli, Romeo; Baraldi, Pier Giovanni; Prencipe, Filippo; Oliva, Paola; Baraldi, Stefania; Salvador, Maria Kimatrai; Lopez-Cara, Luisa Carlota; Brancale, Andrea; Ferla, Salvatore; Hamel, Ernest; Ronca, Roberto; Bortolozzi, Roberta; Mariotto, Elena; Porcù, Elena; Basso, Giuseppe; Viola, Giampietro

2017-04-01

Antimitotic agents that interfere with microtubule formation are one of the major classes of cytotoxic drugs for cancer treatment. Multiple 2-methyl-4-(3‧,4‧,5‧-trimethoxyphenyl)-5-substituted oxazoles and their related 4-substituted-5-(3‧,4‧,5‧-trimethoxyphenyl) regioisomeric derivatives designed as cis-constrained combretastatin A-4 (CA-4) analogues were synthesized and evaluated for their antiproliferative activity in vitro against a panel of cancer cell lines and, for selected highly active compounds, interaction with tubulin, cell cycle effects and in vivo potency. Both these series of compounds were characterized by the presence of a common 3‧,4‧,5‧-trimethoxyphenyl ring at either the C-4 or C-5 position of the 2-methyloxazole ring. Compounds 4g and 4i, bearing a m-fluoro-p-methoxyphenyl or p-ethoxyphenyl moiety at the 5-position of 2-methyloxazole nucleus, respectively, exhibited the greatest antiproliferative activity, with IC50 values of 0.35-4.6 nM (4g) and 0.5-20.2 nM (4i), which are similar to those obtained with CA-4. These compounds bound to the colchicine site of tubulin and inhibited tubulin polymerization at submicromolar concentrations. Furthermore, 4i strongly induced apoptosis that follows the mitochondrial pathway. In vivo, 4i in a mouse syngeneic model demonstrated high antitumor activity which significantly reduced the tumor mass at doses ten times lower than that required for CA-4P, suggesting that 4i warrants further evaluation as a potential anticancer drug.

Effects of Medication and Subthalamic Nucleus Deep Brain Stimulation on Tongue Movements in Speakers with Parkinson's Disease Using Electropalatography: A Pilot Study

ERIC Educational Resources Information Center

Hartinger, Mariam; Tripoliti, Elina; Hardcastle, William J.; Limousin, Patricia

2011-01-01

Parkinson's disease (PD) affects speech in the majority of patients. Subthalamic nucleus deep brain stimulation (STN-DBS) is particularly effective in reducing tremor and rigidity. However, its effect on speech is variable. The aim of this pilot study was to quantify the effects of bilateral STN-DBS and medication on articulation, using…

Synthesis of Pyridine and Spiropyridine Derivatives Derived from 2-aminoprop- 1-ene-1,1,3-tricarbonitrile Together with their c-Met Kinase and Antiproliferative Evaluations.

PubMed

Mohareb, Rafat M; Abouzied, Amr S; Abbas, Nermeen S

2018-02-07

Among a wide range of pyridines, 3-cyanopyridines acquired a special attention due to their wide range of pharmacological activities especially the therapeutic activities. Many pharmacological drugs containing the pyridine nucleus were known in the market. The aim of this work was to synthesize target molecules not only possess anti-tumor activities but also kinase inhibitors. To achieve this goal, our strategy was to synthesize a series of 3-cyanopyridine derivatives using 2-aminoprop-1-ene-1,1,3-tricarbonitrile (1) as the key starting material for many heterocyclization reactions. Muticoponent reactions were adopted using compound 1 to get different pyridine derivatives that were capable for different heterocyclization reactions. Antiproliferative evaluations and c-Met kinase, Pim-1 kinse inhibitions were perform where some compounds gave high activities. Compounds that showed high antiprolifeative activity were tested gor c-Met-independent and the results showed that compounds 5c, 5e, 5f, 7c, 7f and 16d were more active than foretinib. The Pim-1 kinase inhibition activity of some selected compounds showed that compounds 5e and 16c were high potent to inhibit Pim-1 activity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The acceleration of boron neutron capture therapy using multi-linked mercaptoundecahydrododecaborate (BSH) fused cell-penetrating peptide.

PubMed

Michiue, Hiroyuki; Sakurai, Yoshinori; Kondo, Natsuko; Kitamatsu, Mizuki; Bin, Feng; Nakajima, Kiichiro; Hirota, Yuki; Kawabata, Shinji; Nishiki, Tei-ichi; Ohmori, Iori; Tomizawa, Kazuhito; Miyatake, Shin-ichi; Ono, Koji; Matsui, Hideki

2014-03-01

New anti-cancer therapy with boron neutron capture therapy (BNCT) is based on the nuclear reaction of boron-10 with neutron irradiation. The median survival of BNCT patients with glioblastoma was almost twice as long as those receiving standard therapy in a Japanese BNCT clinical trial. In this clinical trial, two boron compounds, BPA (boronophenylalanine) and BSH (sodium borocaptate), were used for BNCT. BPA is taken up into cells through amino acid transporters that are expressed highly in almost all malignant cells, but BSH cannot pass through the cell membrane and remains outside the cell. We simulated the energy transfer against the nucleus at different locations of boron from outside the cell to the nuclear region with neutron irradiation and concluded that there was a marked difference between inside and outside the cell in boron localization. To overcome this disadvantage of BSH in BNCT, we used a cell-penetrating peptide system for transduction of BSH. CPP (cell-membrane penetrating peptide) is very common peptide domains that transduce many physiologically active substances into cells in vitro and in vivo. BSH-fused CPPs can penetrate the cell membrane and localize inside a cell. To increase the boron ratio in one BSH-peptide molecule, 8BSH fused to 11R with a dendritic lysine structure was synthesized and administrated to malignant glioma cells and a brain tumor mouse model. 8BSH-11R localized at the cell nucleus and showed a very high boron value in ICP results. With neutron irradiation, the 8BSH-11R administrated group showed a significant cancer killing effect compared to the 100 times higher concentration of BSH-administrated group. We concluded that BSH-fused CPPs were one of the most improved and potential boron compounds in the next-stage BNCT trial and 8BSH-11R may be applied in the clinical setting. Copyright © 2013 Elsevier Ltd. All rights reserved.

Thieno[3,2-b]- and thieno[2,3-b]pyrrole bioisosteric analogues of the hallucinogen and serotonin agonist N,N-dimethyltryptamine.

PubMed

Blair, J B; Marona-Lewicka, D; Kanthasamy, A; Lucaites, V L; Nelson, D L; Nichols, D E

1999-03-25

The synthesis and biological activity of 6-[2-(N, N-dimethylamino)ethyl]-4H-thieno[3,2-b]pyrrole (3a) and 4-[2-(N, N-dimethylamino)ethyl]-6H-thieno[2,3-b]pyrrole (3b), thienopyrroles as potential bioisosteres of N,N-dimethyltryptamine (1a), are reported. Hallucinogen-like activity was evaluated in the two-lever drug discrimination paradigm using LSD- and DOI-trained rats. Neither 3a nor 3b substituted for LSD or DOI up to doses of 50 micromol/kg. By comparison, 1a fully substituted in LSD-trained rats. However, 3a and 3b fully substituted for the 5-HT1A agonist LY293284 ((-)-(4R)-6-acetyl-4-(di-n-propylamino)-1,3,4, 5-tetrahydrobenz[c,d]indole). Both 3a and 3b induced a brief "serotonin syndrome" and salivation, an indication of 5-HT1A receptor activation. At the cloned human 5-HT2A receptor 3b had about twice the affinity of 3a. At the cloned human 5-HT2B and 5-HT2C receptors, however, 3a had about twice the affinity of 3b. Therefore, thiophene lacks equivalence as a replacement for the phenyl ring in the indole nucleus of tryptamines that bind to 5-HT2 receptor subtypes and possess LSD-like behavioral effects. Whereas both of the thienopyrroles had lower affinity than the corresponding 1a at 5-HT2 receptors, 3a and 3b had significantly greater affinity than 1a at the 5-HT1A receptor. Thus, thienopyrrole does appear to serve as a potent bioisostere for the indole nucleus in compounds that bind to the serotonin 5-HT1A receptor. These differences in biological activity suggest that serotonin receptor isoforms are very sensitive to subtle changes in the electronic character of the aromatic systems of indole compounds.

Hit optimization studies of 3-hydroxy-indolin-2-one analogs as potential anti-HIV-1 agents.

PubMed

Chander, Subhash; Tang, Cheng-Run; Penta, Ashok; Wang, Ping; Bhagwat, Deepak P; Vanthuyne, Nicolas; Albalat, Muriel; Patel, Payal; Sankpal, Sanskruti; Zheng, Yong-Tang; Sankaranarayanan, Murugesan

2018-09-01

In the current study, twenty-two compounds based upon 3-hydroxy-3-(2-oxo-2-phenylethyl)indolin-2-one nucleus were designed, synthesized and in vitro evaluated for HIV-1 RT inhibition and anti-HIV-1 activity. Compounds 3d, 5c and 5e demonstrated encouraging potency against RT enzyme as well as HIV-1 in low micromolar to nanomolar concentration with good to excellent safety index. Structure activity relationship studies revealed that halogens such as bromo or chloro at 5th the position of oxindole ring remarkably enhanced the potency against RT. Moreover, methoxy or chloro groups at the ortho position of phenyl ring also significantly favored RT inhibition activity. Seven compounds (3b, 3c, 3d, 3e, 5b, 5c and 5e) with better anti-HIV-1 potency were tested against the mutant HIV-1 K103N strain . The putative binding mode, as well as interaction patterns of the best active compound 5c with wild HIV-1 RT were studied via docking studies. Copyright © 2018 Elsevier Inc. All rights reserved.

Point-by-point model calculation of the prompt neutron multiplicity distribution ν(A) in the incident neutron energy range of multi-chance fission

NASA Astrophysics Data System (ADS)

Tudora, Anabella; Hambsch, Franz-Josef; Tobosaru, Viorel

2017-09-01

Prompt neutron multiplicity distributions ν(A) are required for prompt emission correction of double energy (2E) measurements of fission fragments to determine pre-neutron fragment properties. The lack of experimental ν(A) data especially at incident neutron energies (En) where the multi-chance fission occurs impose the use of ν(A) predicted by models. The Point-by-Point model of prompt emission is able to provide the individual ν(A) of the compound nuclei of the main and secondary nucleus chains undergoing fission at a given En. The total ν(A) is obtained by averaging these individual ν(A) over the probabilities of fission chances (expressed as total and partial fission cross-section ratios). An indirect validation of the total ν(A) results is proposed. At high En, above 70 MeV, the PbP results of individual ν(A) of the first few nuclei of the main and secondary nucleus chains exhibit an almost linear increase. This shape is explained by the damping of shell effects entering the super-fluid expression of the level density parameters. They tend to approach the asymptotic values for most of the fragments. This fact leads to a smooth and almost linear increase of fragment excitation energy with the mass number that is reflected in a smooth and almost linear behaviour of ν(A).

Astrocytes in the nucleus of the solitary tract are activated by low glucose or glucoprivation: evidence for glial involvement in glucose homeostasis.

PubMed

McDougal, David H; Hermann, Gerlinda E; Rogers, Richard C

2013-01-01

Glucose homeostasis is maintained through interplay between central and peripheral control mechanisms which are aimed at storing excess glucose following meals and mobilizing these same stores during periods of fasting. The nucleus of the solitary tract (NST) in the dorsal medulla has long been associated with the central detection of glucose availability and the control of glucose homeostasis. Recent evidence has emerged which supports the involvement of astrocytes in glucose homeostasis. The aim of the present study was to investigate whether NST-astrocytes respond to physiologically relevant decreases in glucose availability, in vitro, as well as to the presence of the glucoprivic compound 2-deoxy-D-Glucose. This report demonstrates that some NST-astrocytes are capable of responding to low glucose or glucoprivation by increasing cytoplasmic calcium; a change that reverses with restoration of normal glucose availability. While some NST-neurons also demonstrate an increase in calcium signaling during low glucose availability, this effect is smaller and somewhat delayed compared to those observed in adjacent astrocytes. TTX did not abolish these hypoglycemia mediated responses of astrocytes, suggesting that NST-astrocytes may be directly sensing low glucose levels as opposed to responding to neuronal detection of hypoglycemia. Thus, chemodetection of low glucose by NST-astrocytes may play an important role in the autonomic regulation of glucose homeostasis.

Preparation, Characterization, and Pharmacological Activity of Cymbopogon winterianus Jowitt ex Bor (Poaceae) Leaf Essential Oil of β-Cyclodextrin Inclusion Complexes

PubMed Central

Santos, Priscila L.; Araújo, Adriano A. S.; Quintans, Jullyana S. S.; Oliveira, Makson G. B.; Brito, Renan G.; Serafini, Mairim R.; Menezes, Paula P.; Santos, Marcio R. V.; Alves, Pericles B.; de Lucca Júnior, Waldecy; Blank, Arie F.; La Rocca, Viviana; Almeida, Reinaldo N.; Quintans-Júnior, Lucindo J.

2015-01-01

This study aimed to evaluate the orofacial antinociceptive effect of the Cymbopogon winterianus essential oil (LEO) complexed in β-cyclodextrin (LEO-CD) and to assess the possible involvement of the central nervous system (CNS). The LEO was extracted, chromatographed, and complexed in β-cyclodextrin. The complex was characterized by differential scanning calorimetry (DSC) and thermogravimetry derivative (TG/DTG). Male Swiss mice (2-3 months) were treated with LEO-CD (50–200 mg/kg, p.o.), vehicle (distilled water, p.o.), or standard drug (i.p.) and subjected to the orofacial nociception formalin-, capsaicin-, and glutamate-induced. After the formalin test, the animals were perfused and the brains subjected to immunofluorescence for Fos. The rota-rod test (7 rpm/min) was carried out. Geraniol (37.57%) was the main compound of LEO. DSC and TG/DTG proved the complexation. The orofacial nociceptive behavior was significantly (p < 0.05) reduced. The number of Fos-positive cells was significantly changed in the dorsal raphe nucleus (p < 0.01), locus coeruleus (p < 0.001), trigeminal nucleus (p < 0.05), and trigeminal thalamic tract (p < 0.05). LEO-CD did not cause changes in motor coordination in the rota-rod test. Thus, our results suggested that LEO-CD has an orofacial antinociceptive profile, probably mediated by the activation of the CNS without changing the motor coordination. PMID:26246838

The enzyme 3-hydroxykynurenine transaminase as potential target for 1,2,4-oxadiazoles with larvicide activity against the dengue vector Aedes aegypti.

PubMed

Oliveira, Vanessa S; Pimenteira, Cecília; da Silva-Alves, Diana C B; Leal, Laylla L L; Neves-Filho, Ricardo A W; Navarro, Daniela M A F; Santos, Geanne K N; Dutra, Kamilla A; dos Anjos, Janaína V; Soares, Thereza A

2013-11-15

The mosquito Aedes aegypti is the vector agent responsible for the transmission of yellow fever and dengue fever viruses to over 80 million people in tropical and subtropical regions of the world. Exhaustive efforts have lead to a vaccine candidate with only 30% effectiveness against the dengue virus and failure to protect patients against the serotype 2. Hence, vector control remains the most viable route to dengue fever control programs. We have synthesized a class of 1,2,4-oxadiazole derivatives whose most biologically active compounds exhibit potent activity against Aedes aegypti larvae (ca. of 15 ppm) and low toxicity in mammals. Exposure to these larvicides results in larvae pigmentation in a manner correlated with the LC50 measurements. Structural comparisons of the 1,2,4-oxadiazole nucleus against known inhibitors of insect enzymes allowed the identification of 3-hydroxykynurenine transaminase as a potential target for these synthetic larvicides. Molecular docking calculations indicate that 1,2,4-oxadiazole compounds can bind to 3-hydroxykynurenine transaminase with similar conformation and binding energies as its crystallographic inhibitor 4-(2-aminophenyl)-4-oxobutanoic acid. Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical studies of elements with Z ⩾ 104 in gas phase

NASA Astrophysics Data System (ADS)

Türler, Andreas; Eichler, Robert; Yakushev, Alexander

2015-12-01

Chemical investigations of superheavy elements in the gas-phase, i.e. elements with Z ≥ 104, allow assessing the influence of relativistic effects on their chemical properties. Furthermore, for some superheavy elements and their compounds quite unique gas-phase chemical properties were predicted. The experimental verification of these properties yields supporting evidence for a firm assignment of the atomic number. Prominent examples are the high volatility observed for HsO4 or the very weak interaction of Cn with gold surfaces. The unique properties of HsO4 were exploited to discover the doubly-magic even-even nucleus 270Hs and the new isotope 271Hs. The combination of kinematic pre-separation and gas-phase chemistry allowed gaining access to a new class of relatively fragile compounds, the carbonyl complexes of elements Sg through Mt. A not yet resolved issue concerns the interaction of Fl with gold surfaces. While competing experiments agree on the fact that Fl is a volatile element, there are discrepancies concerning its adsorption on gold surfaces with respect to its daughter Cn. The elucidation of these and other questions amounts to the fascination that gas-phase chemical investigations exert on current research at the extreme limits of chemistry today.

Electric field effects on nuclear magnetic shielding of the 1:1 and 2:1 (homo and heterochiral) complexes of XOOX' (X, X' = H, CH3) with lithium cation and their chiral discrimination.

PubMed

Alkorta, Ibon; Elguero, José; Provasi, Patricio F; Pagola, Gabriel I; Ferraro, Marta B

2011-09-14

The set of 1:1 and 2:1 complexes of XOOX' (X, X' = H, CH(3)) with lithium cation has been studied to determine if they are suitable candidates for chiral discrimination in an isotropic medium via nuclear magnetic resonance spectroscopy. Conventional nuclear magnetic resonance is unable to distinguish between enantiomers in the absence of a chiral solvent. The criterion for experimental detection is valuated by the isotropic part of nuclear shielding polarisability tensors, related to a pseudoscalar of opposite sign for two enantiomers. The study includes calculations at coupled Hartree-Fock and density functional theory schemes for (17)O nucleus in each compound. Additional calculations for (1)H are also included for some compounds. A huge static homogeneous electric field, perpendicular to the magnetic field of the spectromer, as big as ≈1.7 × 10(8) V m(-1) should be applied to observe a shift of ≈1 ppm for (17)O magnetic shielding in the proposed set of complexes. © 2011 American Institute of Physics

Estrogen regulates histone deacetylases to prevent cardiac hypertrophy

PubMed Central

Pedram, Ali; Razandi, Mahnaz; Narayanan, Ramesh; Dalton, James T.; McKinsey, Timothy A.; Levin, Ellis R.

2013-01-01

The development and progression of cardiac hypertrophy often leads to heart failure and death, and important modulators of hypertrophy include the histone deacetylase proteins (HDACs). Estrogen inhibits cardiac hypertrophy and progression in animal models and humans. We therefore investigated the influence of 17-β-estradiol on the production, localization, and functions of prohypertrophic (class I) and antihypertrophic (class II) HDACs in cultured neonatal rat cardiomyocytes. 17-β-Estradiol or estrogen receptor β agonists dipropylnitrile and β-LGND2 comparably suppressed angiotensin II–induced HDAC2 (class I) production, HDAC-activating phosphorylation, and the resulting prohypertrophic mRNA expression. In contrast, estrogenic compounds derepressed the opposite effects of angiotensin II on the same parameters for HDAC4 and 5 (class II), resulting in retention of these deacetylases in the nucleus to inhibit hypertrophic gene expression. Key aspects were confirmed in vivo from the hearts of wild-type but not estrogen receptor β (ERβ) gene–deleted mice administered angiotensin II and estrogenic compounds. Our results identify a novel dual regulation of cardiomyocyte HDACs, shown here for the antihypertrophic sex steroid acting at ERβ. This mechanism potentially supports using ERβ agonists as HDAC modulators to treat cardiac disease. PMID:24152730

Airborne polycyclic aromatic hydrocarbons trigger human skin cells aging through aryl hydrocarbon receptor.

PubMed

Qiao, Yuan; Li, Qiang; Du, Hong-Yang; Wang, Qiao-Wei; Huang, Ye; Liu, Wei

2017-07-01

Accumulating evidence suggests that polycyclic aromatic hydrocarbons (PAH) which adsorbed on the surface of ambient air particulate matters (PM), are the major toxic compound to cause cardiovascular and respiratory diseases, even cancer. However, its detrimental effects on human skin cell remain unclear. Here, we demonstrated that SRM1649b, a reference urban dust material of PAH, triggers human skin cells aging through cell cycle arrest, cell growth inhibition and apoptosis. Principally, SRM1649b facilitated Aryl hydrocarbon receptor (AhR) translocated into nucleus, subsequently activated ERK/MAPK signaling pathway, and upregulated aging-related genes expression. Most important, we found that AhR antagonist efficiently revert the aging of skin cells. Thus our novel findings firstly revealed the mechanism of skin aging under PAH contamination and provided potential strategy for clinical application. Copyright © 2017. Published by Elsevier Inc.

Water/rock interactions in experimentally simulated dirty snowball and dirty iceball cometary nuclei

NASA Technical Reports Server (NTRS)

Gooding, James L.; Allton, Judith H.

1991-01-01

In the dirty snowball model for cometary nuclei, comet-nucleus materials are regarded as mixtures of volatile ices and relatively non-volatile minerals or chemical compounds. Carbonaceous chondrite meteorites are regarded as useful analogs for the rocky component. To help elucidate the possible physical geochemistry of cometary nuclei, preliminary results are reported of calorimetric experiments with two-component systems involving carbonaceous chondrites and water ice. Based on collective knowledge of the physics of water ice, three general types of interactions can be expected between water and minerals at sub-freezing temperatures: (1) heterogeneous nucleation of ice by insoluble minerals; (2) adsorption of water vapor by hygroscopic phases; and (3) freezing- and melting-point depression of liquid water sustained by soluble minerals. The relative and absolute magnitude of all three effects are expected to vary with mineral composition.

Resting state functional MRI in Parkinson's disease: the impact of deep brain stimulation on 'effective' connectivity.

PubMed

Kahan, Joshua; Urner, Maren; Moran, Rosalyn; Flandin, Guillaume; Marreiros, Andre; Mancini, Laura; White, Mark; Thornton, John; Yousry, Tarek; Zrinzo, Ludvic; Hariz, Marwan; Limousin, Patricia; Friston, Karl; Foltynie, Tom

2014-04-01

Depleted of dopamine, the dynamics of the parkinsonian brain impact on both 'action' and 'resting' motor behaviour. Deep brain stimulation has become an established means of managing these symptoms, although its mechanisms of action remain unclear. Non-invasive characterizations of induced brain responses, and the effective connectivity underlying them, generally appeals to dynamic causal modelling of neuroimaging data. When the brain is at rest, however, this sort of characterization has been limited to correlations (functional connectivity). In this work, we model the 'effective' connectivity underlying low frequency blood oxygen level-dependent fluctuations in the resting Parkinsonian motor network-disclosing the distributed effects of deep brain stimulation on cortico-subcortical connections. Specifically, we show that subthalamic nucleus deep brain stimulation modulates all the major components of the motor cortico-striato-thalamo-cortical loop, including the cortico-striatal, thalamo-cortical, direct and indirect basal ganglia pathways, and the hyperdirect subthalamic nucleus projections. The strength of effective subthalamic nucleus afferents and efferents were reduced by stimulation, whereas cortico-striatal, thalamo-cortical and direct pathways were strengthened. Remarkably, regression analysis revealed that the hyperdirect, direct, and basal ganglia afferents to the subthalamic nucleus predicted clinical status and therapeutic response to deep brain stimulation; however, suppression of the sensitivity of the subthalamic nucleus to its hyperdirect afferents by deep brain stimulation may subvert the clinical efficacy of deep brain stimulation. Our findings highlight the distributed effects of stimulation on the resting motor network and provide a framework for analysing effective connectivity in resting state functional MRI with strong a priori hypotheses.

Cross section calculations for subthreshold pion production in peripheral heavy-ion collisions

NASA Technical Reports Server (NTRS)

Norbury, J. W.; Cucinotta, F. A.; Deutchman, P. A.; Townsend, L. W.

1986-01-01

Total cross sections angular distributions, and spectral distributions for the exclusive production of charged and neutral subthreshold pions produced in peripheral nucleus-nucleus collisions are calculated by using a particle-hole formalism. The pions result from the formation and decay of an isobar giant resonance state formed in a C-12 nucleus. From considerations of angular momentum conservation and for the sake of providing a unique experimental signature, the other nucleus, chosen for this work to be C-12 also, is assumed to be excited to one of its isovector (1+) giant resonance states. The effects of nucleon recoil by the pion emission are included, and Pauli blocking and pion absorption effects are studied by varying the isobar width. Detailed comparisons with experimental subthreshold pion data for incident energies between 35 and 86 MeV/nucleon are made.

Local administration of sarizotan into the subthalamic nucleus attenuates levodopa-induced dyskinesias in 6-OHDA-lesioned rats.

PubMed

Marin, C; Aguilar, E; Rodríguez-Oroz, M C; Bartoszyk, G D; Obeso, J A

2009-06-01

Dyskinesia affects the majority of levodopa-treated parkinsonian patients within 5-10 years of treatment with levodopa. Clinical and preclinical observations suggest that an increase in serotoninergic transmission can contribute to the appearance of dyskinesias. It is thus conceivable that a modulation of synaptic dopamine (DA) levels induced by the inhibition of serotonin (5-HT) release, as a consequence of 5-HT(1A) agonists administration, might alleviate dyskinesias. Since 5-HT(1A) receptors are expressed in the subthalamic nucleus (STN), the aim of the present study was to assess the effect of the intrasubthalamic administration of sarizotan, a compound with full 5-HT(1A) agonist properties, on levodopa-induced dyskinesias in the 6-hydroxydopamine (6-OHDA) model of parkinsonism. Male Sprague-Dawley rats received a unilateral 6-OHDA administration in the nigrostriatal pathway. A test of apomorphine was performed to evaluate dopamine depletion. One week later, a cannula was implanted in the STN. Animals were treated with levodopa (6 mg/kg, i.p., twice at day) for 22 consecutive days. On day 23, several doses (1 ng, 10 ng, or 1 microg) of sarizotan were administered through the cannula to the STN. The higher doses of sarizotan effectively attenuated all levodopa-induced dyskinesias including axial, limb, and orolingual subtypes. These results suggest that the STN is a target structure for the antidyskinetic action of sarizotan and indicate that drug-mediated modulation of STN activity may be an alternative option for the treatment of levodopa-induced dyskinesias in Parkinson's disease.

Bisphenol-A: Epigenetic Reprogramming and Effects on Reproduction and Behavior

PubMed Central

Mileva, Guergana; Baker, Stephanie L.; Konkle, Anne T.M.; Bielajew, Catherine

2014-01-01

Bisphenol A (BPA) is a synthetic compound used in the production of many polycarbonate plastics and epoxy resins. It is one of the most widely produced chemicals in the world today and is found in most canned goods, plastics, and even household dust. Exposure to BPA is almost universal: most people have measurable amounts of BPA in both urine and serum. BPA is similar in structure to estradiol and can bind to multiple targets both inside and outside the nucleus, in effect acting as an endocrine disruptor. Research on BPA exposure has accelerated in the past decade with findings suggesting that perinatal exposure to BPA can negatively impact both male and female reproduction, create alterations in behavior, and act as a carcinogen. BPA can have both short term and long term effects with the latter typically occurring through epigenetic mechanisms such as DNA methylation. This review will draw on both human and animal studies in an attempt to synthesize the literature and examine the effects of BPA exposure on reproduction, behavior, and carcinogenesis with a focus on the potential epigenetic mechanisms by which it acts. PMID:25054232

Determination of the effective sample thickness via radiative capture

DOE PAGES

Hurst, A. M.; Summers, N. C.; Szentmiklosi, L.; ...

2015-09-14

Our procedure for determining the effective thickness of non-uniform irregular-shaped samples via radiative capture is described. In this technique, partial γ-ray production cross sections of a compound nucleus produced in a neutron-capture reaction are measured using Prompt Gamma Activation Analysis and compared to their corresponding standardized absolute values. For the low-energy transitions, the measured cross sections are lower than their standard values due to significant photoelectric absorption of the γ rays within the bulk-sample volume itself. Using standard theoretical techniques, the amount of γ-ray self absorption and neutron self shielding can then be calculated by iteratively varying the sample thicknessmore » until the observed cross sections converge with the known standards. The overall attenuation provides a measure of the effective sample thickness illuminated by the neutron beam. This procedure is illustrated through radiative neutron capture using powdered oxide samples comprising enriched 186W and 182W from which their tungsten-equivalent effective thicknesses are deduced to be 0.077(3) mm and 0.042(8) mm, respectively.« less

Structure-Based Design: Synthesis, X-ray Crystallography, and Biological Evaluation of N-Substituted-4-Hydroxy-2-Quinolone-3-Carboxamides as Potential Cytotoxic Agents.

PubMed

Sabbah, Dima A; Hishmah, Bayan; Sweidan, Kamal; Bardaweel, Sanaa; AlDamen, Murad; Zhong, Haizhen A; Abu Khalaf, Reema; Hasan Ibrahim, Ameerah; Al-Qirim, Tariq; Abu Sheikha, Ghassan; Mubarak, Mohammad S

2018-01-01

Oncogenic potential of phosphatidylinositol 3-kinase (PI3Kα) has been highlighted as a therapeutic target for anticancer drug design. Target compounds were designed to address the effect of different substitution patterns at the N atom of the carboxamide moiety on the bioactivity of this series. Synthesis of the targeted compounds, crystallography, biological evaluation tests against human colon carcinoma (HCT-116), and Glide docking studies. A new series of N-substituted- 4-hydroxy-2-quinolone-3-carboxamides was prepared and characterized by means of FT-IR, 1H and 13C NMR, and elemental analysis. In addition, the identity of the core nucleus 5 was successfully characterized with the aid of X-ray crystallography. Biological activity of prepared compounds was investigated in vitro against human colon carcinoma (HCT-116) cell line. Results revealed that these compounds inhibit cell proliferation and induce apoptosis through an increase in caspase-3 activity and a decrease in DNA cellular content. Compounds 7, 14, and 17 which have H-bond acceptor moiety on p-position displayed promising PI3Kα inhibitory activity. On the other hand, derivatives tailored with bulky and hydrophobic motifs (16 and 18) on o- and m-positions exhibited moderate activity. Molecular docking studies against PI3Kα and caspase-3 showed an agreement between the predicted binding affinity (ΔGobsd) and IC50 values of the derivatives for the caspase-3 model. Furthermore, Glide docking studies against PI3Kα demonstrated that the newly synthesized compounds accommodate PI3Kα kinase catalytic domain and form H-bonding with key binding residues. The series exhibited a potential PI3Kα inhibitory activity in HCT-116 cell line. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Novel Anthra[1,2-c][1,2,5]Thiadiazole-6,11-Diones as Promising Anticancer Lead Compounds: Biological Evaluation, Characterization & Molecular Targets Determination.

PubMed

Ali, Ahmed Atef Ahmed; Lee, Yu-Ru; Chen, Tsung-Chih; Chen, Chun-Liang; Lee, Chia-Chung; Shiau, Chia-Yang; Chiang, Chiao-Hsi; Huang, Hsu-Shan

2016-01-01

The novel compounds NSC745885 and NSC757963 developed at our laboratory were tested against a panel of 60 cancer cell lines at the National Cancer Institute, USA, and a panel of 39 cancer cell lines at the Japanese Foundation of Cancer Research. Both compounds demonstrated selective unique multi-log differential patterns of activity, with GI50 values in the sub-micro molar range against cancer cells rather than normal cardiac cells. NSC757963 showed high selectivity towards the leukemia subpanel. Activities of both compounds strongly correlated to expression of NFKB1 and CSNK2B genes, implying that they may inhibit the NF-κB pathway. Immunocytochemical microscopy of OVCAR-3 cells showed clear cytosolic accumulation of the NF-κB p65 subunit following treatment. Western blotting showed dose dependent inhibition of the nuclear expression of the NF-κB p65 subunit with subsequent accumulation in the cytosol following treatment. Docking experiments showed binding of both compounds to the NF-κB activator IKKβ subunit preventing its translocation to the nucleus. Collectively, these results confirm the ability of our compounds to inhibit the constitutively active NF-κB pathway of OVCAR-3 cells. Furthermore, COMPARE analysis indicated that the activity of NSC757963 is similar to the antituberculosis agent rifamycin SV, this was confirmed by testing the antimycobacterial activity of NSC757963 against Mycobacterium tuberculosis, results revealed potent activity suitable for use in clinical practice. Molecular properties and Lipinski's parameters predicted acceptable bioavailability properties with no indication of mutagenicity, tumorigenicity, irritability and reproductive effects. Oral absorption experiments using the human Caco-2 model showed high intestinal absorption of NSC745885 by passive transport mechanism with no intestinal efflux or active transport mechanisms. The unique molecular characterization as well as the illustrated anticancer spectra of activity and bioavailability properties warrant further development of our compounds and present a foundation brick in the pre-clinical investigations to implement such compounds in clinical practice.

Subthalamic Nucleus Stimulation and Dysarthria in Parkinson's Disease: A PET Study

ERIC Educational Resources Information Center

Pinto, Serge; Thobois, Stephane; Costes, Nicolas; Le Bars, Didier; Benabid, Alim-Louis; Broussolle, Emmanuel; Pollak, Pierre; Gentil, Michele

2004-01-01

In Parkinson's disease, functional imaging studies during limb motor tasks reveal cerebral activation abnormalities that can be reversed by subthalamic nucleus (STN) stimulation. The effect of STN stimulation on parkinsonian dysarthria has not, however, been investigated using PET. The aim of the present study was to evaluate the effect of STN…

Reversible inactivation and excitation of nucleus raphe magnus can modulate tail blood flow of male Wistar rats in response to hypothermia.

PubMed

Malakouti, Seyed Mansour; Kourosh Arami, Masoomeh; Sarihi, Abdorahman; Hajizadeh, Sohrab; Behzadi, Gila; Shahidi, Siamak; Komaki, Alireza; Heshmatian, Behnam; Vahabian, Mehrangiz

2008-10-01

The nucleus raphe magnus (NRM) is involved in thermoregulatory processing. There is a correlation between changes in the firing rates of the cells in the NRM and the application of the peripheral thermal stimulus. we examined the effect of reversible inactivation and excitation of NRM on mechanisms involved in tail blood flow (TBF) regulation in hypothermia. Hypothermia was induced in Male Wistar rats and cannula was implanted above the NRM. To evaluate the effect of nucleus inactivation on TBF, the amount of TBF was measured by Laser Doppler in hypothermic rats, before and after lidocaine microinjection into NRM. TBF was also measured after glutamate microinjection to assess the effect of nucleus excitation in hypothermic rats. Results indicated that after dropping TBF by hypothermia, microinjection of lidocaine into NRM significantly decreased TBF from 54.43 +- 5.7 to 46.81 +- 3.4, whereas glutamate microinjection caused a significant increase from 44.194 +- 0.6 to 98 +- 10.0 CONCLUSION: These data suggest that NRM have thermoregulatory effect in response to hypothermia.

The nucleus of Comet Borrelly: A study of morphology and surface brightness

USGS Publications Warehouse

Oberst, J.; Howington-Kraus, E.; Kirk, R.; Soderblom, L.; Buratti, B.; Hicks, M.; Nelson, R.; Britt, D.

2004-01-01

Stereo images obtained during the DS1 flyby were analyzed to derive a topographic model for the nucleus of Comet 19P/Borrelly for morphologic and photometric studies. The elongated nucleus has an overall concave shape, resembling a peanut, with the lower end tilted towards the camera. The bimodal character of surface-slopes and curvatures support the idea that the nucleus is a gravitational aggregate, consisting of two fragments in contact. Our photometric modeling suggests that topographic shading effects on Borrelly's surface are very minor (<10%) at the given resolution of the terrain model. Instead, albedo effects are thought to dominate Borrelly's large variations in surface brightness. With 90% of the visible surface having single scattering albedos between 0.008 and 0.024, Borrelly is confirmed to be among the darkest of the known Solar System objects. Photometrically corrected images emphasize that the nucleus has distinct, contiguous terrains covered with either bright or dark, smooth or mottled materials. Also, mapping of the changes in surface brightness with phase angle suggests that terrain roughness at subpixel scale is not uniform over the nucleus. High surface roughness is noted in particular near the transition between the upper and lower end of the nucleus, as well as near the presumed source region of Borrelly's main jets. Borrelly's surface is complex and characterized by distinct types of materials that have different compositional and/or physical properties. ?? 2003 Elsevier Inc. All rights reserved.

In Situ Live-Cell Nucleus Fluorescence Labeling with Bioinspired Fluorescent Probes.

PubMed

Ding, Pan; Wang, Houyu; Song, Bin; Ji, Xiaoyuan; Su, Yuanyuan; He, Yao

2017-08-01

Fluorescent imaging techniques for visualization of nuclear structure and function in live cells are fundamentally important for exploring major cellular events. The ideal cellular labeling method is capable of realizing label-free, in situ, real-time, and long-term nucleus labeling in live cells, which can fully obtain the nucleus-relative information and effectively alleviate negative effects of alien probes on cellular metabolism. However, current established fluorescent probes-based strategies (e.g., fluorescent proteins-, organic dyes-, fluorescent organic/inorganic nanoparticles-based imaging techniques) are unable to simultaneously realize label-free, in situ, long-term, and real-time nucleus labeling, resulting in inevitable difficulties in fully visualizing nuclear structure and function in live cells. To this end, we present a type of bioinspired fluorescent probes, which are highly efficacious for in situ and label-free tracking of nucleus in long-term and real-time manners. Typically, the bioinspired polydopamine (PDA) nanoparticles, served as fluorescent probes, can be readily synthesized in situ within live cell nucleus without any further modifications under physiological conditions (37 °C, pH ∼7.4). Compared with other conventional nuclear dyes (e.g., propidium iodide (PI), Hoechst), superior spectroscopic properties (e.g., quantum yield of ∼35.8% and high photostability) and low cytotoxicity of PDA-based probes enable long-term (e.g., 3 h) fluorescence tracking of nucleus. We also demonstrate the generality of this type of bioinspired fluorescent probes in different cell lines and complex biological samples.

Effects of aripiprazole on caffeine-induced hyperlocomotion and neural activation in the striatum.

PubMed

Batista, Luara A; Viana, Thércia G; Silveira, Vívian T; Aguiar, Daniele C; Moreira, Fabrício A

2016-01-01

Aripiprazole is an antipsychotic that acts as a partial agonist at dopamine D2 receptors. In addition to its antipsychotic activity, this compound blocks the effects of some psychostimulant drugs. It has not been verified, however, if aripiprazole interferes with the effects of caffeine. Hence, this study tested the hypothesis that aripiprazole prevents caffeine-induced hyperlocomotion and investigated the effects of these drugs on neural activity in the striatum. Male Swiss mice received injections of vehicle or antipsychotic drugs followed by vehicle or caffeine. Locomotion was analyzed in a circular arena and c-Fos protein expression was quantified in the dorsolateral, dorsomedial, and ventrolateral striatum, and in the core and shell regions of nucleus accumbens. Aripiprazole (0.1, 1, and 10 mg/kg) prevented caffeine (10 mg/kg)-induced hyperlocomotion at doses that do not change basal locomotion. Haloperidol (0.01, 0.03, and 0.1 mg/kg) also decreased caffeine-induced hyperlocomotion at all doses, although at the two higher doses, this compound reduced basal locomotion. Immunohistochemistry analysis showed that aripiprazole increases c-Fos protein expression in all regions studied, whereas caffeine did not alter c-Fos protein expression. Combined treatment of aripiprazole and caffeine resulted in a decrease in the number of c-Fos positive cells as compared to the group receiving aripiprazole alone. In conclusion, aripiprazole prevents caffeine-induced hyperlocomotion and increases neural activation in the striatum. This latter effect is reduced by subsequent administration of caffeine. These results advance our understanding on the pharmacological profile of aripiprazole.

Featured Article: Effect of copper on nuclear translocation of copper chaperone for superoxide dismutase-1

PubMed Central

Wang, Lin; Ge, Yan

2016-01-01

Copper chaperone for superoxide dismutase-1 (CCS-1), facilitating copper insertion into superoxide dismutase 1 (SOD-1), is present in the nucleus. However, it is unknown how CCS-1 is translocated to the nucleus. The present study was undertaken to determine the effect of copper on nuclear translocation of CCS-1. Human umbilical vein endothelial cells (HUVECs) were subjected to hypoxia, causing an increase in both copper and CCS-1 in the nucleus. Treatment with tetraethylenepentamine (TEPA) not only decreased the total cellular concentration and the nuclear translocation of copper, but also completely suppressed the entry of CCS-1 to the nucleus. On the other hand, siRNA targeting CCS-1 neither inhibited the increase in total concentrations nor blocked the nuclear translocation of copper. This study thus demonstrates that under hypoxia condition, both copper and CCS-1 are transported to the nucleus. The nuclear translocation of CCS-1 is copper dependent, but the nuclear translocation of copper could take place alternatively in a CCS-1-independent pathway. PMID:27190267

Nuclear Forensics and Radiochemistry: Fission

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rundberg, Robert S.

Radiochemistry has been used to study fission since it’ discovery. Radiochemical methods are used to determine cumulative mass yields. These measurements have led to the two-mode fission hypothesis to model the neutron energy dependence of fission product yields. Fission product yields can be used for the nuclear forensics of nuclear explosions. The mass yield curve depends on both the fuel and the neutron spectrum of a device. Recent studies have shown that the nuclear structure of the compound nucleus can affect the mass yield distribution.

Construction of New Potential Reactivators of Phosphonylated Acetylcholinesterase. Substitution of F for H in the Nucleus of Pyridinecarboxaldehyde Oximes.

DTIC Science & Technology

1983-11-01

essential to the content of the re- port and in all cases NMR data subjected to interpretation in this report have been entered in typography to...compared. In the Second Quarter reactions in the synthetic pathway to 3-F-2-PAM were scaled-up. Low yields were encountered for the specific nitration...oxime was synthetically achieved by way of the Markovac-Stevens-Ash-Hackley reaction , and the compound was characterized by its mass spectrum, NMR

Astrocytes potentiate GABAergic transmission in the thalamic reticular nucleus via endozepine signaling.

PubMed

Christian, Catherine A; Huguenard, John R

2013-12-10

Emerging evidence indicates that diazepam-binding inhibitor (DBI) mediates an endogenous benzodiazepine-mimicking (endozepine) effect on synaptic inhibition in the thalamic reticular nucleus (nRT). Here we demonstrate that DBI peptide colocalizes with both astrocytic and neuronal markers in mouse nRT, and investigate the role of astrocytic function in endozepine modulation in this nucleus by testing the effects of the gliotoxin fluorocitrate (FC) on synaptic inhibition and endozepine signaling in the nRT using patch-clamp recordings. FC treatment reduced the effective inhibitory charge of GABAA receptor (GABAAR)-mediated spontaneous inhibitory postsynaptic currents in WT mice, indicating that astrocytes enhance GABAAR responses in the nRT. This effect was abolished by both a point mutation that inhibits classical benzodiazepine binding to GABAARs containing the α3 subunit (predominant in the nRT) and a chromosomal deletion that removes the Dbi gene. Thus, astrocytes are required for positive allosteric modulation via the α3 subunit benzodiazepine-binding site by DBI peptide family endozepines. Outside-out sniffer patches pulled from neurons in the adjacent ventrobasal nucleus, which does not contain endozepines, show a potentiated response to laser photostimulation of caged GABA when placed in the nRT. FC treatment blocked the nRT-dependent potentiation of this response, as did the benzodiazepine site antagonist flumazenil. When sniffer patches were placed in the ventrobasal nucleus, however, subsequent treatment with FC led to potentiation of the uncaged GABA response, suggesting nucleus-specific roles for thalamic astrocytes in regulating inhibition. Taken together, these results suggest that astrocytes are required for endozepine actions in the nRT, and as such can be positive modulators of synaptic inhibition.

Astrocytes potentiate GABAergic transmission in the thalamic reticular nucleus via endozepine signaling

PubMed Central

Christian, Catherine A.; Huguenard, John R.

2013-01-01

Emerging evidence indicates that diazepam-binding inhibitor (DBI) mediates an endogenous benzodiazepine-mimicking (endozepine) effect on synaptic inhibition in the thalamic reticular nucleus (nRT). Here we demonstrate that DBI peptide colocalizes with both astrocytic and neuronal markers in mouse nRT, and investigate the role of astrocytic function in endozepine modulation in this nucleus by testing the effects of the gliotoxin fluorocitrate (FC) on synaptic inhibition and endozepine signaling in the nRT using patch-clamp recordings. FC treatment reduced the effective inhibitory charge of GABAA receptor (GABAAR)-mediated spontaneous inhibitory postsynaptic currents in WT mice, indicating that astrocytes enhance GABAAR responses in the nRT. This effect was abolished by both a point mutation that inhibits classical benzodiazepine binding to GABAARs containing the α3 subunit (predominant in the nRT) and a chromosomal deletion that removes the Dbi gene. Thus, astrocytes are required for positive allosteric modulation via the α3 subunit benzodiazepine-binding site by DBI peptide family endozepines. Outside-out sniffer patches pulled from neurons in the adjacent ventrobasal nucleus, which does not contain endozepines, show a potentiated response to laser photostimulation of caged GABA when placed in the nRT. FC treatment blocked the nRT-dependent potentiation of this response, as did the benzodiazepine site antagonist flumazenil. When sniffer patches were placed in the ventrobasal nucleus, however, subsequent treatment with FC led to potentiation of the uncaged GABA response, suggesting nucleus-specific roles for thalamic astrocytes in regulating inhibition. Taken together, these results suggest that astrocytes are required for endozepine actions in the nRT, and as such can be positive modulators of synaptic inhibition. PMID:24262146

Nigral stimulation for resistant axial motor impairment in Parkinson’s disease? A randomized controlled trial

PubMed Central

Walach, Margarete; Meisner, Christoph; Fritz, Melanie; Scholten, Marlieke; Breit, Sorin; Plewnia, Christian; Bender, Benjamin; Gharabaghi, Alireza; Wächter, Tobias

2013-01-01

Gait and balance disturbances typically emerge in advanced Parkinson’s disease with generally limited response to dopaminergic medication and subthalamic nucleus deep brain stimulation. Therefore, advanced programming with interleaved pulses was put forward to introduce concomittant nigral stimulation on caudal contacts of a subthalamic lead. Here, we hypothesized that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata improves axial symptoms compared with standard subthalamic nucleus stimulation. Twelve patients were enrolled in this 2 × 2 cross-over double-blind randomized controlled clinical trial and both the safety and efficacy of combined subthalamic nucleus and substantia nigra pars reticulata stimulation were evaluated compared with standard subthalamic nucleus stimulation. The primary outcome measure was the change of a broad-scaled cumulative axial Unified Parkinson’s Disease Rating Scale score (Scale II items 13–15, Scale III items 27–31) at ‘3-week follow-up’. Secondary outcome measures specifically addressed freezing of gait, balance, quality of life, non-motor symptoms and neuropsychiatric symptoms. For the primary outcome measure no statistically significant improvement was observed for combined subthalamic nucleus and substantia nigra pars reticulata stimulation at the ‘3-week follow-up’. The secondary endpoints, however, revealed that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata might specifically improve freezing of gait, whereas balance impairment remained unchanged. The combined stimulation of subthalamic nucleus and substantia nigra pars reticulata was safe, and of note, no clinically relevant neuropsychiatric adverse effect was observed. Patients treated with subthalamic nucleus and substantia nigra pars reticulata stimulation revealed no ‘global’ effect on axial motor domains. However, this study opens the perspective that concomittant stimulation of the substantia nigra pars reticulata possibly improves otherwise resistant freezing of gait and, therefore, highly warrants a subsequent phase III randomized controlled trial. PMID:23757762

Accelerator-driven boron neutron capture therapy

NASA Astrophysics Data System (ADS)

Edgecock, Rob

2014-05-01

Boron Neutron Capture Therapy is a binary treatment for certain types of cancer. It works by loading the cancerous cells with a boron-10 carrying compound. This isotope has a large cross-section for thermal neutrons, the reaction producing a lithium nucleus and alpha particle that kill the cell in which they are produced. Recent studies of the boron carrier compound indicate that the uptake process works best in particularly aggressive cancers. Most studied is glioblastoma multiforme and a trial using a combination of BNCT and X-ray radiotherapy has shown an increase of nearly a factor of two in mean survival over the state of the art. However, the main technical problem with BNCT remains producing a sufficient flux of neutrons for a reasonable treatment duration in a hospital environment. This paper discusses this issue.

Aromatic fluorine compounds. X. The 2,3- and 2,6-difluoropyridines

USGS Publications Warehouse

Finger, G.C.; Starr, L.D.; Roe, A.; Link, W.J.

1962-01-01

The preparation of difluoropyridines by the Schiemann reaction was investigated. 2-Amino-6-fluoropyridine (IIIa), necessary for the synthesis of 2,6-difluoropyridine (IVa) by the Schiemann reaction, was conveniently prepared by the Curtius degradation of 6-fluoropicolinic hydrazide (IIa) and by the Hofmann reaction on 6-fluoropicolinamide (IId). Since an ??-fluorine on a pyridine nucleus is preferentially replaced by hydrazine when it is either adjacent to or opposite a carbomethoxy group, the hydrazides necessary for the synthesis of 3-amino-2- and 6-fluoropyridine could not be prepared. These amines were prepared from the appropriate 2-fluoropyridinecarboxamide by the Hofmann reaction. The preparation of difluoropyridines was successful with two of the aminofluoropyridines and led to the following new compounds: 2,3-difluoro(IVb) and 2,6-difluoropyridine (IVa).

(14)N overtone transition in double rotation solid-state NMR.

PubMed

Haies, Ibraheem M; Jarvis, James A; Brown, Lynda J; Kuprov, Ilya; Williamson, Philip T F; Carravetta, Marina

2015-10-07

Solid-state NMR transitions involving outer energy levels of the spin-1 (14)N nucleus are immune, to first order in perturbation theory, to the broadening caused by the nuclear quadrupole interaction. The corresponding overtone spectra, when acquired in conjunction with magic-angle sample spinning, result in lines, which are just a few kHz wide, permitting the direct detection of nitrogen compounds without the need for labeling. Despite the success of this technique, "overtone" resonances are still broadened due to indirect, second order effects arising from the large quadrupolar interaction. Here we demonstrate that another order of magnitude in spectral resolution may be gained by using double rotation. This brings the width of the (14)N solid-state NMR lines much closer to the region commonly associated with high-resolution solid-state NMR spectroscopy of (15)N and demonstrates the improvements in resolution that may be possible through the development of pulsed methodologies to suppress these second order effects.

On the Extraction of Aromatic Compounds from Hydrocarbons by Imidazolium Ionic Liquids

PubMed Central

Cassol, Cláudia C.; Umpierre, Alexandre P.; Ebeling, Günter; Ferrera, Bauer; Chiaro, Sandra S. X.; Dupont, Jairton

2007-01-01

The liquid-liquid equilibrium for the ternary system formed by n-octane and aromatic (alkylbenzenes) and heteroaromatic compounds (nitrogen and sulfur containing heterocyles) and 1-alkyl-3-methylimidazolium ionic liquids (ILs) associated with various anions has been investigated. The selectivity on the extraction of a specific aromatic compound is influenced by anion volume, hydrogen bond strength between the anion and the imidazolium cation and the length of the 1-methyl-3-alkylimidazolium alkyl side chain. The interaction of alkylbenzenes and sulfur heterocyles with the IL is preferentially through CH-π hydrogen bonds and the quantity of these aromatics in the IL phase decreases with the increase of the steric hindrance imposed by the substituents on the aromatic nucleus. In the case of nitrogen heterocycles the interaction occurs preferentially through N(heteroaromatic)-H(imidazolium) hydrogen bonds and the extraction process is largely controlled by the nitrogen heterocycle pKa. Competitive extraction experiments suggest that benzene, pyridine and dibenzothiophene do not compete for the same hydrogen bond sites of the IL.

Determination of electron-nucleus collisions geometry with forward neutrons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zheng, L.; Aschenauer, E.; Lee, J. H.

2014-12-29

There are a large number of physics programs one can explore in electron-nucleus collisions at a future electron-ion collider. Collision geometry is very important in these studies, while the measurement for an event-by-event geometric control is rarely discussed in the prior deep-inelastic scattering experiments off a nucleus. This paper seeks to provide some detailed studies on the potential of tagging collision geometries through forward neutron multiplicity measurements with a zero degree calorimeter. As a result, this type of geometry handle, if achieved, can be extremely beneficial in constraining nuclear effects for the electron-nucleus program at an electron-ion collider.

Surface-peaked medium effects in the interaction of nucleons with finite nuclei

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aguayo, F. J.; Arellano, H. F.

We investigate the asymptotic separation of the optical model potential for nucleon-nucleus scattering in momentum space, where the potential is split into a medium-independent term and another depending exclusively on the gradient of the density-dependent g matrix. This decomposition confines the medium sensitivity of the nucleon-nucleus coupling to the surface of the nucleus. We examine this feature in the context of proton-nucleus scattering at beam energies between 30 and 100 MeV and find that the pn coupling accounts for most of this sensitivity. Additionally, based on this general structure of the optical potential we are able to treat both, themore » medium dependence of the effective interaction and the full mixed density as described by single-particle shell models. The calculated scattering observables agree within 10% with those obtained by Arellano, Brieva, and Love in their momentum-space g-folding approach.« less

l-tetrahydropalmatine reduces nicotine self-administration and reinstatement in rats.

PubMed

Faison, Shamia L; Schindler, Charles W; Goldberg, Steven R; Wang, Jia Bei

2016-11-07

The negative consequences of nicotine use are well known and documented, however, abstaining from nicotine use and achieving abstinence poses a major challenge for the majority of nicotine users trying to quit. l-Tetrahydropalmatine (l-THP), a compound extracted from the Chinese herb Corydalis, displayed utility in the treatment of cocaine and heroin addiction via reduction of drug-intake and relapse. The present study examined the effects of l-THP on abuse-related effects of nicotine. Self-administration and reinstatement testing was conducted. Rats trained to self-administer nicotine (0.03 mg/kg/injection) under a fixed-ratio 5 schedule (FR5) of reinforcement were pretreated with l-THP (3 or 5 mg/kg), varenicline (1 mg/kg), bupropion (40 mg/kg), or saline before daily 2-h sessions. Locomotor, food, and microdialysis assays were also conducted in separate rats. l-THP significantly reduced nicotine self-administration (SA). l-THP's effect was more pronounced than the effect of varenicline and similar to the effect of bupropion. In reinstatement testing, animals were pretreated with the same compounds, challenged with nicotine (0.3 mg/kg, s.c.), and reintroduced to pre-extinction conditions. l-THP blocked reinstatement of nicotine seeking more effectively than either varenicline or bupropion. Locomotor data revealed that therapeutic doses of l-THP had no inhibitory effects on ambulatory ability and that l-THP (3 and 5 mg/kg) significantly blocked nicotine induced hyperactivity when administered before nicotine. In in-vivo microdialysis experiments, l-THP, varenicline, and bupropion alone elevated extracellular dopamine (DA) levels in the nucleus accumbens shell (nAcb). Since l-THP reduces nicotine taking and blocks relapse it could be a useful alternative to varenicline and bupropion as a treatment for nicotine addiction.

Dynein-Based Accumulation of Membranes Regulates Nuclear Expansion in Xenopus laevis Egg Extracts.

PubMed

Hara, Yuki; Merten, Christoph A

2015-06-08

Nuclear size changes dynamically during development and has long been observed to correlate with the space surrounding the nucleus, as well as with the volume of the cell. Here we combine an in vitro cell-free system of Xenopus laevis egg extract with microfluidic devices to systematically analyze the effect of spatial constraints. The speed of nuclear expansion depended on the available space surrounding the nucleus up to a threshold volume in the nanoliter range, herein referred to as the nuclear domain. Under spatial constraints smaller than this nuclear domain, the size of microtubule-occupied space surrounding the nucleus turned out to be limiting for the accumulation of membranes around the nucleus via the motor protein dynein, therefore determining the speed of nuclear expansion. This mechanism explains how spatial information surrounding the nucleus, such as the positioning of the nucleus inside the cell, can control nuclear expansion. Copyright © 2015 Elsevier Inc. All rights reserved.

Finite Element Study of a Lumbar Intervertebral Disc Nucleus Replacement Device.

PubMed

Coogan, Jessica S; Francis, W Loren; Eliason, Travis D; Bredbenner, Todd L; Stemper, Brian D; Yoganandan, Narayan; Pintar, Frank A; Nicolella, Daniel P

2016-01-01

Nucleus replacement technologies are a minimally invasive alternative to spinal fusion and total disc replacement that have the potential to reduce pain and restore motion for patients with degenerative disc disease. Finite element modeling can be used to determine the biomechanics associated with nucleus replacement technologies. The current study focuses on a new nucleus replacement device designed as a conforming silicone implant with an internal void. A validated finite element model of the human lumbar L3-L4 motion segment was developed and used to investigate the influence of the nucleus replacement device on spine biomechanics. In addition, the effect of device design changes on biomechanics was determined. A 3D, L3-L4 finite element model was constructed from medical imaging data. Models were created with the normal intact nucleus, the nucleus replacement device, and a solid silicone implant. Probabilistic analysis was performed on the normal model to provide quantitative validation metrics. Sensitivity analysis was performed on the silicone Shore A durometer of the device. Models were loaded under axial compression followed by flexion/extension, lateral bending, or axial rotation. Compressive displacement, endplate stresses, reaction moment, and annulus stresses were determined and compared between the different models. The novel nucleus replacement device resulted in similar compressive displacement, endplate stress, and annulus stress and slightly higher reaction moment compared with the normal nucleus. The solid implant resulted in decreased displacement, increased endplate stress, decreased annulus stress, and decreased reaction moment compared with the novel device. With increasing silicone durometer, compressive displacement decreased, endplate stress increased, reaction moment increased, and annulus stress decreased. Finite element analysis was used to show that the novel nucleus replacement device results in similar biomechanics compared with the normal intact nucleus.

Finite Element Study of a Lumbar Intervertebral Disc Nucleus Replacement Device

PubMed Central

Coogan, Jessica S.; Francis, W. Loren; Eliason, Travis D.; Bredbenner, Todd L.; Stemper, Brian D.; Yoganandan, Narayan; Pintar, Frank A.; Nicolella, Daniel P.

2016-01-01

Nucleus replacement technologies are a minimally invasive alternative to spinal fusion and total disc replacement that have the potential to reduce pain and restore motion for patients with degenerative disc disease. Finite element modeling can be used to determine the biomechanics associated with nucleus replacement technologies. The current study focuses on a new nucleus replacement device designed as a conforming silicone implant with an internal void. A validated finite element model of the human lumbar L3–L4 motion segment was developed and used to investigate the influence of the nucleus replacement device on spine biomechanics. In addition, the effect of device design changes on biomechanics was determined. A 3D, L3–L4 finite element model was constructed from medical imaging data. Models were created with the normal intact nucleus, the nucleus replacement device, and a solid silicone implant. Probabilistic analysis was performed on the normal model to provide quantitative validation metrics. Sensitivity analysis was performed on the silicone Shore A durometer of the device. Models were loaded under axial compression followed by flexion/extension, lateral bending, or axial rotation. Compressive displacement, endplate stresses, reaction moment, and annulus stresses were determined and compared between the different models. The novel nucleus replacement device resulted in similar compressive displacement, endplate stress, and annulus stress and slightly higher reaction moment compared with the normal nucleus. The solid implant resulted in decreased displacement, increased endplate stress, decreased annulus stress, and decreased reaction moment compared with the novel device. With increasing silicone durometer, compressive displacement decreased, endplate stress increased, reaction moment increased, and annulus stress decreased. Finite element analysis was used to show that the novel nucleus replacement device results in similar biomechanics compared with the normal intact nucleus. PMID:27990418

Cytotoxicity Mechanism of Two Naphthoquinones (Menadione and Plumbagin) in Saccharomyces cerevisiae

PubMed Central

Castro, Frederico Augusto Vieira; Mariani, Diana; Panek, Anita Dolly; Eleutherio, Elis Cristina Araújo; Pereira, Marcos Dias

2008-01-01

Background Quinones are compounds extensively used in studies of oxidative stress due to their role in plants as chemicals for defense. These compounds are of great interest for pharmacologists and scientists, in general, because several cancer chemotherapeutic agents contain the quinone nucleus. However, due to differences in structures and diverse pharmacological effects, the exact toxicity mechanisms exerted by quinones are far from elucidatation. Methodology/Principal Findings Using Saccharomyces cerevisiae, we evaluated the main mechanisms of toxicity of two naphthoquinones, menadione and plumbagin, by determining tolerance and oxidative stress biomarkers such as GSH and GSSG, lipid peroxidation levels, as well as aconitase activity. The importance of glutathione transferases (GST) in quinone detoxification was also addressed. The GSSG/GSH ratio showed that menadione seemed to exert its toxicity mainly through the generation of ROS while plumbagin acted as an electrophile reacting with GSH. However, the results showed that, even by different pathways, both drugs were capable of generating oxidative stress through their toxic effects. Our results showed that the control strain, BY4741, and the glutathione transferase deficient strains (gtt1Δ and gtt2Δ) were sensitive to both compounds. With respect to the role of GST isoforms in cellular protection against quinone toxicity, we observed that the Gtt2 deficient strain was unable to overcome lipid peroxidation, even after a plumbagin pre-treatment, indicating that this treatment did not improve tolerance when compared with the wild type strain. Cross-tolerance experiments confirmed distinct cytotoxicity mechanisms for these naphthoquinones since only a pre-treatment with menadione was able to induce acquisition of tolerance against stress with plumbagin. Conclusions/Significance These results suggest different responses to menadione and plumbagin which could be due to the fact that these compounds use different mechanisms to exert their toxicity. In addition, the Gtt2 isoform seemed to act as a general protective factor involved in quinone detoxification. PMID:19098979

Salting out the polar polymorph: analysis by alchemical solvent transformation.

PubMed

Duff, Nathan; Dahal, Yuba Raj; Schmit, Jeremy D; Peters, Baron

2014-01-07

We computationally examine how adding NaCl to an aqueous solution with α- and γ-glycine nuclei alters the structure and interfacial energy of the nuclei. The polar γ-glycine nucleus in pure aqueous solution develops a melted layer of amorphous glycine around the nucleus. When NaCl is added, a double layer is formed that stabilizes the polar glycine polymorph and eliminates the surface melted layer. In contrast, the non-polar α-glycine nucleus is largely unaffected by the addition of NaCl. To quantify the stabilizing effect of NaCl on γ-glycine nuclei, we alchemically transform the aqueous glycine solution into a brine solution of glycine. The alchemical transformation is performed both with and without a nucleus in solution and for nuclei of α-glycine and γ-glycine polymorphs. The calculations show that adding 80 mg/ml NaCl reduces the interfacial free energy of a γ-glycine nucleus by 7.7 mJ/m(2) and increases the interfacial free energy of an α-glycine nucleus by 3.1 mJ/m(2). Both results are consistent with experimental reports on nucleation rates which suggest: J(α, brine) < J(γ, brine) < J(α, water). For γ-glycine nuclei, Debye-Hückel theory qualitatively, but not quantitatively, captures the effect of salt addition. Only the alchemical solvent transformation approach can predict the results for both polar and non-polar polymorphs. The results suggest a general "salting out" strategy for obtaining polar polymorphs and also a general approach to computationally estimate the effects of solvent additives on interfacial free energies for nucleation.

Histone deacetylase 3 indirectly modulates tubulin acetylation

PubMed Central

Bacon, Travis; Seiler, Caroline; Wolny, Marcin; Hughes, Ruth; Watson, Peter; Schwabe, John; Grigg, Ronald; Peckham, Michelle

2015-01-01

Histone deacetylase 3 (HDAC3), a member of the Class I subfamily of HDACs, is found in both the nucleus and the cytoplasm. Its roles in the nucleus have been well characterized, but its cytoplasmic roles are still not elucidated fully. We found that blocking HDAC3 activity using MI192, a compound specific for HDAC3, modulated tubulin acetylation in the human prostate cancer cell line PC3. A brief 1 h treatment of PC3 cells with MI192 significantly increased levels of tubulin acetylation and ablated the dynamic behaviour of microtubules in live cells. siRNA-mediated knockdown (KD) of HDAC3 in PC3 cells, significantly increased levels of tubulin acetylation, and overexpression reduced it. However, the active HDAC3–silencing mediator of retinoic and thyroid receptors (SMRT)–deacetylase-activating domain (DAD) complex did not directly deacetylate tubulin in vitro. These data suggest that HDAC3 indirectly modulates tubulin acetylation. PMID:26450925

On the Lamb shift in neutral muonic helium

NASA Astrophysics Data System (ADS)

Amusia, Miron; Karshenboim, Savely; Ivanov, Vladimir

2015-05-01

The neutral muonic helium is an exotic atomic system consisting of an electron, muon and a nucleus. We consider it as a hydrogen-like atom with a compound nucleus that is also hydrogen-like system. There are a number of corrections to the Bohr energy levels, which all can be treated as contributions of generic hydrogen-like theory. While the form of those contributions is the same for all hydrogen-like atoms, their relative numerical importance differs from an atom to an atom. Here, the leading contribution to the electronic Lamb shift in the neutral muonic helium is found in a close analytic form together with the most important corrections. We believe that the Lamb shift in the neutral muonic hydrogen is measurable, at least through a measurement of the electronic 1 s - 2 s transition. We present a theoretical prediction for the 1 s - 2 s transitions with the uncertainty of 2 ppm (4 GHz), as well as for the 2 s - 2 p Lamb shift with the uncertainty of 0.6 GHz.

Monte Carlo based toy model for fission process

NASA Astrophysics Data System (ADS)

Kurniadi, R.; Waris, A.; Viridi, S.

2014-09-01

There are many models and calculation techniques to obtain visible image of fission yield process. In particular, fission yield can be calculated by using two calculations approach, namely macroscopic approach and microscopic approach. This work proposes another calculation approach in which the nucleus is treated as a toy model. Hence, the fission process does not represent real fission process in nature completely. The toy model is formed by Gaussian distribution of random number that randomizes distance likesthe distance between particle and central point. The scission process is started by smashing compound nucleus central point into two parts that are left central and right central points. These three points have different Gaussian distribution parameters such as mean (μCN, μL, μR), and standard deviation (σCN, σL, σR). By overlaying of three distributions, the number of particles (NL, NR) that are trapped by central points can be obtained. This process is iterated until (NL, NR) become constant numbers. Smashing process is repeated by changing σL and σR, randomly.

Project Fog Drops. Part 2: Laboratory investigations

NASA Technical Reports Server (NTRS)

Kocmond, W. C.; Mack, E. J.; Katz, U.; Pilie, R. J.

1972-01-01

Measurements of the total nucleus concentration and cloud condensation nuclei (CCN) were acquired for several conditions representing both high normal and severe pollution levels for the Los Angeles Basin as well as clean filtered air. The data show that in filtered air there is a large photochemically induced increase in the total particle content within a few minutes after starting the lamp. The concentration of CCN remains near zero, until sufficient coagulation and condensation occurs on the smaller Aitken particles. The addition of gaseous pollutants to filtered air results in large increases in the photochemical production of both the cloud and Aitken nucleus concentration. Fogs were also generated under controlled, reproducible conditions in the cloud chamber and seeded with aerosols of various compounds which form monomolecular surface films at air-water interfaces. Visibility characteristics and droplet data were obtained. The data suggest that droplet growth on treated nuclei can be retarded but fog formation was not significantly altered by the chemical seeding.

D1 and D2 antagonists reverse the effects of appetite suppressants on weight loss, food intake, locomotion, and rebalance spiking inhibition in the rat NAc shell

PubMed Central

Kalyanasundar, B.; Perez, Claudia I.; Luna, Alvaro; Solorio, Jessica; Moreno, Mario G.; Elias, David; Simon, Sidney A.

2015-01-01

Obesity is a worldwide health problem that has reached epidemic proportions. To ameliorate this problem, one approach is the use of appetite suppressants. These compounds are frequently amphetamine congeners such as diethylpropion (DEP), phentermine (PHEN), and bupropion (BUP), whose effects are mediated through serotonin, norepinephrine, and dopaminergic pathways. The nucleus accumbens (NAc) shell receives dopaminergic inputs and is involved in feeding and motor activity. However, little is known about how appetite suppressants modulate its activity. Therefore, we characterized behavioral and neuronal NAc shell responses to short-term treatments of DEP, PHEN, and BUP. These compounds caused a transient decrease in weight and food intake while increasing locomotion, stereotypy, and insomnia. They evoked a large inhibitory imbalance in NAc shell spiking activity that correlated with the onset of locomotion and stereotypy. Analysis of the local field potentials (LFPs) showed that all three drugs modulated beta, theta, and delta oscillations. These oscillations do not reflect an aversive-malaise brain state, as ascertained from taste aversion experiments, but tracked both the initial decrease in weight and food intake and the subsequent tolerance to these drugs. Importantly, the appetite suppressant-induced weight loss and locomotion were markedly reduced by intragastric (and intra-NAc shell) infusions of dopamine antagonists SCH-23390 (D1 receptor) or raclopride (D2 receptor). Furthermore, both antagonists attenuated appetite suppressant-induced LFP oscillations and partially restored the imbalance in NAc shell activity. These data reveal that appetite suppressant-induced behavioral and neuronal activity recorded in the NAc shell depend, to various extents, on dopaminergic activation and thus point to an important role for D1/D2-like receptors (in the NAc shell) in the mechanism of action for these anorexic compounds. PMID:25972577

Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users.

PubMed

Gilman, Jodi M; Kuster, John K; Lee, Sang; Lee, Myung Joo; Kim, Byoung Woo; Makris, Nikos; van der Kouwe, Andre; Blood, Anne J; Breiter, Hans C

2014-04-16

Marijuana is the most commonly used illicit drug in the United States, but little is known about its effects on the human brain, particularly on reward/aversion regions implicated in addiction, such as the nucleus accumbens and amygdala. Animal studies show structural changes in brain regions such as the nucleus accumbens after exposure to Δ9-tetrahydrocannabinol, but less is known about cannabis use and brain morphometry in these regions in humans. We collected high-resolution MRI scans on young adult recreational marijuana users and nonusing controls and conducted three independent analyses of morphometry in these structures: (1) gray matter density using voxel-based morphometry, (2) volume (total brain and regional volumes), and (3) shape (surface morphometry). Gray matter density analyses revealed greater gray matter density in marijuana users than in control participants in the left nucleus accumbens extending to subcallosal cortex, hypothalamus, sublenticular extended amygdala, and left amygdala, even after controlling for age, sex, alcohol use, and cigarette smoking. Trend-level effects were observed for a volume increase in the left nucleus accumbens only. Significant shape differences were detected in the left nucleus accumbens and right amygdala. The left nucleus accumbens showed salient exposure-dependent alterations across all three measures and an altered multimodal relationship across measures in the marijuana group. These data suggest that marijuana exposure, even in young recreational users, is associated with exposure-dependent alterations of the neural matrix of core reward structures and is consistent with animal studies of changes in dendritic arborization.

Thioredoxin, thioredoxin reductase, and alpha-crystallin revive inactivated glyceraldehyde 3-phosphate dehydrogenase in human aged and cataract lens extracts.

PubMed

Yan, Hong; Lou, Marjorie F; Fernando, M Rohan; Harding, John J

2006-10-02

To investigate whether mammalian thioredoxin (Trx) and thioredoxin reductase (TrxR), with or without alpha-crystallin can revive inactivated glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in both the cortex and nucleus of human aged clear and cataract lenses. The lens cortex (including capsule-epithelium) and the nucleus were separated from human aged clear and cataract lenses (grade II and grade IV) with similar average age. The activity of GAPDH in the water-soluble fraction after incubation with or without Trx or/and TrxR for 60 min at 30 degrees C was measured spectrophotometrically. In addition, the effect of a combination of Trx/TrxR and bovine lens alpha-crystallin was investigated. GAPDH activity was lower in the nucleus of clear lenses than in the cortex, and considerably diminished in the cataractous lenses, particularly in the nucleus of cataract lenses grade IV. Trx and TrxR were able to revive the activity of GAPDH markedly in both the cortex and nucleus of the clear and cataract lenses. The percentage increase of activity in the cortex of the clear lenses was less than that of the nucleus in the presence of Trx and TrxR, whereas it was opposite in the cataract lenses. The revival of activity in both the cortex and nucleus from the cataract lenses grade II was higher than that of the grade IV. Moreover, Trx alone, but not TrxR, efficiently enhanced GAPDH activity. The combination of Trx and TrxR had greater effect than that of either alone. In addition, alpha(L)-crystallin enhanced the activity in the cortex of cataract grade II with Trx and TrxR present. However, it failed to provide a statistically significant increase of activity in the nucleus. This is the first evidence to show that mammalian Trx and TrxR are able to revive inactivated GAPDH in human aged clear and cataract lenses, and alpha-crystallin helped this effect. The inactivation of GAPDH during aging and cataract development must be caused in part by disulphide formation and in part by unfolding, and can be recovered by reducing agents and a molecular chaperone.

1,4-Bis(5-(naphthalen-1-yl)thiophen-2-yl)naphthalene, a small molecule, functions as a novel anti-HIV-1 inhibitor targeting the interaction between integrase and cellular Lens epithelium-derived growth factor.

PubMed

Gu, Wan-gang; Ip, Denis Tsz-Ming; Liu, Si-jie; Chan, Joseph H; Wang, Yan; Zhang, Xuan; Zheng, Yong-tang; Wan, David Chi-Cheong

2014-04-25

Translocation of viral integrase (IN) into the nucleus is a critical precondition of integration during the life cycle of HIV, a causative agent of Acquired Immunodeficiency Syndromes (AIDS). As the first discovered cellular factor to interact with IN, Lens epithelium-derived growth factor (LEDGF/p75) plays an important role in the process of integration. Disruption of the LEDGF/p75-IN interaction has provided a great interest for anti-HIV agent discovery. In this work, we reported that one small molecular compound, 1,4-bis(5-(naphthalen-1-yl)thiophen-2-yl)naphthalene(Compound 15), potently inhibit the IN-LEDGF/p75 interaction and affect the HIV-1 IN nuclear distribution at 1 μM. The putative binding mode of Compound 15 was constructed by a molecular docking simulation to provide structural insights into the ligand-binding mechanism. Compound 15 suppressed viral replication by measuring p24 antigen production in HIV-1IIIB acute infected C8166 cells with EC50 value of 11.19 μM. Compound 15 might supply useful structural information for further anti-HIV agent discovery. Copyright © 2014. Published by Elsevier Ireland Ltd.

Resting state functional MRI in Parkinson’s disease: the impact of deep brain stimulation on ‘effective’ connectivity

PubMed Central

Kahan, Joshua; Urner, Maren; Moran, Rosalyn; Flandin, Guillaume; Marreiros, Andre; Mancini, Laura; White, Mark; Thornton, John; Yousry, Tarek; Zrinzo, Ludvic; Hariz, Marwan; Limousin, Patricia; Friston, Karl

2014-01-01

Depleted of dopamine, the dynamics of the parkinsonian brain impact on both ‘action’ and ‘resting’ motor behaviour. Deep brain stimulation has become an established means of managing these symptoms, although its mechanisms of action remain unclear. Non-invasive characterizations of induced brain responses, and the effective connectivity underlying them, generally appeals to dynamic causal modelling of neuroimaging data. When the brain is at rest, however, this sort of characterization has been limited to correlations (functional connectivity). In this work, we model the ‘effective’ connectivity underlying low frequency blood oxygen level-dependent fluctuations in the resting Parkinsonian motor network—disclosing the distributed effects of deep brain stimulation on cortico-subcortical connections. Specifically, we show that subthalamic nucleus deep brain stimulation modulates all the major components of the motor cortico-striato-thalamo-cortical loop, including the cortico-striatal, thalamo-cortical, direct and indirect basal ganglia pathways, and the hyperdirect subthalamic nucleus projections. The strength of effective subthalamic nucleus afferents and efferents were reduced by stimulation, whereas cortico-striatal, thalamo-cortical and direct pathways were strengthened. Remarkably, regression analysis revealed that the hyperdirect, direct, and basal ganglia afferents to the subthalamic nucleus predicted clinical status and therapeutic response to deep brain stimulation; however, suppression of the sensitivity of the subthalamic nucleus to its hyperdirect afferents by deep brain stimulation may subvert the clinical efficacy of deep brain stimulation. Our findings highlight the distributed effects of stimulation on the resting motor network and provide a framework for analysing effective connectivity in resting state functional MRI with strong a priori hypotheses. PMID:24566670

Acoustic vibration effects in classical nucleation theory

NASA Astrophysics Data System (ADS)

Baird, James K.; Su, C.-H.

2018-04-01

Acoustic vibration is often used to improve the yield of crystals and nanoparticles growing from solutions and melts. As there is still a debate on how acoustic vibration actually works, we have examined the possibility that acoustic pressure can affect the rate of nucleation. Our method is based on an expansion of the free energy of the nucleus in powers of the acoustic pressure. With the assumption that the period of the sound wave is short as compared to the time scale for nucleation, we replace the powers of the acoustic pressure by their time averages, retaining the average of the square of the acoustic pressure as the leading term. By assuming a nucleus having spherical shape, we use the Young-Laplace equation to relate the pressure inside the nucleus to the ambient pressure. Without making further approximations not already standard in classical nucleation theory, we find that the proximate effect of acoustic pressure is to reduce both the size of the critical nucleus as well as the work required to form it from monomers. As the work serves as the activation energy, the ultimate effect of acoustic pressure is to increase the rate of nucleation. If we assume that the atomic structure of the nucleus is the same as that of an ordinary solid, however, we find the compressibility is too small for acoustic vibration effects to be noticeable. If on the other hand, we assume that the structure is similar to that of a loosely bound colloidal particle, then the effects of acoustic vibration become potentially observable.

Radiochemistry and the Study of Fission

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rundberg, Robert S.

These are slides from a lecture given at UC Berkeley. Radiochemistry has been used to study fission since its discovery. Radiochemical methods are used to determine cumulative mass yields. These measurements have led to the two-mode fission hypothesis to model the neutron energy dependence of fission product yields. Fission product yields can be used for the nuclear forensics of nuclear explosions. The mass yield curve depends on both the fuel and the neutron spectrum of a device. Recent studies have shown that the nuclear structure of the compound nucleus can affect the mass yield distribution. The following topics are covered:more » In the beginning: the discovery of fission; forensics using fission products: what can be learned from fission products, definitions of R-values and Q-values, fission bases, K-factors and fission chambers, limitations; the neutron energy dependence of the mass yield distribution (the two mode fission hypothesis); the influence of nuclear structure on the mass yield distribution. In summary: Radiochemistry has been used to study fission since its discovery. Radiochemical measurement of fission product yields have provided the highest precision data for developing fission models and for nuclear forensics. The two-mode fission hypothesis provides a description of the neutron energy dependence of the mass yield curve. However, data is still rather sparse and more work is needed near second and third chance fission. Radiochemical measurements have provided evidence for the importance of nuclear states in the compound nucleus in predicting the mass yield curve in the resonance region.« less

Selective Cooperation between Fatty Acid Binding Proteins and Peroxisome Proliferator-Activated Receptors in Regulating Transcription

PubMed Central

Tan, Nguan-Soon; Shaw, Natacha S.; Vinckenbosch, Nicolas; Liu, Peng; Yasmin, Rubina; Desvergne, Béatrice; Wahli, Walter; Noy, Noa

2002-01-01

Lipophilic compounds such as retinoic acid and long-chain fatty acids regulate gene transcription by activating nuclear receptors such as retinoic acid receptors (RARs) and peroxisome proliferator-activated receptors (PPARs). These compounds also bind in cells to members of the family of intracellular lipid binding proteins, which includes cellular retinoic acid-binding proteins (CRABPs) and fatty acid binding proteins (FABPs). We previously reported that CRABP-II enhances the transcriptional activity of RAR by directly targeting retinoic acid to the receptor. Here, potential functional cooperation between FABPs and PPARs in regulating the transcriptional activities of their common ligands was investigated. We show that adipocyte FABP and keratinocyte FABP (A-FABP and K-FABP, respectively) selectively enhance the activities of PPARγ and PPARβ, respectively, and that these FABPs massively relocate to the nucleus in response to selective ligands for the PPAR isotype which they activate. We show further that A-FABP and K-FABP interact directly with PPARγ and PPARβ and that they do so in a receptor- and ligand-selective manner. Finally, the data demonstrate that the presence of high levels of K-FABP in keratinocytes is essential for PPARβ-mediated induction of differentiation of these cells. Taken together, the data establish that A-FABP and K-FABP govern the transcriptional activities of their ligands by targeting them to cognate PPARs in the nucleus, thereby enabling PPARs to exert their biological functions. PMID:12077340

Bitter-responsive brainstem neurons: characteristics and functions.

PubMed

Travers, Susan P; Geran, Laura C

2009-07-14

The sensation that humans describe as "bitter" is evoked by a large group of chemically diverse ligands. Bitter stimuli are avoided by a range of species and elicit reflex rejection, behaviors considered adaptations to the toxicity of many of these compounds. We review novel evidence for neurons that are narrowly tuned to bitter ligands at the initial stages of central processing. These "B-best" neurons in the nucleus of the solitary tract (NST) and parabrachial nucleus (PBN) respond to multiple types of bitter stimuli and exhibit average responses to bitter tastants that are 6-8 times larger than to moderate concentrations of compounds representing other qualities. However, in the PBN B-best units are appreciably activated by intense salt and acid. Neurons broadly sensitive to salts and acids ("AN" neurons) also responded to bitter stimuli. This sensitivity appeared restricted to stronger intensities of ionic bitters, as cycloheximide remained ineffective across concentrations. In addition to chemosensitive profile, B-best neurons were also distinctive with regard to their posterior receptive fields, long latencies, slow firing rates and projection status. Compared to B-best NST cells, those in the PBN received increased convergence from anterior and posterior receptive fields and responded to a greater number of bitter stimuli. We conclude that B-best neurons likely contribute to pathways underlying gaping, aversive hedonic quality and taste coding. The differential responsiveness of B-best and AN neurons to ionic and nonionic bitter ligands also suggests a potential substrate for discrimination within this quality.

Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression.

PubMed

Yang, Bangkun; Zhang, Ji-Chun; Han, Mei; Yao, Wei; Yang, Chun; Ren, Qian; Ma, Min; Chen, Qian-Xue; Hashimoto, Kenji

2016-10-01

The N-methyl-D-aspartate (NMDA) receptor antagonists, including R-ketamine and rapastinel (formerly GLYX-13), show rapid antidepressant effects in animal models of depression. We compared the rapid and sustained antidepressant effects of R-ketamine and rapastinel in the social defeat stress model. In the tail suspension and forced swimming tests, R-ketamine (10 mg/kg, intraperitoneal (i.p.)) or rapastinel (10 mg/kg, i.p.) significantly attenuated the increased immobility time in the susceptible mice, compared with the vehicle-treated group. In the sucrose preference test, both compounds significantly enhanced the reduced preference in susceptible mice 2, 4, or 7 days after a single injection. All mice were sacrificed 8 days after a single injection. Western blot analyses showed that R-ketamine, but not rapastinel, significantly attenuated the reduced brain-derived neurotrophic factor (BDNF)-TrkB signaling, postsynaptic density protein 95 (PSD-95), and GluA1 (a subtype of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor) in the prefrontal cortex, dentate gyrus, and CA3 of the hippocampus in the susceptible mice. In contrast, both compounds had no effect against the increased BDNF-TrkB signaling, PSD-95, and GluA1 seen in the nucleus accumbens of susceptible mice. Moreover, sustained antidepressant effect of R-ketamine (3 mg/kg, intravenous (i.v.)), but not rapastinel (3 mg/kg, i.v.), was detected 7 days after a single dose. These results highlight R-ketamine as a longer lasting antidepressant compared with rapastinel in social defeat stress model. It is likely that synaptogenesis including BDNF-TrkB signaling in the prefrontal cortex (PFC) and hippocampus may be required for the mechanisms promoting this sustained antidepressant effect.

Synthesis and Biological Evaluation of 2-Methyl-4,5-Disubstituted Oxazoles as a Novel Class of Highly Potent Antitubulin Agents

PubMed Central

Romagnoli, Romeo; Baraldi, Pier Giovanni; Prencipe, Filippo; Oliva, Paola; Baraldi, Stefania; Salvador, Maria Kimatrai; Lopez-Cara, Luisa Carlota; Brancale, Andrea; Ferla, Salvatore; Hamel, Ernest; Ronca, Roberto; Bortolozzi, Roberta; Mariotto, Elena; Porcù, Elena; Basso, Giuseppe; Viola, Giampietro

2017-01-01

Antimitotic agents that interfere with microtubule formation are one of the major classes of cytotoxic drugs for cancer treatment. Multiple 2-methyl-4-(3′,4′,5′-trimethoxyphenyl)-5-substituted oxazoles and their related 4-substituted-5-(3′,4′,5′-trimethoxyphenyl) regioisomeric derivatives designed as cis-constrained combretastatin A-4 (CA-4) analogues were synthesized and evaluated for their antiproliferative activity in vitro against a panel of cancer cell lines and, for selected highly active compounds, interaction with tubulin, cell cycle effects and in vivo potency. Both these series of compounds were characterized by the presence of a common 3′,4′,5′-trimethoxyphenyl ring at either the C-4 or C-5 position of the 2-methyloxazole ring. Compounds 4g and 4i, bearing a m-fluoro-p-methoxyphenyl or p-ethoxyphenyl moiety at the 5-position of 2-methyloxazole nucleus, respectively, exhibited the greatest antiproliferative activity, with IC50 values of 0.35-4.6 nM (4g) and 0.5–20.2 nM (4i), which are similar to those obtained with CA-4. These compounds bound to the colchicine site of tubulin and inhibited tubulin polymerization at submicromolar concentrations. Furthermore, 4i strongly induced apoptosis that follows the mitochondrial pathway. In vivo, 4i in a mouse syngeneic model demonstrated high antitumor activity which significantly reduced the tumor mass at doses ten times lower than that required for CA-4P, suggesting that 4i warrants further evaluation as a potential anticancer drug. PMID:28406191

Effects of Nucleus Basalis Magnocellularis Stimulation on a Socially Transmitted Food Preference and c-Fos Expression

ERIC Educational Resources Information Center

Boix-Trelis, Nuria; Vale-Martinez, Anna; Guillazo-Blanch, Gemma; Costa-Miserachs, David; Marti-Nicolovius, Margarita

2006-01-01

Experiment 1 examined the effects of electrical stimulation of nucleus basalis magnocellularis (NBM) on a relational odor-association task--the social transmission of food preference (STFP). Rats were stimulated unilaterally in the NBM for 20 min (100 [mu]A, 1 Hz) immediately before the social training. They were tested on their ability to…

Characterization of beta-phenylethylamine-induced monoamine release in rat nucleus accumbens: a microdialysis study.

PubMed

Nakamura, M; Ishii, A; Nakahara, D

1998-05-22

In vivo microdialysis was used to investigate the effect of beta-phenylethylamine on extracellular levels of monoamines and their metabolites in the nucleus accumbens of conscious rats. At all doses tested (1, 10 and 100 microM), infusion of beta-phenylethylamine through the microdialysis probe significantly increased extracellular levels of dopamine in the nucleus accumbens. These increases were dose-related. The increase in dopamine levels induced by 100 microM beta-phenylethylamine was not affected by co-perfusion of 4 microM tetrodotoxin. The ability of 100 microM beta-phenylethylamine to increase the extracellular level of dopamine was comparable to that of the same dose of methamphetamine. On the other hand, beta-phenylethylamine had a much less potent enhancing effect on 5-hydroxytryptamine (5-HT) than dopamine levels. Only the highest dose (100 microM) caused a statistically significant effect on 5-HT levels. Over the dose range tested (1, 10 and 100 microM), beta-phenylethylamine had no effect on extracellular metabolite levels of dopamine and 5-HT. The results suggest that beta-phenylethylamine increases the efflux of monoamines, preferentially dopamine, without affecting monoamine metabolism, in the nucleus accumbens.

Opposite roles for neuropeptide S in the nucleus accumbens and bed nucleus of the stria terminalis in learned helplessness rats.

PubMed

Shirayama, Yukihiko; Ishima, Tamaki; Oda, Yasunori; Okamura, Naoe; Iyo, Masaomi; Hashimoto, Kenji

2015-09-15

The role of neuropeptide S (NPS) in depression remains unclear. We examined the antidepressant-like effects of NPS infusions into the shell or core regions of the nucleus accumbens (NAc) and into the bed nucleus of the stria terminalis (BNST) of learned helplessness (LH) rats (an animal model of depression). Infusions of NPS (10 pmol/side) into the NAc shell, but not the NAc core and BNST, exerted antidepressant-like effects in the LH paradigm. Implying that behavioral deficits could be improved in the conditioned avoidance test. Coinfusion of SHA68 (an NPS receptor antagonist, 100 pmol/side) with NPS into the NAc shell blocked these effects. In contrast, NPS receptor antagonism by SHA68 in the BNST induced antidepressant-like effects. Infusions of NPS into the NAc shell or SHA68 into the BNST did not produce memory deficits or locomotor activation in the passive avoidance and open field tests. These results suggest that excitatory and inhibitory actions by the NPS system are integral to the depression in LH animals. Copyright © 2015 Elsevier B.V. All rights reserved.

FISH Finder: a high-throughput tool for analyzing FISH images

PubMed Central

Shirley, James W.; Ty, Sereyvathana; Takebayashi, Shin-ichiro; Liu, Xiuwen; Gilbert, David M.

2011-01-01

Motivation: Fluorescence in situ hybridization (FISH) is used to study the organization and the positioning of specific DNA sequences within the cell nucleus. Analyzing the data from FISH images is a tedious process that invokes an element of subjectivity. Automated FISH image analysis offers savings in time as well as gaining the benefit of objective data analysis. While several FISH image analysis software tools have been developed, they often use a threshold-based segmentation algorithm for nucleus segmentation. As fluorescence signal intensities can vary significantly from experiment to experiment, from cell to cell, and within a cell, threshold-based segmentation is inflexible and often insufficient for automatic image analysis, leading to additional manual segmentation and potential subjective bias. To overcome these problems, we developed a graphical software tool called FISH Finder to automatically analyze FISH images that vary significantly. By posing the nucleus segmentation as a classification problem, compound Bayesian classifier is employed so that contextual information is utilized, resulting in reliable classification and boundary extraction. This makes it possible to analyze FISH images efficiently and objectively without adjustment of input parameters. Additionally, FISH Finder was designed to analyze the distances between differentially stained FISH probes. Availability: FISH Finder is a standalone MATLAB application and platform independent software. The program is freely available from: http://code.google.com/p/fishfinder/downloads/list Contact: gilbert@bio.fsu.edu PMID:21310746

[Comparative study of effects of cortical nucleus of amygdala and pyriform cortex on activity of bulbar respiratory neurons in cats].

PubMed

Nersesian, L B; Eganova, V S; Pogosian, N L; Avetisian, I N

2011-01-01

Comparative microelectrophysiological study of character and peculiarities of effects of the cortical nucleus of amygdala and of the periamygdalar area of pyriform cortex on impulse activity was performed on the same single functionally identified respiratory medullar neurons. A high reactivity of bulbar respiratory neurons on stimulation is established in both studied limbic structures. There is established the qualitatively different character of their response reactions at stimulation of the cortical amygdala nucleus and the periamygdalar cortex. The cortical amygdala nucleus has been shown to produce on the activity of medullar respiratory neurons both facilitating and inhibitory action with predominance of the activating one (without topographical orderliness). The effect of periamygdalar cortex at stimulation of various parts was characterized by topographic differentiation. The suppressing reactions of neurons in the majority of cases were recorded at stimulation of the rostral area of periamygdalar cortex, whereas the excitatory reactions--at stimulation of its caudal part. Functional organization of respiratory control of the studied limbic system structures is discussed.

Acute and repeated ECS treatment increases CRF, POMC and PENK gene expression in selected regions of the rat hypothalamus.

PubMed

Garcia-Garcia, L; Llewellyn-Jones, V; Fernandez Fernandez, I; Fuentes, J A; Manzanares, J

1998-01-05

The purpose of this study was to investigate the effects of acute and repeated electroconvulsive shock (ECS) on corticotropin releasing factor (CRF), proopiomelanocortin (POMC) and proenkephalin (PENK) gene expression in selected regions of the brain and pituitary of the rat. Acute ECS increased CRF gene expression in the paraventricular nucleus (PVN) by 20%, an effect that was further enhanced to 38% when rats received repeated ECS treatment. Acute and repeated ECS increased POMC gene expression in the arcuate nucleus (ARC) by 49-59% but failed to alter these mRNA levels in the anterior lobe (AL) of the pituitary gland. PENK gene expression was increased by 35% in the nucleus accumbens (NA) and by 180% the ventromedial nucleus (VMN) after acute or repeated ECS treatment but no significant changes were found in the PVN or striatum (ST). Taken together, these results indicate a differential CRF and opioid gene expression regulation after acute or repeated ECS treatment that may be relevant to their therapeutic or side effects in depression.

Nitric oxide facilitates GABAergic neurotransmission in the cat oculomotor system: a physiological mechanism in eye movement control

PubMed Central

Moreno-López, Bernardo; Escudero, Miguel; Estrada, Carmen

2002-01-01

Nitric oxide (NO) synthesis by prepositus hypoglossi (PH) neurons is necessary for the normal performance of horizontal eye movements. We have previously shown that unilateral injections of NO synthase (NOS) inhibitors into the PH nucleus of alert cats produce velocity imbalance without alteration of the eye position control, both during spontaneous eye movements and the vestibulo-ocular reflex (VOR). This NO effect is exerted on the dorsal PH neuropil, whose fibres increase their cGMP content when stimulated by NO. In an attempt to determine whether NO acts by modulation of a specific neurotransmission system, we have now compared the oculomotor effects of NOS inhibition with those produced by local blockade of glutamatergic, GABAergic or glycinergic receptors in the PH nucleus of alert cats. Both glutamatergic antagonists used, 2-amino-5-phosphonovaleric acid (APV) and 2,3-dihydro-6-nitro-7-sulphamoyl-benzo quinoxaline (NBQX), induced a nystagmus contralateral to that observed upon NOS inhibition, and caused exponential eye position drift. In contrast, bicuculline and strychnine induced eye velocity alterations similar to those produced by NOS inhibitors, suggesting that NO oculomotor effects were due to facilitation of some inhibitory input to the PH nucleus. To investigate the anatomical location of the putative NO target neurons, the retrograde tracer Fast Blue was injected in one PH nucleus, and the brainstem sections containing Fast Blue-positive neurons were stained with double immunohistochemistry for NO-sensitive cGMP and glutamic acid decarboxylase. GABAergic neurons projecting to the PH nucleus and containing NO-sensitive cGMP were found almost exclusively in the ipsilateral medial vestibular nucleus and marginal zone. The results suggest that the nitrergic PH neurons control their own firing rate by a NO-mediated facilitation of GABAergic afferents from the ipsilateral medial vestibular nucleus. This self-control mechanism could play an important role in the maintenance of the vestibular balance necessary to generate a stable and adequate eye position signal. PMID:11927688

Targeting tubulin polymerization by novel 7-aryl-pyrroloquinolinones: Synthesis, biological activity and SARs.

PubMed

Bortolozzi, Roberta; Mattiuzzo, Elena; Dal Pra, Matteo; Sturlese, Mattia; Moro, Stefano; Hamel, Ernest; Carta, Davide; Viola, Giampietro; Ferlin, Maria Grazia

2018-01-01

Earlier studies had confirmed that the 7-phenylpyrroloquinolinone (7-PPyQ) nucleus was an important scaffold for new chemotherapeutic drugs targeting microtubules. For wide-ranging SARs, a series of derivatives were synthesized through a robust procedure. For comparison with the reference 3-ethyl-7-PPyQ 31, the angular geometry and substituents at the 3 and 7 positions were varied to explore interactions inside the colchicine site of tubulin. Of the new compounds synthesized, potent cytotoxicity (low and sub-nanomolar GI 50 values) was observed with 21 and 24, both more potent than 31, in both leukemic and solid tumor cell lines. Neither compound 21 nor 24 induced significant cell death in normal human lymphocytes, suggesting that the compounds may be selectively active against cancer cells. In particular, 24 was a potent inducer of apoptosis in the A549 and HeLa cell lines. With both compounds, induction of apoptosis was associated with dissipation of the mitochondrial transmembrane potential and production of reactive oxygen species, indicating that cells treated with the compounds followed the intrinsic pathway of apoptosis. Moreover, immunoblot analysis revealed that compound 24 even at 50 nM reduced the expression of anti-apoptotic proteins such as Bcl-2 and Mcl-1. Finally, molecular docking studies of the newly synthesized compounds demonstrate that active pyrroloquinolinone derivatives strongly bind in the colchicine site of β-tubulin. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Giant dipole resonance and shape transitions in hot and rotating 88Mo

NASA Astrophysics Data System (ADS)

Rhine Kumar, A. K.; Arumugam, P.; Dang, N. Dinh; Mazumdar, I.

2017-08-01

The giant dipole resonance (GDR) observables are calculated within the thermal shape fluctuation model by considering the probability distributions of different angular momentum (I ) and temperature (T ) values estimated recently in the deexcitation process of the compound nucleus 88Mo. These results are found to be very similar to the results obtained with the average T (Tave) and average I (Iave) corresponding to those distributions. The shape transitions in 88Mo at different T and I are also studied through the free energy surfaces calculated within the microscopic-macroscopic approach. The deformation of 88Mo is found to increase considerably with T and I , leading to the Jacobi shape transition at I ˜50 ℏ . The combined effect of increasing deformation, larger fluctuations at higher T , and larger Coriolis splitting of GDR components at higher I , leads to a rapid increase in the GDR width.

Design, synthesis, and biological evaluation of the first podophyllotoxin analogues as potential vascular-disrupting agents.

PubMed

Labruère, Raphaël; Gautier, Benoît; Testud, Marlène; Seguin, Johanne; Lenoir, Christine; Desbène-Finck, Stéphanie; Helissey, Philippe; Garbay, Christiane; Chabot, Guy G; Vidal, Michel; Giorgi-Renault, Sylviane

2010-12-03

We designed and synthesized two novel series of azapodophyllotoxin analogues as potential antivascular agents. A linker was inserted between the trimethoxyphenyl ring E and the tetracyclic ABCD moiety of the 4-aza-1,2-didehydropodophyllotoxins. In the first series, the linker enables free rotation between the two moieties; in the second series, conformational restriction of the E nucleus was considered. We have identified several new compounds with inhibitory activity toward tubulin polymerization similar to that of CA-4 and colchicine, while displaying low cytotoxic activity against normal and/or cancer cells. An aminologue and a methylenic analogue were shown to disrupt endothelial cell cords on Matrigel at subtoxic concentrations, and an original assay of drug washout allowed us to demonstrate the rapid reversibility of this effect. These two new analogues are promising leads for the development of vascular-disrupting agents in the podophyllotoxin series.

SPY: A new scission point model based on microscopic ingredients to predict fission fragments properties

NASA Astrophysics Data System (ADS)

Lemaître, J.-F.; Dubray, N.; Hilaire, S.; Panebianco, S.; Sida, J.-L.

2013-12-01

Our purpose is to determine fission fragments characteristics in a framework of a scission point model named SPY for Scission Point Yields. This approach can be considered as a theoretical laboratory to study fission mechanism since it gives access to the correlation between the fragments properties and their nuclear structure, such as shell correction, pairing, collective degrees of freedom, odd-even effects. Which ones are dominant in final state? What is the impact of compound nucleus structure? The SPY model consists in a statistical description of the fission process at the scission point where fragments are completely formed and well separated with fixed properties. The most important property of the model relies on the nuclear structure of the fragments which is derived from full quantum microscopic calculations. This approach allows computing the fission final state of extremely exotic nuclei which are inaccessible by most of the fission model available on the market.

Subthalamic nucleus stimulation influences expression and suppression of impulsive behaviour in Parkinson’s disease

PubMed Central

Ridderinkhof, K. Richard; Elias, William J.; Frysinger, Robert C.; Bashore, Theodore R.; Downs, Kara E.; van Wouwe, Nelleke C.; van den Wildenberg, Wery P. M.

2010-01-01

Past studies show beneficial as well as detrimental effects of subthalamic nucleus deep-brain stimulation on impulsive behaviour. We address this paradox by investigating individuals with Parkinson’s disease treated with subthalamic nucleus stimulation (n = 17) and healthy controls without Parkinson’s disease (n = 17) on performance in a Simon task. In this reaction time task, conflict between premature response impulses and goal-directed action selection is manipulated. We applied distributional analytic methods to separate the strength of the initial response impulse from the proficiency of inhibitory control engaged subsequently to suppress the impulse. Patients with Parkinson’s disease were tested when stimulation was either turned on or off. Mean conflict interference effects did not differ between controls and patients, or within patients when stimulation was on versus off. In contrast, distributional analyses revealed two dissociable effects of subthalamic nucleus stimulation. Fast response errors indicated that stimulation increased impulsive, premature responding in high conflict situations. Later in the reaction process, however, stimulation improved the proficiency with which inhibitory control was engaged to suppress these impulses selectively, thereby facilitating selection of the correct action. This temporal dissociation supports a conceptual framework for resolving past paradoxical findings and further highlights that dynamic aspects of impulse and inhibitory control underlying goal-directed behaviour rely in part on neural circuitry inclusive of the subthalamic nucleus. PMID:20861152

Characteristics study of projectile's lightest fragment for 84Kr36-emulsion interaction at around 1 A GeV

NASA Astrophysics Data System (ADS)

Marimuthu, N.; Singh, V.; Inbanathan, S. S. R.

2017-04-01

In this article, we present the results of our investigations on the projectile's lightest fragment (proton) multiplicity and probability distributions with 84Kr36 emulsion collision at around 1 A GeV. The multiplicity and normalized multiplicity of projectile's lightest fragment (proton) are correlated with the compound particles, shower particles, black particles, grey particles; alpha (helium nucleus) fragments and heavily ionizing charged particles. It is found that projectile's lightest fragment (proton) is strongly correlated with compound particles and shower particles rather than other particles and the average multiplicity of projectile's lightest fragment (proton) increases with increasing compound, shower and heavily ionizing charge particles. Normalized projectile's lightest fragment (proton) is strongly correlated with compound particles, shower particles and heavily ionizing charge particles. The multiplicity distribution of the projectile's lightest fragment (proton) emitted in the 84Kr36 + emulsion interaction at around 1 A GeV with different target has been well explained by KNO scaling. The mean multiplicity of projectile's lightest fragments (proton) depends on the mass number of the projectile and does not significantly dependent of the projectile energy. The mean multiplicity of projectile's lightest fragment (proton) increases with increasing the target mass number.

c-Met must translocate to the nucleus to initiate calcium signals.

PubMed

Gomes, Dawidson A; Rodrigues, Michele A; Leite, M Fatima; Gomez, Marcus V; Varnai, Peter; Balla, Tamas; Bennett, Anton M; Nathanson, Michael H

2008-02-15

Hepatocyte growth factor (HGF) is important for cell proliferation, differentiation, and related activities. HGF acts through its receptor c-Met, which activates downstream signaling pathways. HGF binds to c-Met at the plasma membrane, where it is generally believed that c-Met signaling is initiated. Here we report that c-Met rapidly translocates to the nucleus upon stimulation with HGF. Ca(2+) signals that are induced by HGF result from phosphatidylinositol 4,5-bisphosphate hydrolysis and inositol 1,4,5-trisphosphate formation within the nucleus rather than within the cytoplasm. Translocation of c-Met to the nucleus depends upon the adaptor protein Gab1 and importin beta1, and formation of Ca(2+) signals in turn depends upon this translocation. HGF may exert its particular effects on cells because it bypasses signaling pathways in the cytoplasm to directly activate signaling pathways in the nucleus.

Nuclear translocation of proteins and the effect of phosphatidic acid.

PubMed

Yao, Hongyan; Wang, Geliang; Wang, Xuemin

2014-01-01

Transport of proteins containing a nuclear localization signal (NLS) into the nucleus is mediated by nuclear transport receptors called importins, typically dimmers of a cargo-binding α-subunit and a β-subunit that mediates translocation through the nuclear pore complexes (NPCs). However, how proteins without canonical NLS move into the nucleus is not well understood. Recent results indicate that phospholipids, such as phosphatidic acid, play important roles in the intracellular translocation of proteins between the nucleus and cytoplasm.

Nuclear translocation of proteins and the effect of phosphatidic acid

PubMed Central

Yao, Hongyan; Wang, Geliang; Wang, Xuemin

2014-01-01

Transport of proteins containing a nuclear localization signal (NLS) into the nucleus is mediated by nuclear transport receptors called importins, typically dimmers of a cargo-binding α-subunit and a β-subunit that mediates translocation through the nuclear pore complexes (NPCs). However, how proteins without canonical NLS move into the nucleus is not well understood. Recent results indicate that phospholipids, such as phosphatidic acid, play important roles in the intracellular translocation of proteins between the nucleus and cytoplasm. PMID:25482760

[The effect of tachykinins microinjections into the solitary tract nucleus on respiration and blood circulation in rats].

PubMed

Chepurnov, S A; Iniushkin, A N

1997-04-01

Administration of substance P and kassinin into the solitary tract nucleus of anesthetized rats induced a dose-dependent increase in ventilation, tidal volume, inspiratory muscle activity, and a decrease in the mean blood pressure and heart rate. Microinjections of peptides caused a decrease in ventilatory response to hypoxia and an inhibition of the Breuer-Hering reflex. The data obtained suggest involvement of tachykinins in the respiratory and circulatory control via the solitary tract nucleus.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lappi, T.; Schenke, B.; Schlichting, S.

Here we examine the origins of azimuthal correlations observed in high energy proton-nucleus collisions by considering the simple example of the scattering of uncorrelated partons off color fields in a large nucleus. We demonstrate how the physics of fluctuating color fields in the color glass condensate (CGC) effective theory generates these azimuthal multiparticle correlations and compute the corresponding Fourier coefficients v n within different CGC approximation schemes. We discuss in detail the qualitative and quantitative differences between the different schemes. Lastly, we will show how a recently introduced color field domain model that captures key features of the observed azimuthalmore » correlations can be understood in the CGC effective theory as a model of non-Gaussian correlations in the target nucleus.« less

[Local GABA-ergic modulation of serotonergic neuron activity in the nucleus raphe magnus].

PubMed

Iniushkin, A N; Merkulova, N A; Orlova, A O; Iniushkina, E M

2009-07-01

In voltage-clamp experimental on slices of the rat brainstem the effects of 5-HT and GABA on serotonergic neurons of nucleus raphe magnus were investigated. Local applications of 5-HT induced an increase in IPCSs frequency and amplitude in 45% of serotonergic cells. The effect suppressed by the blocker of fast sodium channels tetradotoxin. Antagonist of GABA receptor gabazine blocked IPSCs in neurons both sensitive and non-sensitive to 5-HT action. Applications of GABA induced a membrane current (I(GABA)), which was completely blocked by gabazine. The data suggest self-control of the activity of serotonergic neurons in nucleus raphe magnus by negative feedback loop via local GABAergic interneurons.

Radioprotective Thiolamines WR-1065 and WR-33278 Selectively Denature Nonhistone Nuclear Proteins

NASA Technical Reports Server (NTRS)

Booth, Valerie K.; Roberts, Jeanette C.; Warters, Raymond L.; Wilmore, Britta H.; Lepock, James R.

2000-01-01

Differential scanning calorimetry was used to study the interactions of nuclei isolated from Chinese hamster V79 cells with the radioprotector WR-1065, other thiol compounds, and polyamines. Differential scanning calorimetry monitors denaturation of macromolecules and resolves the major nuclear components (e.g. constrained and relaxed DNA, nucleosome core, and nuclear matrix) of intact nuclei on the basis of thermal stability. WR-1065 treatment (0.5-10 mM) of isolated nuclei led to the irreversible denaturation of nuclear proteins, a fraction of which are nuclear matrix proteins. Denaturation of 50% of the total nonhistone nuclear protein content of isolated nuclei occurred after exposure to 4.7 mM WR-1065 for 20 min at 23 C. In addition, a 22% increase in the insoluble protein content of nuclei isolated from V79 cells that had been treated with 4 mM WR-1065 for 30 min at 37 C was observed, indicating that WR-1065-induced protein denaturation occurs not only in isolated nuclei but also in the nuclei of intact cells. From the extent of the increase in insoluble protein in the nucleus, protein denaturation by WR-1065 is expected to contribute to drug toxicity at concentrations greater than approximately 4 mM. WR-33278, the disulfide form of WR1065, was approximately twice as effective as the free thiol at denaturing nuclear proteins. The proposed mechanism for nucleoprotein denaturation is through direct interactions with protein cysteine groups with the formation of destabilizing protein-WR-1065 disulfides. In comparison to its effect on nuclear proteins in isolated nuclei, WR-1065 had only a very small effect on non-nuclear proteins of whole cells, isolated nuclear matrix, or the thiol-rich Ca (2+) ATPase of sarcoplasmic reticulum, indicating that WR-1065 can effectively denature protein only inside an intact nucleus, probably due to the increased concentration of the positively charged drug in the vicinity of DNA.

Benzomorphan scaffold for opioid analgesics and pharmacological tools development: A comprehensive review.

PubMed

Turnaturi, Rita; Marrazzo, Agostino; Parenti, Carmela; Pasquinucci, Lorella

2018-03-25

Benzomorphan, derived by morphine skeleton simplification, has been the subject of exploration in medicinal chemistry for the development of new drugs and pharmacological tools to explore opioid pharmacology in vitro and in vivo. Building upon these evidences, the design and synthesis of benzomorphan-based compounds, appropriately modified at the basic nitrogen and/or the phenolic hydroxyl (8-OH) group, represent a valid and versatile strategy to obtain analgesics. In this review, to improve the body of information in this field, we report structure activity-relationships (SARs) of benzomorphan-based compounds analysing data literature of last 25 years. Collectively, SARs data highlighted that the benzomorphan nucleus represents a template in the achievement of a specific functional profile, by modifying N-substituent or 8-OH group. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Uncertainties and understanding of experimental and theoretical results regarding reactions forming heavy and superheavy nuclei

NASA Astrophysics Data System (ADS)

Giardina, G.; Mandaglio, G.; Nasirov, A. K.; Anastasi, A.; Curciarello, F.; Fazio, G.

2018-02-01

Experimental and theoretical results of the PCN fusion probability of reactants in the entrance channel and the Wsur survival probability against fission at deexcitation of the compound nucleus formed in heavy-ion collisions are discussed. The theoretical results for a set of nuclear reactions leading to formation of compound nuclei (CNs) with the charge number Z = 102- 122 reveal a strong sensitivity of PCN to the characteristics of colliding nuclei in the entrance channel, dynamics of the reaction mechanism, and excitation energy of the system. We discuss the validity of assumptions and procedures for analysis of experimental data, and also the limits of validity of theoretical results obtained by the use of phenomenological models. The comparison of results obtained in many investigated reactions reveals serious limits of validity of the data analysis and calculation procedures.

EPR investigation of gamma-irradiated L-citrulline, α-methyl-DL-serine, 3-fluoro-DL-valine and N-acetyl-L-cysteine

NASA Astrophysics Data System (ADS)

Osmanoğlu, Y. Emre; Sütçü, Kerem; Başkan, M. Halim

2017-02-01

The spectroscopic parameters of the paramagnetic species produced in gamma-irradiated L-citrulline, α-methyl-DL-serine, 3-fluoro-DL-valine and N-acetyl-L-cysteine were investigated at room temperature at a dose of 20 kGy by using EPR technique. The paramagnetic species were attributed to NH2CONH(CH2)3ĊNH2COOH, HOCH2ĊCH3COOH and HOĊHCCH3NH2COOH, CH3CH3ĊCHNH2COOH and SHCH2ĊNHCOCH3COOH radicals, respectively. EPR data of the unpaired electron with the environmental protons and 14N nucleus were used to characterize the contributing radicals produced in gamma irradiated compounds. In this paper, the stability of these compounds at room temperature after irradiation was also studied.

Random-matrix approach to the statistical compound nuclear reaction at low energies using the Monte-Carlo technique [PowerPoint

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kawano, Toshihiko

2015-11-10

This theoretical treatment of low-energy compound nucleus reactions begins with the Bohr hypothesis, with corrections, and various statistical theories. The author investigates the statistical properties of the scattering matrix containing a Gaussian Orthogonal Ensemble (GOE) Hamiltonian in the propagator. The following conclusions are reached: For all parameter values studied, the numerical average of MC-generated cross sections coincides with the result of the Verbaarschot, Weidenmueller, Zirnbauer triple-integral formula. Energy average and ensemble average agree reasonably well when the width I is one or two orders of magnitude larger than the average resonance spacing d. In the strong-absorption limit, the channel degree-of-freedommore » ν a is 2. The direct reaction increases the inelastic cross sections while the elastic cross section is reduced.« less

Multiconfigurational nature of 5f orbitals in uranium and plutonium intermetallics

PubMed Central

Booth, C.H.; Jiang, Yu; Wang, D.L.; Mitchell, J.N.; Tobash, P.H.; Bauer, E.D.; Wall, M.A.; Allen, P.G.; Sokaras, D.; Nordlund, D.; Weng, T.-C.; Torrez, M.A.; Sarrao, J.L.

2012-01-01

Uranium and plutonium’s 5f electrons are tenuously poised between strongly bonding with ligand spd-states and residing close to the nucleus. The unusual properties of these elements and their compounds (e.g., the six different allotropes of elemental plutonium) are widely believed to depend on the related attributes of f-orbital occupancy and delocalization for which a quantitative measure is lacking. By employing resonant X-ray emission spectroscopy (RXES) and X-ray absorption near-edge structure (XANES) spectroscopy and making comparisons to specific heat measurements, we demonstrate the presence of multiconfigurational f-orbital states in the actinide elements U and Pu and in a wide range of uranium and plutonium intermetallic compounds. These results provide a robust experimental basis for a new framework toward understanding the strongly-correlated behavior of actinide materials. PMID:22706643

Synthesis and nematocide activity of S-glycopyranosyl-6,7-diarylthiolumazines.

PubMed

Martins Alho, Miriam A; D'Accorso, Norma B; Ochoa, Carmen; Castro, Ana; Calderón, Félix; Chana, Antonio; Reviriego, Felipe; Páez, Juan Antonio; Campillo, Nuria E; Martínez-Grueiro, Mercedes; López-Santa Cruz, Ana María; Martínez, Antonio R

2004-08-15

6,7-Diaryl derivatives of mono and di-S-glycopyranosylthiolumazine derivatives 5-8 were prepared to test their nematocide activity. In vitro tests against Caenorhabditis elegans were performed and it was found that monosubstituted derivatives 5-7 showed higher activity than the corresponding unsubstituted 2-thiolumazines 1-3, whilst 2-S,4-S-di-glycopyranosylpteridine derivative 8 was inactive in contrast to unsubstituted derivative 4. In order to check whether the lack of activity of 8 was due to the two bulky substituents of the pteridine nucleus, 2-S,4-S-dimethyl derivative 9 was synthesized and assayed showing also lack of activity. A theoretical study on the stability of the different possible tautomers of compound 4 was carried out in an attempt to explain some, in appearance, anomalous (13)C NMR data of this compound.

Benzomorphan skeleton, a versatile scaffold for different targets: A comprehensive review.

PubMed

Turnaturi, Rita; Montenegro, Lucia; Marrazzo, Agostino; Parenti, Rosalba; Pasquinucci, Lorella; Parenti, Carmela

2018-06-07

Despite the fact that the benzomorphan skeleton has mainly been employed in medicinal chemistry for the development of opioid analgesics, it is a versatile structure. Its stereochemistry, as well as opportune modifications at the phenolic hydroxyl group and at the basic nitrogen, play a pivotal role addressing the benzomorphan-based compounds to a specific target. In this review, we describe the structure activity-relationships (SARs) of benzomorphan-based compounds acting at sigma 1 receptor (σ1R), sigma 2 receptor (σ2R), voltage-dependent sodium channel, N-Methyl-d-Aspartate (NMDA) receptor-channel complex and other targets. Collectively, the SARs data have highlighted that the benzomorphan nucleus could be regarded as a useful template for the synthesis of drug candidates for different targets. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Effect of novel atypical antipsychotic, blonanserin, on extracellular neurotransmitter level in rat prefrontal cortex.

PubMed

Ohoyama, Keiko; Yamamura, Satoshi; Hamaguchi, Tatsuya; Nakagawa, Masanori; Motomura, Eishi; Shiroyama, Takashi; Tanii, Hisashi; Okada, Motohiro

2011-02-25

To clarify the mechanisms of action of blonanserin, an atypical antipsychotic drug, we studied the effects of systemic administration of blonanserin and risperidone on extracellular levels of norepinephrine, dopamine, serotonin, GABA and glutamate in the medial prefrontal cortex using microdialysis, and neuronal firing in the ventral tegmental area, locus coeruleus, dorsal raphe nucleus and mediodorsal thalamic nucleus using radiotelemetry. The binding affinities of blonanserin to D(2) and 5-HT(2A) receptors in the rat brain were confirmed and found to be similar. Blonanserin transiently increased neuronal firing in locus coeruleus and ventral tegmental area but not in dorsal raphe nucleus or mediodorsal thalamic nucleus, whereas risperidone increased the firing in locus coeruleus, ventral tegmental area and dorsal raphe nucleus but not in mediodorsal thalamic nucleus. Blonanserin persistently increased frontal extracellular levels of norepinephrine and dopamine but not serotonin, GABA or glutamate, whereas risperidone persistently increased those of norepinephrine, dopamine and serotonin but not GABA or glutamate. These results suggest a pharmacological correlation between the stimulatory effects of these antipsychotics on frontal monoamine release and neuronal activity in monoaminergic nuclei. Inhibition of the α(2) adrenoceptor increased extracellular monoamine levels and enhanced blonanserin-induced increase in extracellular serotonin level. These results indicated that the combination of antagonism of D(2) and 5-HT(2A) receptors contribute to the rise in extracellular levels of norepinephrine and dopamine, and that α(2) adrenoceptors play important roles in frontal serotonin release. They also suggest that blonanserin-induced activation of monoaminergic transmission could be, at least partially, involved in atypical antipsychotic properties of blonanserin. Copyright © 2010 Elsevier B.V. All rights reserved.

Temperature-induced labelling of Fluo-3 AM selectively yields brighter nucleus in adherent cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meng, Guixian; Pan, Leiting, E-mail: plt@nankai.edu.cn; Li, Cunbo

2014-01-17

Highlights: •We detailedly examine temperature effects of Fluo-3 AM labelling in adherent cells. •4 °C Loading and 20 °C de-esterification of Fluo-3 AM yields brighter nuclei. •Brighter nuclei labelling by Fluo-3 AM also depends on cell adhesion quality. •A qualitative model of the brighter nucleus is proposed. -- Abstract: Fluo-3 is widely used to study cell calcium. Two traditional approaches: (1) direct injection and (2) Fluo-3 acetoxymethyl ester (AM) loading, often bring conflicting results in cytoplasmic calcium ([Ca{sup 2+}]{sub c}) and nuclear calcium ([Ca{sup 2+}]{sub n}) imaging. AM loading usually yields a darker nucleus than in cytoplasm, while direct injectionmore » always induces a brighter nucleus which is more responsive to [Ca{sup 2+}]{sub n} detection. In this work, we detailedly investigated the effects of loading and de-esterification temperatures on the fluorescence intensity of Fluo-3 in response to [Ca{sup 2+}]{sub n} and [Ca{sup 2+}]{sub c} in adherent cells, including osteoblast, HeLa and BV2 cells. Interestingly, it showed that fluorescence intensity of nucleus in osteoblast cells was about two times larger than that of cytoplasm when cells were loaded with Fluo-3 AM at 4 °C and allowed a subsequent step for de-esterification at 20 °C. Brighter nuclei were also acquired in HeLa and BV2 cells using the same experimental condition. Furthermore, loading time and adhesion quality of cells had effect on fluorescence intensity. Taken together, cold loading and room temperature de-esterification treatment of Fluo-3 AM selectively yielded brighter nucleus in adherent cells.« less

Heavy-flavour and quarkonium production in the LHC era: from proton-proton to heavy-ion collisions

DOE PAGES

Andronic, A.; Arleo, F.; Arnaldi, R.; ...

2016-02-29

This report reviews the study of open heavy-flavour and quarkonium production in high-energy hadronic collisions, as tools to investigate fundamental aspects of Quantum Chromodynamics, from the proton and nucleus structure at high energy to deconfinement and the properties of the Quark-Gluon Plasma. Emphasis is given to the lessons learnt from LHC Run 1 results, which are reviewed in a global picture with the results from SPS and RHIC at lower energies, as well as to the questions to be addressed in the future. The report covers heavy flavour and quarkonium production in proton-proton, proton-nucleus and nucleus-nucleus collisions. This includes discussionmore » of the effects of hot and cold strongly interacting matter, quarkonium photo-production in nucleus-nucleus collisions and perspectives on the study of heavy flavour and quarkonium with upgrades of existing experiments and new experiments. The report results from the activity of the SaporeGravis network of the I3 Hadron Physics programme of the European Union 7th Framework Programme.« less

Single neurons in the nucleus of the solitary tract respond selectively to bitter taste stimuli.

PubMed

Geran, Laura C; Travers, Susan P

2006-11-01

Molecular data suggest that receptors for all bitter ligands are coexpressed in the same taste receptor cells (TRCs), whereas physiological results indicate that individual TRCs respond to only a subset of bitter stimuli. It is also unclear to what extent bitter-responsive neurons are stimulated by nonbitter stimuli. To explore these issues, single neuron responses were recorded from the rat nucleus of the solitary tract (NST) during whole mouth stimulation with a variety of bitter compounds: 10 microM cycloheximide, 7 mM propylthiouracil, 10 mM denatonium benzoate, and 3 mM quinine hydrochloride at intensities matched for behavioral effectiveness. Stimuli representing the remaining putative taste qualities were also tested. Particular emphasis was given to activating taste receptors in the foliate papillae innervated by the quinine-sensitive glossopharyngeal nerve. This method revealed a novel population of bitter-best (B-best) cells with foliate receptive fields and significant selectivity for bitter tastants. Across all neurons, multidimensional scaling depicted bitter stimuli as loosely clustered yet clearly distinct from nonbitter tastants. When neurons with posterior receptive fields were analyzed alone, bitter stimuli formed a tighter cluster. Nevertheless, responses to bitter stimuli were variable across B-best neurons, with cycloheximide the most, and quinine the least frequent optimal stimulus. These results indicate heterogeneity for the processing of ionic and nonionic bitter tastants, which is dependent on receptive field. Further, they suggest that neurons selective for bitter substances could contribute to taste coding.

Pitch Variability in Patients with Parkinson's Disease: Effects of Deep Brain Stimulation of Caudal Zona Incerta and Subthalamic Nucleus

ERIC Educational Resources Information Center

Karlsson, Fredrik; Olofsson, Katarina; Blomstedt, Patric; Linder, Jan; van Doorn, Jan

2013-01-01

Purpose: The purpose of the present study was to examine the effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) and the caudal zona incerta (cZi) pitch characteristics of connected speech in patients with Parkinson's disease (PD). Method: The authors evaluated 16 patients preoperatively and 12 months after DBS surgery. Eight…

Intracellular Physiology of the Rat Suprachiasmatic Nucleus: Electrical Properties, Neurotransmission, and Effects of Neuromodulators.

DTIC Science & Technology

1992-08-24

Rat Suprachiasmatic Nucleus: Electrical Properties, Neurotransmission, and Effects of Neuromodulators 12. PERSONAL AUTHOR(S) F. Edward Dudek 13a...intrinsic electrical properties, synaptic and non-synaptic transmission, and neuromodulation . We have studied the role of excitatory and inhibitory amino... Neuromodulation : Smithson. K.G.. MacVicar. B.A. and Hatton. G.I. (1983) The Biochemical Control of Neuronal Excitability. Oxford Polyethylene glycol

Charge radius of the 13N* proton halo nucleus with Halo Effective Field Theory

NASA Astrophysics Data System (ADS)

Mosavi Khansari, M.; Khalili, H.; Sadeghi, H.

2018-02-01

We evaluated the charge radius of the first excited state of 13N with halo Effective Field Theory (hEFT) at the low energies. The halo effective field theory without pion is used to examine the halo nucleus bound state with a large S-wave scattering length. We built Lagrangian from the effective core and the valence proton of the fields and obtained the charge form factor at Leading-Order (LO). The charge radius at leading order for the first excited state of the proton halo nucleus, 13N, has been estimated as rc = 2.52 fm. This result is without any finite-size contributions included from the core and the proton. If we consider the contributions of the charge radius of the proton and the core, the result will be [rC]13N* = 5.85 fm.

Interplay between presynaptic and postsynaptic activities is required for dendritic plasticity and synaptogenesis in the supraoptic nucleus.

PubMed

Chevaleyre, Vivien; Moos, Francoise C; Desarménien, Michel G

2002-01-01

Developing oxytocin and vasopressin (OT/AVP) supraoptic nucleus (SON) neurons positively autocontrol their electrical activity via dendritic release of their respective peptide. The effects of this autocontrol are maximum during the second postnatal week (PW2), when the dendritic arbor transiently increases and glutamatergic postsynaptic potentials appear. Here, we studied the role and interaction of dendritic OT/AVP release and glutamate release in dendritic plasticity and synaptogenesis in SON. In vivo treatment with the peptides antagonists or with an NMDA antagonist suppressed the transient increase in dendritic arbor of SON neurons at the beginning of PW2. Incubation of acute slices with these compounds decreased the dendritic arbor on a short time scale (3-8 hr) in slices of postnatal day 7 (P7) to P9 rats. Conversely, application of OT/AVP or NMDA increased dendritic branches in slices of P3-P6 rats. Their effects were inhibited by blockade of electrical activity, voltage-gated Ca2+ channels, or intracellular Ca2+ mobilization. They were also interdependent because both OT/AVP and NMDA (but not AMPA) receptor activation were required for increasing the dendritic arbor. Part of this interdependence probably results from a retrograde action of the peptides facilitating glutamate release. Finally, blocking OT/AVP receptors by in vivo treatment with the peptides antagonists during development decreased spontaneous glutamatergic synaptic activity recorded in young adults. These results show that an interplay between postsynaptic dendritic peptide release and presynaptic glutamate release is involved in the transient increase in dendritic arbor of SON neurons and indicate that OT/AVP are required for normal synaptogenesis of glutamatergic inputs in SON.

Decisional impulsivity and the associative-limbic subthalamic nucleus in obsessive-compulsive disorder: stimulation and connectivity

PubMed Central

Voon, Valerie; Droux, Fabien; Morris, Laurel; Chabardes, Stephan; Bougerol, Thierry; David, Olivier; Krack, Paul; Polosan, Mircea

2017-01-01

Abstract Why do we make hasty decisions for short-term gain? Rapid decision-making with limited accumulation of evidence and delay discounting are forms of decisional impulsivity. The subthalamic nucleus is implicated in inhibitory function but its role in decisional impulsivity is less well-understood. Here we assess decisional impulsivity in subjects with obsessive compulsive disorder who have undergone deep brain stimulation of the limbic and associative subthalamic nucleus. We show that stimulation of the subthalamic nucleus is causally implicated in increasing decisional impulsivity with less accumulation of evidence during probabilistic uncertainty and in enhancing delay discounting. Subthalamic stimulation shifts evidence accumulation in subjects with obsessive-compulsive disorder towards a functional less cautious style closer to that of healthy controls emphasizing its adaptive nature. Thus, subjects with obsessive compulsive disorder on subthalamic stimulation may be less likely to check for evidence (e.g. checking that the stove is on) with no difference in subjective confidence (or doubt). In a separate study, we replicate in humans (154 healthy controls) using resting state functional connectivity, tracing studies conducted in non-human primates dissociating limbic, associative and motor frontal hyper-direct connectivity with anterior and posterior subregions of the subthalamic nucleus. We show lateralization of functional connectivity of bilateral ventral striatum to right anterior ventromedial subthalamic nucleus consistent with previous observations of lateralization of emotionally evoked activity to right ventral subthalamic nucleus. We use a multi-echo sequence with independent components analysis, which has been shown to have enhanced signal-to-noise ratio, thus optimizing visualization of small subcortical structures. These findings in healthy controls converge with the effective contacts in obsessive compulsive disorder patients localized within the anterior and ventral subthalamic nucleus. We further show that evidence accumulation is associated with anterior associative-limbic subthalamic nucleus and right dorsolateral prefrontal functional connectivity in healthy controls, a region implicated in decision-making under uncertainty. Together, our findings highlight specificity of the anterior associative-limbic subthalamic nucleus in decisional impulsivity. Given increasing interest in the potential for subthalamic stimulation in psychiatric disorders and the neuropsychiatric symptoms of Parkinson’s disease, these findings have clinical implications for behavioural symptoms and cognitive effects as a function of localization of subthalamic stimulation. PMID:28040671

Decisional impulsivity and the associative-limbic subthalamic nucleus in obsessive-compulsive disorder: stimulation and connectivity.

PubMed

Voon, Valerie; Droux, Fabien; Morris, Laurel; Chabardes, Stephan; Bougerol, Thierry; David, Olivier; Krack, Paul; Polosan, Mircea

2017-02-01

Why do we make hasty decisions for short-term gain? Rapid decision-making with limited accumulation of evidence and delay discounting are forms of decisional impulsivity. The subthalamic nucleus is implicated in inhibitory function but its role in decisional impulsivity is less well-understood. Here we assess decisional impulsivity in subjects with obsessive compulsive disorder who have undergone deep brain stimulation of the limbic and associative subthalamic nucleus. We show that stimulation of the subthalamic nucleus is causally implicated in increasing decisional impulsivity with less accumulation of evidence during probabilistic uncertainty and in enhancing delay discounting. Subthalamic stimulation shifts evidence accumulation in subjects with obsessive-compulsive disorder towards a functional less cautious style closer to that of healthy controls emphasizing its adaptive nature. Thus, subjects with obsessive compulsive disorder on subthalamic stimulation may be less likely to check for evidence (e.g. checking that the stove is on) with no difference in subjective confidence (or doubt). In a separate study, we replicate in humans (154 healthy controls) using resting state functional connectivity, tracing studies conducted in non-human primates dissociating limbic, associative and motor frontal hyper-direct connectivity with anterior and posterior subregions of the subthalamic nucleus. We show lateralization of functional connectivity of bilateral ventral striatum to right anterior ventromedial subthalamic nucleus consistent with previous observations of lateralization of emotionally evoked activity to right ventral subthalamic nucleus. We use a multi-echo sequence with independent components analysis, which has been shown to have enhanced signal-to-noise ratio, thus optimizing visualization of small subcortical structures. These findings in healthy controls converge with the effective contacts in obsessive compulsive disorder patients localized within the anterior and ventral subthalamic nucleus. We further show that evidence accumulation is associated with anterior associative-limbic subthalamic nucleus and right dorsolateral prefrontal functional connectivity in healthy controls, a region implicated in decision-making under uncertainty. Together, our findings highlight specificity of the anterior associative-limbic subthalamic nucleus in decisional impulsivity. Given increasing interest in the potential for subthalamic stimulation in psychiatric disorders and the neuropsychiatric symptoms of Parkinson's disease, these findings have clinical implications for behavioural symptoms and cognitive effects as a function of localization of subthalamic stimulation. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.

Non-Natural Linker Configuration in 2,6-Dipeptidyl-Anthraquinones Enhances the Inhibition of TAR RNA Binding/Annealing Activities by HIV-1 NC and Tat Proteins.

PubMed

Sosic, Alice; Saccone, Irene; Carraro, Caterina; Kenderdine, Thomas; Gamba, Elia; Caliendo, Giuseppe; Corvino, Angela; Di Vaio, Paola; Fiorino, Ferdinando; Magli, Elisa; Perissutti, Elisa; Santagada, Vincenzo; Severino, Beatrice; Spada, Valentina; Fabris, Dan; Frecentese, Francesco; Gatto, Barbara

2018-06-12

The HIV-1 nucleocapsid (NC) protein represents an excellent molecular target for the development of anti-retrovirals by virtue of its well-characterized chaperone activities, which play pivotal roles in essential steps of the viral life cycle. Our ongoing search for candidates able to impair NC binding/annealing activities led to the identification of peptidyl-anthraquinones as a promising class of nucleic acid ligands. Seeking to elucidate the inhibition determinants and increase the potency of this class of compounds, we have now explored the effects of chirality in the linker connecting the planar nucleus to the basic side chains. We show here that the non-natural linker configuration imparted unexpected TAR RNA targeting properties to the 2,6-peptidyl-anthraquinones and significantly enhanced their potency. Even if the new compounds were able to interact directly with the NC protein, they manifested a consistently higher affinity for the TAR RNA substrate and their TAR-binding properties mirrored their ability to interfere with NC-TAR interactions. Based on these findings, we propose that the viral Tat protein, sharing the same RNA substrate but acting in distinct phases of the viral life cycle, constitutes an additional druggable target for this class of peptidyl-anthraquinones. The inhibition of Tat-TAR interaction for the test compounds correlated again with their TAR-binding properties, while simultaneously failing to demonstrate any direct Tat-binding capabilities. These considerations highlighted the importance of TAR RNA in the elucidation of their inhibition mechanism, rather than direct protein inhibition. We have therefore identified anti-TAR compounds with dual in vitro inhibitory activity on different viral proteins, demonstrating that it is possible to develop multitarget compounds capable of interfering with processes mediated by the interactions of this essential RNA domain of HIV-1 genome with NC and Tat proteins.

Oral alprazolam acutely increases nucleus accumbens perfusion

PubMed Central

Wolf, Daniel H.; Pinkham, Amy E.; Satterthwaite, Theodore D.; Ruparel, Kosha; Elliott, Mark A.; Valdez, Jeffrey; Smith, Mark A.; Detre, John A.; Gur, Ruben C.; Gur, Raquel E.

2014-01-01

Benzodiazepines treat anxiety, but can also produce euphoric effects, contributing to abuse. Using perfusion magnetic resonance imaging, we provide the first direct evidence in humans that alprazolam (Xanax) acutely increases perfusion in the nucleus accumbens, a key reward-processing region linked to addiction. PMID:23070072

The migration and growth of nuclei in an ideal vortex flow

NASA Astrophysics Data System (ADS)

Zhang, Lingxin; Chen, Linya; Shao, Xueming

2016-12-01

Tip vortex cavitation occurs on ship propellers which can cause significant noise compared to the wet flow. In order to predict the inception of tip vortex cavitation, numerous researches have been investigated about the detailed flow field around the tip. According to informed studies, the inception of tip vortex cavitation is affected by many factors. To understand the effect of water quality on cavitation inception, the motion of nuclei in an ideal vortex flow, i.e., the Rankine vortex flow, was investigated. The one-way coupling point-particle tracking model was employed to simulate the trajectory of nuclei. Meanwhile, Rayleigh-Plesset equation was introduced to describe the growth of nuclei. The results show that the nucleus size has a significant effect on nucleus' trajectory. The capture time of a nucleus is approximately inversely proportional to its radius. The growth of nucleus accelerates its migration in the vortex flow and shortens its capture time, especially for the case of explosive growth.

New high resolution measurements of open and hidden charm production in proton-nucleus collisions at √{ s} = 110GeV with LHCb

NASA Astrophysics Data System (ADS)

Maurice, Émilie; LHCb Collaboration

2017-11-01

Open and hidden charm production in nucleus-nucleus collisions is considered as a key probe of Quark Gluon Plasma (QGP) formation. In the search of specific QGP effects, proton-nucleus collisions are used as the reference as they account for the corresponding Cold Nuclear Matter (CNM) effects. The LHCb experiment, thanks to its System for Measuring Overlap with Gas (SMOG) can be operated in a fixed target mode with the LHC beams, at an intermediate center-of-mass energy between nominal SPS and RHIC energies. In 2015, for the first time, reactions of incident LHC proton beams on noble gas targets have been recorded by the LHCb experiment at a center-of-mass energy of 110 GeV and within the center-of-mass rapidity range - 2.77

Parvovirus particles and movement in the cellular cytoplasm and effects of the cytoskeleton

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lyi, Sangbom Michael; Tan, Min Jie Alvin, E-mail: tanmja@gis.a-star.edu.sg; Parrish, Colin R., E-mail: crp3@cornell.edu

2014-05-15

Cell infection by parvoviruses requires that capsids be delivered from outside the cell to the cytoplasm, followed by genome trafficking to the nucleus. Here we microinject capsids into cells that lack receptors and followed their movements within the cell over time. In general the capsids remained close to the positions where they were injected, and most particles did not move to the vicinity of or enter the nucleus. When 70 kDa-dextran was injected along with the capsids that did not enter the nucleus in significant amounts. Capsids conjugated to peptides containing the SV40 large T-antigen nuclear localization signal remained inmore » the cytoplasm, although bovine serum albumen conjugated to the same peptide entered the nucleus rapidly. No effects of disruption of microfilaments, intermediate filaments, or microtubules on the distribution of the capsids were observed. These results suggest that movement of intact capsids within cells is primarily associated with passive processes.« less

Construction of New Potential Reactivators of Phosphonylated Acetylcholinesterase. Substitution of F for H in the Nucleus of Pyridinecarboxaldehyde Oximes.

DTIC Science & Technology

1982-11-01

interpretation in this report have been entered in typography to insure legibility. 4 u 4A V * i List of Figures Page Fig. la HPLC chromatogram of...crude oximation reaction mixture (4 nMoles) 14 Fig. lb HPLC chromatogram of crude oximation reaction mixture (20 nMoles) 15 Fig. 2a HPLC chromatogram of...of classical organic reactions starting with commercial 2-Amino-4-picoline and progressing to 3-Fluoro-4-picoline. The latter compound was then

Cholinergic, Glutamatergic, and GABAergic Neurons of the Pedunculopontine Tegmental Nucleus Have Distinct Effects on Sleep/Wake Behavior in Mice

PubMed Central

Kroeger, Daniel; Ferrari, Loris L.; Mahoney, Carrie E.; Arrigoni, Elda

2017-01-01

The pedunculopontine tegmental (PPT) nucleus has long been implicated in the regulation of cortical activity and behavioral states, including rapid eye-movement (REM) sleep. For example, electrical stimulation of the PPT region during sleep leads to rapid awakening, whereas lesions of the PPT in cats reduce REM sleep. Though these effects have been linked with the activity of cholinergic PPT neurons, the PPT also includes intermingled glutamatergic and GABAergic cell populations, and the precise roles of cholinergic, glutamatergic, and GABAergic PPT cell groups in regulating cortical activity and behavioral state remain unknown. Using a chemogenetic approach in three Cre-driver mouse lines, we found that selective activation of glutamatergic PPT neurons induced prolonged cortical activation and behavioral wakefulness, whereas inhibition reduced wakefulness and increased non-REM (NREM) sleep. Activation of cholinergic PPT neurons suppressed lower-frequency electroencephalogram rhythms during NREM sleep. Last, activation of GABAergic PPT neurons slightly reduced REM sleep. These findings reveal that glutamatergic, cholinergic, and GABAergic PPT neurons differentially influence cortical activity and sleep/wake states. SIGNIFICANCE STATEMENT More than 40 million Americans suffer from chronic sleep disruption, and the development of effective treatments requires a more detailed understanding of the neuronal mechanisms controlling sleep and arousal. The pedunculopontine tegmental (PPT) nucleus has long been considered a key site for regulating wakefulness and REM sleep. This is mainly because of the cholinergic neurons contained in the PPT nucleus. However, the PPT nucleus also contains glutamatergic and GABAergic neurons that likely contribute to the regulation of cortical activity and sleep–wake states. The chemogenetic experiments in the present study reveal that cholinergic, glutamatergic, and GABAergic PPT neurons each have distinct effects on sleep/wake behavior, improving our understanding of how the PPT nucleus regulates cortical activity and behavioral states. PMID:28039375

Cholinergic, Glutamatergic, and GABAergic Neurons of the Pedunculopontine Tegmental Nucleus Have Distinct Effects on Sleep/Wake Behavior in Mice.

PubMed

Kroeger, Daniel; Ferrari, Loris L; Petit, Gaetan; Mahoney, Carrie E; Fuller, Patrick M; Arrigoni, Elda; Scammell, Thomas E

2017-02-01

The pedunculopontine tegmental (PPT) nucleus has long been implicated in the regulation of cortical activity and behavioral states, including rapid eye-movement (REM) sleep. For example, electrical stimulation of the PPT region during sleep leads to rapid awakening, whereas lesions of the PPT in cats reduce REM sleep. Though these effects have been linked with the activity of cholinergic PPT neurons, the PPT also includes intermingled glutamatergic and GABAergic cell populations, and the precise roles of cholinergic, glutamatergic, and GABAergic PPT cell groups in regulating cortical activity and behavioral state remain unknown. Using a chemogenetic approach in three Cre-driver mouse lines, we found that selective activation of glutamatergic PPT neurons induced prolonged cortical activation and behavioral wakefulness, whereas inhibition reduced wakefulness and increased non-REM (NREM) sleep. Activation of cholinergic PPT neurons suppressed lower-frequency electroencephalogram rhythms during NREM sleep. Last, activation of GABAergic PPT neurons slightly reduced REM sleep. These findings reveal that glutamatergic, cholinergic, and GABAergic PPT neurons differentially influence cortical activity and sleep/wake states. More than 40 million Americans suffer from chronic sleep disruption, and the development of effective treatments requires a more detailed understanding of the neuronal mechanisms controlling sleep and arousal. The pedunculopontine tegmental (PPT) nucleus has long been considered a key site for regulating wakefulness and REM sleep. This is mainly because of the cholinergic neurons contained in the PPT nucleus. However, the PPT nucleus also contains glutamatergic and GABAergic neurons that likely contribute to the regulation of cortical activity and sleep-wake states. The chemogenetic experiments in the present study reveal that cholinergic, glutamatergic, and GABAergic PPT neurons each have distinct effects on sleep/wake behavior, improving our understanding of how the PPT nucleus regulates cortical activity and behavioral states. Copyright © 2017 the authors 0270-6474/17/371352-15$15.00/0.

Microdosimetric study for nanosecond pulsed electric fields on a cell circuit model with nucleus.

PubMed

Denzi, Agnese; Merla, Caterina; Camilleri, Paola; Paffi, Alessandra; d'Inzeo, Guglielmo; Apollonio, Francesca; Liberti, Micaela

2013-10-01

Recently, scientific interest in electric pulses, always more intense and shorter and able to induce biological effects on both plasma and nuclear membranes, has greatly increased. Hence, microdosimetric models that include internal organelles like the nucleus have assumed increasing importance. In this work, a circuit model of the cell including the nucleus is proposed, which accounts for the dielectric dispersion of all cell compartments. The setup of the dielectric model of the nucleus is of fundamental importance in determining the transmembrane potential (TMP) induced on the nuclear membrane; here, this is demonstrated by comparing results for three different sets of nuclear dielectric properties present in the literature. The results have been compared, even including or disregarding the dielectric dispersion of the nucleus. The main differences have been found when using pulses shorter than 10 ns. This is due to the fact that the high spectral components of the shortest pulses are differently taken into account by the nuclear membrane transfer functions computed with and without nuclear dielectric dispersion. The shortest pulses are also the most effective in porating the intracellular structures, as confirmed by the time courses of the TMP calculated across the plasma and nuclear membranes. We show how dispersive nucleus models are unavoidable when dealing with pulses shorter than 10 ns because of the large spectral contents arriving above 100 MHz, i.e., over the typical relaxation frequencies of the dipolar mechanism of the molecules constituting the nuclear membrane and the subcellular cell compartments.

Injections of the selective adenosine A2A antagonist MSX-3 into the nucleus accumbens core attenuate the locomotor suppression induced by haloperidol in rats.

PubMed

Ishiwari, Keita; Madson, Lisa J; Farrar, Andrew M; Mingote, Susana M; Valenta, John P; DiGianvittorio, Michael D; Frank, Lauren E; Correa, Merce; Hockemeyer, Jörg; Müller, Christa; Salamone, John D

2007-03-28

There is considerable evidence of interactions between adenosine A2A receptors and dopamine D2 receptors in striatal areas, and antagonists of the A2A receptor have been shown to reverse the motor effects of DA antagonists in animal models. The D2 antagonist haloperidol produces parkinsonism in humans, and also induces motor effects in rats, such as suppression of locomotion. The present experiments were conducted to study the ability of the adenosine A2A antagonist MSX-3 to reverse the locomotor effects of acute or subchronic administration of haloperidol in rats. Systemic (i.p.) injections of MSX-3 (2.5-10.0 mg/kg) were capable of attenuating the suppression of locomotion induced by either acute or repeated (i.e., 14 day) administration of 0.5 mg/kg haloperidol. Bilateral infusions of MSX-3 directly into the nucleus accumbens core (2.5 microg or 5.0 microg in 0.5 microl per side) produced a dose-related increase in locomotor activity in rats treated with 0.5 mg/kg haloperidol either acutely or repeatedly. There were no overall significant effects of MSX-3 infused directly into the dorsomedial nucleus accumbens shell or the ventrolateral neostriatum. These results indicate that antagonism of adenosine A2A receptors can attenuate the locomotor suppression produced by DA antagonism, and that this effect may be at least partially mediated by A2A receptors in the nucleus accumbens core. These studies suggest that adenosine and dopamine systems interact to modulate the locomotor and behavioral activation functions of nucleus accumbens core.

Injections of the selective adenosine A2A antagonist MSX-3 into the nucleus accumbens core attenuate the locomotor suppression induced by haloperidol in rats

PubMed Central

Ishiwari, Keita; Madson, Lisa J.; Farrar, Andrew M.; Mingote, Susana M.; Valenta, John P.; DiGianvittorio, Michael D.; Frank, Lauren E.; Correa, Merce; Hockemeyer, Jörg; Müller, Christa; Salamone, John D.

2009-01-01

There is considerable evidence of interactions between adenosine A2A receptors and dopamine D2 receptors in striatal areas, and antagonists of the A2A receptor have been shown to reverse the motor effects of DA antagonists in animal models. The D2 antagonist haloperidol produces parkinsonism in humans, and also induces motor effects in rats, such as suppression of locomotion. The present experiments were conducted to study the ability of the adenosine A2A antagonist MSX-3 to reverse the locomotor effects of acute or subchronic administration of haloperidol in rats. Systemic (i.p.) injections of MSX-3 (2.5–10.0 mg/kg) were capable of attenuating the suppression of locomotion induced by either acute or repeated (i.e., 14 day) administration of 0.5 mg/kg haloperidol. Bilateral infusions of MSX-3 directly into the nucleus accumbens core (2.5 µg or 5.0 µg in 0.5 µl per side) produced a dose-related increase in locomotor activity in rats treated with 0.5 mg/kg haloperidol either acutely or repeatedly. There were no overall significant effects of MSX-3 infused directly into the dorsomedial nucleus accumbens shell or the ventrolateral neostriatum. These results indicate that antagonism of adenosine A2A receptors can attenuate the locomotor suppression produced by DA antagonism, and that this effect may be at least partially mediated by A2A receptors in the nucleus accumbens core. These studies suggest that adenosine and dopamine systems interact to modulate the locomotor and behavioral activation functions of nucleus accumbens core. PMID:17223207

Deep brain stimulation of the pedunculopontine nucleus for treatment of gait and balance disorder in progressive supranuclear palsy: Effects of frequency modulations and clinical outcome.

PubMed

Galazky, Imke; Kaufmann, Jörn; Lorenzl, Stefan; Ebersbach, Georg; Gandor, Florin; Zaehle, Tino; Specht, Sylke; Stallforth, Sabine; Sobieray, Uwe; Wirkus, Edyta; Casjens, Franziska; Heinze, Hans-Jochen; Kupsch, Andreas; Voges, Jürgen

2018-05-01

The pedunculopontine nucleus has been suggested as a potential deep brain stimulation target for axial symptoms such as gait and balance impairment in idiopathic Parkinson's disease as well as atypical Parkinsonian disorders. Seven consecutive patients with progressive supranuclear palsy received bilateral pedunculopontine nucleus deep brain stimulation. Inclusion criteria comprised of the clinical diagnosis of progressive supranuclear palsy, a levodopa-resistant gait and balance disorder, age <75 years, and absence of dementia or major psychiatric co-morbidities. Effects of stimulation frequencies at 8, 20, 60 and 130 Hz on motor scores and gait were assessed. Motor scores were followed up for two years postoperatively. Activities of daily living, frequency of falls, health-related quality of life, cognition and mood at 12 months were compared to baseline parameters. Surgical and stimulation related adverse events were assessed. Bilateral pedunculopontine nucleus deep brain stimulation at 8 Hz significantly improved axial motor symptoms and cyclic gait parameters, while high frequency stimulation did not ameliorate gait and balance but improved hypokinesia. This improvement however did not translate into clinically relevant benefits. Frequency of falls was not reduced. Activities of daily living, quality of life and frontal cognitive functions declined, while mood remained unchanged. Bilateral pedunculopontine nucleus deep brain stimulation in progressive supranuclear palsy generates frequency-dependent effects with improvement of cyclic gait parameters at low frequency and amelioration of hypokinesia at high frequency stimulation. However, these effects do not translate into a clinically important improvement. Copyright © 2018. Published by Elsevier Ltd.

Differential Activation of Pontomedullary Nuclei by Acid Perfusion of Different Regions of the Esophagus

PubMed Central

Lang, Ivan M.; Medda, Bidyut K.; Shaker, Reza

2010-01-01

The objective of this study was to determine the brain stem nuclei and physiological responses activated by esophageal acidification. The effects of perfusion of the cervical (ESOc), or thoracic (ESOt) esophagus with PBS or HCl on c-fos immunoreactivity of the brain stem or on physiological variables, and the effects of vagotomy were examined in anesthetized cats. We found that acidification of the ESOc increased the number of c-fos positive neurons in the area postrema (AP), vestibular nucleus (VN), parabrachial nucleus (PBN), nucleus ambiguus (NA), dorsal motor nucleus (DMN), and all subnuclei of the nucleus tractus solitarius (NTS), but one. Acidification of the ESOt activated neurons in the central (CE), caudal (CD), dorsomedial (DM), dorsolateral (DL), ventromedial (VM) subnuclei of NTS, and the DMN. Vagotomy blocked all c-fos responses to acid perfusion of the whole esophagus (ESOw). Perfusion of the ESOc or ESOt with PBS activated secondary peristalsis (2P), but had no effect on blood pressure, heart rate, or respiratory rate. Perfusion of the ESOc, but not ESOt, with HCL activated pharyngeal swallowing (PS), profuse salivation, or physiological correlates of emesis. Vagotomy blocked all physiological effects of ESOw perfusion. We conclude that acidification of the ESOc and ESOt activate different sets of pontomedullary nuclei and different physiological responses. The NTSce, NTScom, NTSdm, and DMN are associated with activation of 2P, the NTSim and NTSis, are associated with activation of PS, and the AP, VN, and PBN are associated with activation of emesis and perhaps nausea. All responses to esophageal fluid perfusion or acidification are mediated by the vagus nerves. PMID:20655885

Gallic acid inhibits the release of ADAMTS4 in nucleus pulposus cells by inhibiting p65 phosphorylation and acetylation of the NF-κB signaling pathway.

PubMed

Huang, Yao; Chen, Jian; Jiang, Tao; Zhou, Zheng; Lv, Bin; Yin, Guoyong; Fan, Jin

2017-07-18

This study investigated the inhibitory effect of gallic acid (GA) on the release of A Disintegrin and Metalloproteinase with Thrombospondin motifs 4 (ADAMTS4) through the regulation of the NF-κB signaling pathway, which is closely related to the matrix metalloproteinases in nucleus pulposus cells. Different concentrations of GA were added to TNF-α-induced human nucleus pulposus cells (hNPCs) and intervertebral disc degeneration rat model. ADAMTS-4 expression increased both in the TNF-α-induced nucleus pulposus cells and intervertebral disc degeneration rat model. By contrast, the release of ADAMTS-4 was reduced, and the TNF-α-induced apoptosis of nucleus pulposus cells was significantly inhibited after addition of GA at different concentrations. Further study found that the levels of phosphorylated p65 (p-p65) was increased and the classical NF-κB signal pathway was activated after the nucleus pulposus cells were stimulated by TNF-α. Meanwhile, GA suppressed the p65 phosphorylation and inceased p65 deacetylation levels. As a consequence, GA can decrease the expression of ADAMTS-4 in nucleus pulposus cells by regulating the phosphorylation and acetylation of p65 in NF-κB signaling pathways.

Phenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruzi.

PubMed

Simões-Silva, M R; Nefertiti, A S G; De Araújo, J S; Batista, M M; Da Silva, P B; Bahia, M T; Menna-Barreto, R S; Pavão, B P; Green, J; Farahat, A A; Kumar, A; Boykin, D W; Soeiro, M N C

2016-08-01

The current treatment of Chagas disease (CD), based on nifurtimox and benznidazole (Bz), is unsatisfactory. In this context, we performed the phenotypic in vitro screening of novel mono- and diamidines and drug interaction assays with selected compounds. Ten novel amidines were tested for their activities against bloodstream trypomastigote (BT) and amastigote forms of Trypanosoma cruzi (Y and Tulahuen strains) and their toxicities for mammalian host cells (L929 cells and cardiac cells). Seven of 10 molecules were more active than Bz against BT, with the most active compound being the diamidine DB2267 (50% effective concentration [EC50] = 0.23 μM; selectivity index = 417), which was 28-fold more active and about 3 times more selective than the standard drug. Five of the six monoamidines were also more active than Bz. The combination of DB2267 and DB2236 in fixed-ratio proportions showed an additive effect (sum of fractional inhibitory concentrations < 4) on BT. Interestingly, when intracellular forms were exposed to DB2267, its activity was dependent on the parasite strain, being effective (EC50 = 0.87 ± 0.05 μM) against a discrete typing unit (DTU) II strain (strain Y) but not against a representative DTU VI strain (strain Tulahuen) even when different vehicles (β-cyclodextrin and dimethyl sulfoxide) were used. The intrinsic fluorescence of several diamidines allowed their uptake to be studied. Testing of the uptake of DB2236 (inactive) and DB2267 (active) by amastigotes of the Y strain showed that the two compounds were localized intracellularly in different compartments: DB2236 in the cytoplasm and DB2267 in the nucleus. Our present data encourage further studies regarding the activities of amidines and provide information which will help with the identification of novel agents for the treatment of CD. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Blocking of valinomycin-mediated bilayer membrane conductance by substituted benzimidazoles.

PubMed Central

Kuo, K H; Fukuto, T R; Miller, T A; Bruner, L J

1976-01-01

Valinomycin selectively transports alkali cations, e.g. potassium ions, across lipid bilayer membranes. The blocking of this carrier-mediated transport by four substituted benzimidazoles has been investigated. The compounds are 4,5,6,7-tetrachloro-2-trifluoromethylbenzimidazole, (TTFB); 4,5,6,7,-tetrachloro-2-methylbenzimidazole, (TMB); 2-trifluoromethylbenzimidazole, (TFB); and 2-methylbenzimidazole, (MBM). Because of its low acidic dissociation constant (pKa = 5.04), the blocking efficiency of TTFB in both neutral and anionic forms in the aqueous phase could be studied. The compounds exhibit the blocking efficiency sequence, TTFB- greater than TTFB0 greater than TMB0 greater than TFB0 greater than MBM0. The corresponding scale of decreasing lipophilicity, as determined by octanol/water partitioning, is TTFB0 greater than TMB0 greater than TTFB- greater than TFB0 greater than MBM0. Comparison of neutral species establishes a positive correlation of blocking efficiency with lipophilicity, with the latter being conferred primarily by chlorination of the benzenoid nucleus. Anionic TTFB, on the other hand, is the most effective blocking agent studied in spite of the fact that its dissociation in the aqueous phase markedly impedes its entry (presumably as a neutral species) into a bulk hydrocarbon phase. This observation suggests that the blocking of valinomycin-mediated bilayer membrane conductance takes place at the membrane/solution interface. PMID:1247644

Radiant energy required for infrared neural stimulation

DOE PAGES

Tan, Xiaodong; Rajguru, Suhrud; Young, Hunter; ...

2015-08-25

Infrared neural stimulation (INS) has been proposed as an alternative method to electrical stimulation because of its spatial selective stimulation. Independent of the mechanism for INS, to translate the method into a device it is important to determine the energy for stimulation required at the target structure. Custom-designed, flat and angle polished fibers, were used to deliver the photons. By rotating the angle polished fibers, the orientation of the radiation beam in the cochlea could be changed. INS-evoked compound action potentials and single unit responses in the central nucleus of the inferior colliculus (ICC) were recorded. X-ray computed tomography wasmore » used to determine the orientation of the optical fiber. Maximum responses were observed when the radiation beam was directed towards the spiral ganglion neurons (SGNs), whereas little responses were seen when the beam was directed towards the basilar membrane. The radiant exposure required at the SGNs to evoke compound action potentials (CAPs) or ICC responses was on average 18.9 ± 12.2 or 10.3 ± 4.9 mJ/cm 2, respectively. For cochlear INS it has been debated whether the radiation directly stimulates the SGNs or evokes a photoacoustic effect. The results support the view that a direct interaction between neurons and radiation dominates the response to INS.« less

Radiant energy required for infrared neural stimulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tan, Xiaodong; Rajguru, Suhrud; Young, Hunter

Infrared neural stimulation (INS) has been proposed as an alternative method to electrical stimulation because of its spatial selective stimulation. Independent of the mechanism for INS, to translate the method into a device it is important to determine the energy for stimulation required at the target structure. Custom-designed, flat and angle polished fibers, were used to deliver the photons. By rotating the angle polished fibers, the orientation of the radiation beam in the cochlea could be changed. INS-evoked compound action potentials and single unit responses in the central nucleus of the inferior colliculus (ICC) were recorded. X-ray computed tomography wasmore » used to determine the orientation of the optical fiber. Maximum responses were observed when the radiation beam was directed towards the spiral ganglion neurons (SGNs), whereas little responses were seen when the beam was directed towards the basilar membrane. The radiant exposure required at the SGNs to evoke compound action potentials (CAPs) or ICC responses was on average 18.9 ± 12.2 or 10.3 ± 4.9 mJ/cm 2, respectively. For cochlear INS it has been debated whether the radiation directly stimulates the SGNs or evokes a photoacoustic effect. The results support the view that a direct interaction between neurons and radiation dominates the response to INS.« less

Component analysis and target cell-based neuroactivity screening of Panax ginseng by ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry.

PubMed

Yuan, Jinbin; Chen, Yang; Liang, Jian; Wang, Chong-Zhi; Liu, Xiaofei; Yan, Zhihong; Tang, Yi; Li, Jiankang; Yuan, Chun-Su

2016-12-01

Ginseng is one of the most widely used natural medicines in the world. Recent studies have suggested Panax ginseng has a wide range of beneficial effects on aging, central nervous system disorders, and neurodegenerative diseases. However, knowledge about the specific bioactive components of ginseng is still limited. This work aimed to screen for the bioactive components in Panax ginseng that act against neurodegenerative diseases, using the target cell-based bioactivity screening method. Firstly, component analysis of Panax ginseng extracts was performed by UPLC-QTOF-MS, and a total of 54 compounds in white ginseng were characterized and identified according to the retention behaviors, accurate MW, MS characteristics, parent nucleus, aglycones, side chains, and literature data. Then target cell-based bioactivity screening method was developed to predict the candidate compounds in ginseng with SH-SY5Y cells. Four ginsenosides, Rg 2 , Rh 1 , Ro, and Rd, were observed to be active. The target cell-based bioactivity screening method coupled with UPLC-QTOF-MS technique has suitable sensitivity and it can be used as a screening tool for low content bioactive constituents in natural products. Copyright © 2016 Elsevier B.V. All rights reserved.

Mechano-adaptation of the stem cell nucleus.

PubMed

Heo, Su-Jin; Cosgrove, Brian D; Dai, Eric N; Mauck, Robert L

2018-01-01

Exogenous mechanical forces are transmitted through the cell and to the nucleus, initiating mechanotransductive signaling cascades with profound effects on cellular function and stem cell fate. A growing body of evidence has shown that the force sensing and force-responsive elements of the nucleus adapt to these mechanotransductive events, tuning their response to future mechanical input. The mechanisms underlying this "mechano-adaptation" are only just beginning to be elucidated, and it remains poorly understood how these components act and adapt in tandem to drive stem cell differentiation. Here, we review the evidence on how the stem cell nucleus responds and adapts to physical forces, and provide a perspective on how this mechano-adaptation may function to drive and enforce stem cell differentiation.

Crowding, Entropic Forces, and Confinement: Crucial Factors for Structures and Functions in the Cell Nucleus.

PubMed

Hancock, R

2018-04-01

The view of the cell nucleus as a crowded system of colloid particles and that chromosomes are giant self-avoiding polymers is stimulating rapid advances in our understanding of its structure and activities, thanks to concepts and experimental methods from colloid, polymer, soft matter, and nano sciences and to increased computational power for simulating macromolecules and polymers. This review summarizes current understanding of some characteristics of the molecular environment in the nucleus, of how intranuclear compartments are formed, and of how the genome is highly but precisely compacted, and underlines the crucial, subtle, and sometimes unintuitive effects on structures and reactions of entropic forces caused by the high concentration of macromolecules in the nucleus.

Mechano-adaptation of the stem cell nucleus

PubMed Central

Heo, Su-Jin; Cosgrove, Brian D.; Dai, Eric N.; Mauck, Robert L.

2018-01-01

ABSTRACT Exogenous mechanical forces are transmitted through the cell and to the nucleus, initiating mechanotransductive signaling cascades with profound effects on cellular function and stem cell fate. A growing body of evidence has shown that the force sensing and force-responsive elements of the nucleus adapt to these mechanotransductive events, tuning their response to future mechanical input. The mechanisms underlying this “mechano-adaptation” are only just beginning to be elucidated, and it remains poorly understood how these components act and adapt in tandem to drive stem cell differentiation. Here, we review the evidence on how the stem cell nucleus responds and adapts to physical forces, and provide a perspective on how this mechano-adaptation may function to drive and enforce stem cell differentiation. PMID:29099288

Role of inhibitory amino acids in control of hypoglossal motor outflow to genioglossus muscle in naturally sleeping rats.

PubMed

Morrison, Janna L; Sood, Sandeep; Liu, Hattie; Park, Eileen; Liu, Xia; Nolan, Philip; Horner, Richard L

2003-11-01

The hypoglossal motor nucleus innervates the genioglossus (GG) muscle of the tongue, a muscle that helps maintain an open airway for effective breathing. Rapid-eye-movement (REM) sleep, however, recruits powerful neural mechanisms that can abolish GG activity even during strong reflex stimulation such as by hypercapnia, effects that can predispose to sleep-related breathing problems in humans. We have developed an animal model to chronically manipulate neurotransmission at the hypoglossal motor nucleus using in vivo microdialysis in freely behaving rats. This study tests the hypothesis that glycine receptor antagonism at the hypoglossal motor nucleus, either alone or in combination with GABAA receptor antagonism, will prevent suppression of GG activity in natural REM sleep during room air and CO2-stimulated breathing. Rats were implanted with electroencephalogram and neck muscle electrodes to record sleep-wake states, and GG and diaphragm electrodes for respiratory muscle recording. Microdialysis probes were implanted into the hypoglossal motor nucleus for perfusion of artificial cerebrospinal fluid (ACSF) and strychnine (glycine receptor antagonist, 0.1 mM) either alone or combined with bicuculline (GABAA antagonist, 0.1 mM) during room air and CO2-stimulated breathing. Compared to ACSF controls, glycine receptor antagonism at the hypoglossal motor nucleus increased respiratory-related GG activity in room air (P = 0.010) but not hypercapnia (P = 0.221). This stimulating effect of strychnine in room air did not depend on the prevailing sleep-wake state (P = 0.625) indicating removal of a non-specific background inhibitory glycinergic tone. Nevertheless, GG activity remained minimal in those REM sleep periods without phasic twitches in GG muscle, with GG suppression from non-REM (NREM) sleep being > 85 % whether ACSF or strychnine was at the hypoglossal motor nucleus or the inspired gas was room air or 7 % CO2. While GG activity was minimal in these REM sleep periods, there was a small but measurable increase in GG activity after strychnine (P < 0.05). GG activity was also minimal, and effectively abolished, in the REM sleep periods without GG twitches with combined glycine and GABAA receptor antagonism at the hypoglossal motor nucleus. We conclude that these data in freely behaving rats confirm that inhibitory glycine and GABAA receptor mechanisms are present at the hypoglossal motor nucleus and are tonically active, but that such inhibitory mechanisms make only a small contribution to the marked suppression of GG activity and reflex responses observed in periods of natural REM sleep.

Synergistic effect of baicalein, wogonin and oroxylin A mixture: multistep inhibition of the NF-κB signalling pathway contributes to an anti-inflammatory effect of Scutellaria root flavonoids.

PubMed

Shimizu, Tomofumi; Shibuya, Nobuhiko; Narukawa, Yuji; Oshima, Naohiro; Hada, Noriyasu; Kiuchi, Fumiyuki

2018-01-01

Scutellaria root, the root of Scutellaria baicalensis Georgi, is a crude drug used for inflammatory diseases. In our previous report, the combination of flavonoids contained in Scutellaria root have been found to inhibit PGE 2 production more strongly than individual flavonoids. Here, to investigate the mechanism of the synergistic effect, we examined the effects of an equimolar mixture (F-mix) of baicalein (1), wogonin (2) and oroxylin A (3) on the production of PGE 2 in LPS-treated J774.1 cells. Although 1 and 3 inhibited COX-2 activity, the F-mix showed no synergistic effect on COX-2 inhibition. Therefore, we investigated the steps leading to the activation of COX-2 protein. Compounds 1-3 and F-mix inhibited the expression of COX-2 protein. However, only 2 inhibited the expression of COX-2 mRNA among the flavonoids, and the F-mix showed no synergistic effect. Only 1 inhibited NF-κB translocation into the nucleus, and the F-mix showed no synergistic effect. Although 2 did not affect NF-κB translocation, it strongly inhibited NF-κB-dependent transcriptional activity, and the F-mix inhibited the activity slightly more than 2. Compounds 1-3 also inhibited NO production, and the F-mix showed a synergistic effect. However, the effects of each flavonoid on the expression of iNOS mRNA were not consistent with those on COX-2 mRNA. Because the flavonoids inhibit different steps in the production of PGE 2 and NO, and their mixture did not show apparent synergistic effects in each step, we conclude that the synergistic effect of the flavonoid mixture reflects the total effect of the flavonoids inhibiting different steps in the NF-κB signalling pathway.

Periodic mechanical stress activates EGFR-dependent Rac1 mitogenic signals in rat nucleus pulpous cells via ERK1/2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gao, Gongming; Shen, Nan; Jiang, Xuefeng

2016-01-15

The mitogenic effects of periodic mechanical stress on nucleus pulpous cells have been studied extensively but the mechanisms whereby nucleus pulpous cells sense and respond to mechanical stimulation remain a matter of debate. We explored this question by performing cell culture experiments in our self-developed periodic stress field and perfusion culture system. Under periodic mechanical stress, rat nucleus pulpous cell proliferation was significantly increased (p < 0.05 for each) and was associated with increases in the phosphorylation and activation of EGFR, Rac1, and ERK1/2 (p < 0.05 for each). Pretreatment with the ERK1/2 selective inhibitor PD98059 reduced periodic mechanical stress-induced nucleus pulpous cell proliferationmore » (p < 0.05 for each), while the activation levels of EGFR and Rac1 were not inhibited. Proliferation and phosphorylation of ERK1/2 were inhibited after pretreatment with the Rac1 inhibitor NSC23766 in nucleus pulpous cells in response to periodic mechanical stress (p < 0.05 for each), while the phosphorylation site of EGFR was not affected. Inhibition of EGFR activity with AG1478 abrogated nucleus pulpous cell proliferation (p < 0.05 for each) and attenuated Rac1 and ERK1/2 activation in nucleus pulpous cells subjected to periodic mechanical stress (p < 0.05 for each). These findings suggest that periodic mechanical stress promotes nucleus pulpous cell proliferation in part through the EGFR-Rac1-ERK1/2 signaling pathway, which links these three important signaling molecules into a mitogenic cascade. - Highlights: • The mechanism involved in nucleus pulpous cells to respond to mechanical stimuli. • Periodic mechanical stress can stimulate the phosphorylation of EGFR. • EGFR activates Rac1 and leads to rat nucleus pulpous cell proliferation. • EGFR and Rac1 activate ERK1/2 mitogenic signals in nucleus pulpous cells. • EGFR-Rac1-ERK1/2 is constitutes at least one critical signal transduction pathway.« less

Agmatine attenuates nicotine induced conditioned place preference in mice through modulation of neuropeptide Y system.

PubMed

Kotagale, Nandkishor R; Walke, Sonali; Shelkar, Gajanan P; Kokare, Dadasaheb M; Umekar, Milind J; Taksande, Brijesh G

2014-04-01

The purpose of the present study was to examine the effect of agmatine on nicotine induced conditioned place preference (CPP) in male albino mice. Intra-peritoneal (ip) administration of nicotine (1mg/kg) significantly increased time spent in drug-paired compartment. Agmatine (20 and 40 mg/kg, ip) co-administered with nicotine during the 6 days conditioning sessions completely abolished the acquisition of nicotine-induced CPP in mice. Concomitant administration of neuropeptide Y (NPY) (1 pg/mouse, icv) or [Leu(31), Pro(34)]-NPY (0.1 pg/mouse, icv), selective NPY Y1 receptor agonist potentiated the inhibitory effect of agmatine (10 mg/kg, ip) on nicotine CPP. Conversely, pretreatment with NPY Y1 receptor antagonist, BIBP3226 (0.01 ng/mouse, icv) blocked the effect of agmatine (20 mg/kg, ip) on nicotine induced CPP. In immunohistochemical study, nicotine decreased NPY-immunoreactivity in nucleus accumbens shell (AcbSh), bed nucleus of stria terminalis, lateral part (BNSTl), arcuate nucleus (ARC) and paraventricular nucleus (PVN). Conversely, administration of agmatine prior to the nicotine significantly reversed the effect of nicotine on NPY-immunoreactivity in the above brain nuclei. This data indicate that agmatine attenuate nicotine induced CPP via modulation of NPYergic neurotransmission in brain. Copyright © 2014 Elsevier B.V. All rights reserved.

Restoring Segmental Biomechanics Through Nucleus Augmentation: An In Vitro Study.

PubMed

Pelletier, Matthew H; Cohen, Charles S; Ducheyne, Paul; Walsh, William R

2016-12-01

In vitro biomechanical laboratory study. The purpose of this study is to evaluate a mechanical treatment to create a degenerative motion segment and the ability of nucleus augmentation to restore biomechanics. In cases with an intact annulus fibrosus, the replacement or augmentation of the nucleus pulposus alone may provide a less invasive option to restore normal biomechanics and disk height when compared with spinal fusion or total disk replacement. Laboratory testing allows these changes to be fully characterized. However, without preexisting pathology, nucleus augmentation therapies are difficult to evaluate in vitro. The present study evaluated pure moment bending and compressive biomechanics in 3 states (n=6): (1) intact, (2) after creep loading and nucleus disruption to induce degenerative biomechanical changes, and (3) after nucleus augmentation through an injectable polymer (DiscCell). Neutral zone and ROM were increased in all modes of bending after the degenerative treatment. The most sensitive mode of bending was lateral bending, with intact ROM (20.0±2.9 degrees) increased to 22.3±2.6 degrees after degenerative treatment and reduced to 18.4±1.6 degrees after injection of the polymer. All bending ROM and NZ changes induced by the degenerative treatment were reversed by nucleus augmentation. This material was shown to be effective at altering motion segment biomechanics and restoring disk height during time zero tests. This technique may provide a model to examine the time zero performance of a nucleus augmentation device/material.

Alpha oscillations in the pedunculopontine nucleus correlate with gait performance in parkinsonism

PubMed Central

Thevathasan, Wesley; Pogosyan, Alek; Hyam, Jonathan A.; Jenkinson, Ned; Foltynie, Tom; Limousin, Patricia; Bogdanovic, Marko; Zrinzo, Ludvic; Green, Alexander L.; Aziz, Tipu Z.

2012-01-01

The pedunculopontine nucleus, a component of the reticular formation, is topographically organized in animal models and implicated in locomotor control. In Parkinson's disease, pedunculopontine nucleus stimulation is an emerging treatment for gait freezing. Local field potentials recorded from pedunculopontine nucleus electrodes in such patients have demonstrated oscillations in the alpha and beta frequency bands, reactive to self-paced movement. Whether these oscillations are topographically organized or relevant to locomotion is unknown. Here, we recorded local field potentials from the pedunculopontine nucleus in parkinsonian patients during rest and unconstrained walking. Relative gait speed was assessed with trunk accelerometry. Peaks of alpha power were present at rest and during gait, when they correlated with gait speed. Gait freezing was associated with attenuation of alpha activity. Beta peaks were less consistently observed across rest and gait, and did not correlate with gait speed. Alpha power was maximal in the caudal pedunculopontine nucleus region and beta power was maximal rostrally. These results indicate a topographic distribution of neuronal activity in the pedunculopontine nucleus region and concur with animal data suggesting that the caudal subregion has particular relevance to gait. Alpha synchronization, proposed to suppress ‘task irrelevant’ distraction, has previously been demonstrated to correlate with performance of cognitive tasks. Here, we demonstrate a correlation between alpha oscillations and improved gait performance. The results raise the possibility that stimulation of caudal and rostral pedunculopontine nucleus regions may differ in their clinical effects. PMID:22232591

The spice for joint inflammation: anti-inflammatory role of curcumin in treating osteoarthritis.

PubMed

Chin, Kok-Yong

2016-01-01

Osteoarthritis is a degenerative disease of the joint affecting aging populations worldwide. It has an underlying inflammatory cause, which contributes to the loss of chondrocytes, leading to diminished cartilage layer at the affected joints. Compounds with anti-inflammatory properties are potential treatment agents for osteoarthritis. Curcumin derived from Curcuma species is an anti-inflammatory compound as such. This review aims to summarize the antiosteoarthritic effects of curcumin derived from clinical and preclinical studies. Many clinical trials have been conducted to determine the effectiveness of curcumin in osteoarthritic patients. Extracts of Curcuma species, curcuminoids and enhanced curcumin, were used in these studies. Patients with osteoarthritis showed improvement in pain, physical function, and quality of life after taking curcumin. They also reported reduced concomitant usage of analgesics and side effects during treatment. In vitro studies demonstrated that curcumin could prevent the apoptosis of chondrocytes, suppress the release of proteoglycans and metal metalloproteases and expression of cyclooxygenase, prostaglandin E-2, and inflammatory cytokines in chondrocytes. These were achieved by blocking the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) system in the chondrocytes, by preventing the activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha, phosphorylation, and translocation of the p65 subunit of NF-κB complexes into the nucleus. In conclusion, curcumin is a potential candidate for the treatment of osteoarthritis. More well-planned randomized control trials and enhanced curcumin formulation are required to justify the use of curcumin in treating osteoarthritis.

The spice for joint inflammation: anti-inflammatory role of curcumin in treating osteoarthritis

PubMed Central

Chin, Kok-Yong

2016-01-01

Osteoarthritis is a degenerative disease of the joint affecting aging populations worldwide. It has an underlying inflammatory cause, which contributes to the loss of chondrocytes, leading to diminished cartilage layer at the affected joints. Compounds with anti-inflammatory properties are potential treatment agents for osteoarthritis. Curcumin derived from Curcuma species is an anti-inflammatory compound as such. This review aims to summarize the antiosteoarthritic effects of curcumin derived from clinical and preclinical studies. Many clinical trials have been conducted to determine the effectiveness of curcumin in osteoarthritic patients. Extracts of Curcuma species, curcuminoids and enhanced curcumin, were used in these studies. Patients with osteoarthritis showed improvement in pain, physical function, and quality of life after taking curcumin. They also reported reduced concomitant usage of analgesics and side effects during treatment. In vitro studies demonstrated that curcumin could prevent the apoptosis of chondrocytes, suppress the release of proteoglycans and metal metalloproteases and expression of cyclooxygenase, prostaglandin E-2, and inflammatory cytokines in chondrocytes. These were achieved by blocking the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) system in the chondrocytes, by preventing the activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha, phosphorylation, and translocation of the p65 subunit of NF-κB complexes into the nucleus. In conclusion, curcumin is a potential candidate for the treatment of osteoarthritis. More well-planned randomized control trials and enhanced curcumin formulation are required to justify the use of curcumin in treating osteoarthritis. PMID:27703331

Comparative effect of lurasidone and blonanserin on cortical glutamate, dopamine, and acetylcholine efflux: role of relative serotonin (5-HT)2A and DA D2 antagonism and 5-HT1A partial agonism.

PubMed

Huang, Mei; Panos, John J; Kwon, Sunoh; Oyamada, Yoshihiro; Rajagopal, Lakshmi; Meltzer, Herbert Y

2014-03-01

Atypical antipsychotic drugs (AAPDs) have been suggested to be more effective in improving cognitive impairment in schizophrenia than typical APDs, a conclusion supported by differences in receptor affinities and neurotransmitter efflux in the cortex and the hippocampus. More potent serotonin (5-HT)2A than dopamine (DA) D2 receptors antagonism, and direct or indirect 5-HT1A agonism, characterize almost all AAPDs. Blonanserin, an AAPD, has slightly greater affinity for D2 than 5-HT2A receptors. Using microdialysis and ultra performance liquid chromatography-mass spectrometry/mass spectrometry, we compared the abilities of the typical APD, haloperidol, three AAPDs, blonanserin, lurasidone, and olanzapine, and a selective 5-HT1A partial agonist, tandospirone, and all, except haloperidol, were found to ameliorate the cognitive deficits produced by the N-methyl-d-aspartate antagonist, phencyclidine, altering the efflux of neurotransmitters and metabolites in the rat cortex and nucleus accumbens. Blonanserin, lurasidone, olanzapine, and tandospirone, but not haloperidol, increased the efflux of cortical DA and its metabolites, homovanillic acid and 3,4-dihydroxyphenylacetic acid. Olanzapine and lurasidone increased the efflux of acetylcholine; lurasidone increased glutamate as well. None of the compounds significantly altered the efflux of 5-HT or its metabolite, 5-hydroxyindole acetic acid, or GABA, serine, and glycine. The ability to increase cortical DA efflux was the only shared effect of the compounds which ameliorates the deficit in cognition in rodents following phencyclidine. © 2013 International Society for Neurochemistry.

Vitamin K3 attenuates lipopolysaccharide-induced acute lung injury through inhibition of nuclear factor-κB activation

PubMed Central

Tanaka, S; Nishiumi, S; Nishida, M; Mizushina, Y; Kobayashi, K; Masuda, A; Fujita, T; Morita, Y; Mizuno, S; Kutsumi, H; Azuma, T; Yoshida, M

2010-01-01

Vitamin K is a family of fat-soluble compounds including phylloquinone (vitamin K1), menaquinone (vitamin K2) and menadione (vitamin K3). Recently, it was reported that vitamin K, especially vitamins K1 and K2, exerts a variety of biological effects, and these compounds are expected to be candidates for therapeutic agents against various diseases. In this study, we investigated the anti-inflammatory effects of vitamin K3 in in vitro cultured cell experiments and in vivo animal experiments. In human embryonic kidney (HEK)293 cells, vitamin K3 inhibited the tumour necrosis factor (TNF)-α-evoked translocation of nuclear factor (NF)-κB into the nucleus, although vitamins K1 and K2 did not. Vitamin K3 also suppressed the lipopolysaccharide (LPS)-induced nuclear translocation of NF-κB and production of TNF-α in mouse macrophage RAW264·7 cells. Moreover, the addition of vitamin K3 before and after LPS administration attenuated the severity of lung injury in an animal model of acute lung injury/acute respiratory distress syndrome (ARDS), which occurs in the setting of acute severe illness complicated by systemic inflammation. In the ARDS model, vitamin K3 also suppressed the LPS-induced increase in the serum TNF-α level and inhibited the LPS-evoked nuclear translocation of NF-κB in lung tissue. Despite marked efforts, little therapeutic progress has been made, and the mortality rate of ARDS remains high. Vitamin K3 may be an effective therapeutic strategy against acute lung injury including ARDS. PMID:20030669

Vitamin K3 attenuates lipopolysaccharide-induced acute lung injury through inhibition of nuclear factor-kappaB activation.

PubMed

Tanaka, S; Nishiumi, S; Nishida, M; Mizushina, Y; Kobayashi, K; Masuda, A; Fujita, T; Morita, Y; Mizuno, S; Kutsumi, H; Azuma, T; Yoshida, M

2010-05-01

Vitamin K is a family of fat-soluble compounds including phylloquinone (vitamin K1), menaquinone (vitamin K2) and menadione (vitamin K3). Recently, it was reported that vitamin K, especially vitamins K1 and K2, exerts a variety of biological effects, and these compounds are expected to be candidates for therapeutic agents against various diseases. In this study, we investigated the anti-inflammatory effects of vitamin K3 in in vitro cultured cell experiments and in vivo animal experiments. In human embryonic kidney (HEK)293 cells, vitamin K3 inhibited the tumour necrosis factor (TNF)-alpha-evoked translocation of nuclear factor (NF)-kappaB into the nucleus, although vitamins K1 and K2 did not. Vitamin K3 also suppressed the lipopolysaccharide (LPS)-induced nuclear translocation of NF-kappaB and production of TNF-alpha in mouse macrophage RAW264.7 cells. Moreover, the addition of vitamin K3 before and after LPS administration attenuated the severity of lung injury in an animal model of acute lung injury/acute respiratory distress syndrome (ARDS), which occurs in the setting of acute severe illness complicated by systemic inflammation. In the ARDS model, vitamin K3 also suppressed the LPS-induced increase in the serum TNF-alpha level and inhibited the LPS-evoked nuclear translocation of NF-kappaB in lung tissue. Despite marked efforts, little therapeutic progress has been made, and the mortality rate of ARDS remains high. Vitamin K3 may be an effective therapeutic strategy against acute lung injury including ARDS.

Tracing the origin of azimuthal gluon correlations in the color glass condensate

NASA Astrophysics Data System (ADS)

Lappi, T.; Schenke, B.; Schlichting, S.; Venugopalan, R.

2016-01-01

We examine the origins of azimuthal correlations observed in high energy proton-nucleus collisions by considering the simple example of the scattering of uncorrelated partons off color fields in a large nucleus. We demonstrate how the physics of fluctuating color fields in the color glass condensate (CGC) effective theory generates these azimuthal multiparticle correlations and compute the corresponding Fourier coefficients v n within different CGC approximation schemes. We discuss in detail the qualitative and quantitative differences between the different schemes. We will show how a recently introduced color field domain model that captures key features of the observed azimuthal correlations can be understood in the CGC effective theory as a model of non-Gaussian correlations in the target nucleus.

Free Radicals Generated by Ionizing Radiation Signal Nuclear Translocation of p53

NASA Technical Reports Server (NTRS)

Martinez, J. D.; Pennington, M. E.; Craven, M. T.; Warters, R. L.

1997-01-01

The p53 tumor suppressor is a transcription factor that regulates several pathways, which function collectively to maintain the integrity of the genome. Nuclear localization is critical for wild-type function. However, the signals that regulate subcellular localization of p53 have not been identified. Here, we examine the effect of ionizing radiation on the subcellular localization of p53 in two cell lines in which p63 is normally sequestered in the cytoplasm and found that ionizing radiation caused a biphasic translocation response. p53 entered the nucleus 1-2 hours postirradiation (early response), subsequently emerged from the nucleus, and then again entered the nucleus 12-24 hours after the cells had been irradiated (delayed response). These changes in subcellular localization could be completely blocked by the free radical scavenger, WR1065. By comparison, two DNA-damaging agents that do not generate free radicals, mitomycin C and doxorubicin, caused translocation only after 12-24 h of exposure to the drugs, and this effect could not be inhibited by WR1065. Hence, although all three DNA-damaging agents induced relocalization of p53 to the nucleus, only the translocation caused by radiation was sensitive to free radical scavenging. We suggest that the free radicals generated by ionizing radiation can signal p53 translocation to the nucleus.

Passive smoke effects on cough and airways in young guinea pigs: role of brainstem substance P.

PubMed

Joad, Jesse P; Munch, Paul A; Bric, John M; Evans, Samuel J; Pinkerton, Kent E; Chen, Chao-Yin; Bonham, Ann C

2004-02-15

Children raised with extended exposure to environmental tobacco smoke (ETS) experience increased cough and wheeze. This study was designed to determine whether extended ETS exposure enhances citric acid-induced cough and bronchoconstriction in young guinea pigs via a neurokinin-1 (NK-1) receptor mechanism at the first central synapse of lung afferent neurons, the nucleus tractus solitarius. Guinea pigs were exposed to ETS from 1 to 6 weeks of age. At 5 weeks of age, guide cannulae were implanted bilaterally in the medial nucleus tractus solitarius at a site that produced apnea in response to the glutamate agonist D,L-homocysteic acid. At 6 weeks of age, either vehicle or a NK-1 receptor antagonist, SR 140333, was injected into the nucleus tractus solitarius of the conscious guinea pigs who were then exposed to citric acid aerosol. ETS exposure significantly enhanced citric acid-induced cough by 56% and maximal Penh (a measure of airway obstruction) by 43%, effects that were attenuated by the NK-1 receptor antagonist in the nucleus tractus solitarius. We conclude that in young guinea pigs extended exposure to ETS increases citric acid-induced cough and bronchoconstriction in part by an NK-1 receptor mechanism in the nucleus tractus solitarius.

Ethanol-induced dopamine elevation in the rat--modulatory effects by subchronic treatment with nicotinic drugs.

PubMed

Löf, Elin; Chau, Pei Pei; Stomberg, Rosita; Söderpalm, Bo

2007-01-26

Chronic nicotine administration is associated with increased ethanol consumption in laboratory animals and in humans. Some smokers report less sedation during acute ethanol intoxication after nicotine administration and the sedative effects from ethanol are mediated by inhibitory GABA(A)-receptors. In a series of in vivo microdialysis experiments we investigated whether subchronic pre-treatment with nicotinic drugs known to enhance ethanol consumption in the rat (nicotine or the peripheral nicotinic antagonist hexamethonium) could modulate the alterations in extracellular dopamine observed in response to administration of ethanol or the sedative GABA(A)-agonist diazepam. In the nucleus accumbens and the dorsal striatum, systemic and/or local ethanol administration resulted in transient increases in extracellular dopamine levels that returned to baseline before the local levels of ethanol started to decline. In hexamethonium pre-treated rats, however, the nucleus accumbens dopamine levels were time-locked to the ethanol levels in the same area after systemic or local ethanol administration. Perfusion of diazepam into the nucleus accumbens produced a significant reduction in nucleus accumbens dopamine in controls. Prior subchronic treatment with nicotine or hexamethonium abolished this effect. The present results suggest that subchronic treatment with the nicotinic acetylcholine receptor antagonist hexamethonium reduces a GABA(A)-R mediated counteraction of the nucleus accumbens dopamine response to ethanol. Additionally, we demonstrate that modulation of nicotinic receptors may reduce the sensitivity of GABA(A) receptors to benzodiazepines. These phenomena may offer a novel explanation to why nicotine and alcohol are often co-abused.

High-Throughput Patch Clamp Screening in Human α6-Containing Nicotinic Acetylcholine Receptors

PubMed Central

Armstrong, Lucas C.; Kirsch, Glenn E.; Fedorov, Nikolai B.; Wu, Caiyun; Kuryshev, Yuri A.; Sewell, Abby L.; Liu, Zhiqi; Motter, Arianne L.; Leggett, Carmine S.; Orr, Michael S.

2017-01-01

Nicotine, the addictive component of tobacco products, is an agonist at nicotinic acetylcholine receptors (nAChRs) in the brain. The subtypes of nAChR are defined by their α- and β-subunit composition. The α6β2β3 nAChR subtype is expressed in terminals of dopaminergic neurons that project to the nucleus accumbens and striatum and modulate dopamine release in brain regions involved in nicotine addiction. Although subtype-dependent selectivity of nicotine is well documented, subtype-selective profiles of other tobacco product constituents are largely unknown and could be essential for understanding the addiction-related neurological effects of tobacco products. We describe the development and validation of a recombinant cell line expressing human α6/3β2β3V273S nAChR for screening and profiling assays in an automated patch clamp platform (IonWorks Barracuda). The cell line was pharmacologically characterized by subtype-selective and nonselective reference agonists, pore blockers, and competitive antagonists. Agonist and antagonist effects detected by the automated patch clamp approach were comparable to those obtained by conventional electrophysiological assays. A pilot screen of a library of Food and Drug Administration–approved drugs identified compounds, previously not known to modulate nAChRs, which selectively inhibited the α6/3β2β3V273S subtype. These assays provide new tools for screening and subtype-selective profiling of compounds that act at α6β2β3 nicotinic receptors. PMID:28298165

Subthalamic Nucleus Deep Brain Stimulation Changes Velopharyngeal Control in Parkinson's Disease

ERIC Educational Resources Information Center

Hammer, Michael J.; Barlow, Steven M.; Lyons, Kelly E.; Pahwa, Rajesh

2011-01-01

Purpose: Adequate velopharyngeal control is essential for speech, but may be impaired in Parkinson's disease (PD). Bilateral subthalamic nucleus deep brain stimulation (STN DBS) improves limb function in PD, but the effects on velopharyngeal control remain unknown. We tested whether STN DBS would change aerodynamic measures of velopharyngeal…

PI3K in the ventromedial hypothalamic nucleus mediates estrogenic actions on energy expenditure in female mice

USDA-ARS?s Scientific Manuscript database

Estrogens act in the ventromedial hypothalamic nucleus (VMH) to regulate body weight homeostasis. However, the molecular mechanisms underlying these estrogenic effects are unknown. We show that activation of estrogen receptor-a (ERa) stimulates neural firing of VMH neurons expressing ERa, and these ...

Effect of the fluctuating proton size on the study of the chiral magnetic effect in proton-nucleus collisions

NASA Astrophysics Data System (ADS)

Kharzeev, Dmitri; Tu, Zhoudunming; Zhang, Aobo; Li, Wei

2018-02-01

High energy proton-nucleus (pA) collisions provide an important constraint on the study of the chiral magnetic effect in QCD matter. Naively, in pA collisions one expects no correlation between the orientation of the event plane as reconstructed from the azimuthal distribution of produced hadrons and the orientation of the magnetic field. If this is the case, any charge-dependent hadron correlations can only result from the background. Nevertheless, in this paper we point out that in high multiplicity pA collisions a correlation between the magnetic field and the event plane can appear. This is because triggering on the high hadron multiplicity amounts to selecting Fock components of the incident proton with a large number of partons that are expected to have a transverse size much larger than the average proton size. We introduce the effect of the fluctuating proton size in the Monte Carlo Glauber model and evaluate the resulting correlation between the magnetic field and the second-order event plane in both pA and nucleus-nucleus (AA) collisions. The fluctuating proton size is found to result in a significant correlation between the magnetic field and the event plane in pA collisions, even though the magnitude of the correlation is still much smaller than in AA collisions. This result opens a possibility of studying the chiral magnetic effect in small systems.

Natural compound cudraflavone B shows promising anti-inflammatory properties in vitro.

PubMed

Hošek, Jan; Bartos, Milan; Chudík, Stanislav; Dall'Acqua, Stefano; Innocenti, Gabbriella; Kartal, Murat; Kokoška, Ladislav; Kollár, Peter; Kutil, Zsófia; Landa, Přemysl; Marek, Radek; Závalová, Veronika; Žemlička, Milan; Šmejkal, Karel

2011-04-25

Cudraflavone B (1) is a prenylated flavonoid found in large amounts in the roots of Morus alba, a plant used as a herbal remedy for its reputed anti-inflammatory properties. The present study shows that this compound causes a significant inhibition of inflammatory mediators in selected in vitro models. Thus, 1 was identified as a potent inhibitor of tumor necrosis factor α (TNFα) gene expression and secretion by blocking the translocation of nuclear factor κB (NF-κB) from the cytoplasm to the nucleus in macrophages derived from a THP-1 human monocyte cell line. The NF-κB activity reduction resulted in the inhibition of cyclooxygenase 2 (COX-2) gene expression. Compound 1 acts as a COX-2 and COX-1 inhibitor with higher selectivity toward COX-2 than indomethacin. Pretreatment of cells by 1 shifted the peak in an regulatory gene zinc-finger protein 36 (ZFP36) expression assay. This natural product has noticeable anti-inflammatory properties, suggesting that 1 potentially could be used for development as a nonsteroidal anti-inflammatory drug lead.

Synthesis, in vitro antimalarial activities and cytotoxicities of amino-artemisinin-ferrocene derivatives.

PubMed

de Lange, Christo; Coertzen, Dina; Smit, Frans J; Wentzel, Johannes F; Wong, Ho Ning; Birkholtz, Lyn-Marie; Haynes, Richard K; N'Da, David D

2017-12-26

Novel derivatives bearing a ferrocene attached via a piperazine linker to C-10 of the artemisinin nucleus were prepared from dihydroartemisinin and screened against chloroquine (CQ) sensitive NF54 and CQ resistant K1 and W2 strains of Plasmodium falciparum (Pf) parasites. The overall aim is to imprint oxidant (from the artemisinin) and redox (from the ferrocene) activities. In a preliminary assessment, these compounds were shown to possess activities in the low nM range with the most active being compound 6 with IC 50 values of 2.79 nM against Pf K1 and 3.2 nM against Pf W2. Overall the resistance indices indicate that the compounds have a low potential for cross resistance. Cytotoxicities were determined with Hek293 human embryonic kidney cells and activities against proliferating cells were assessed against A375 human malignant melanoma cells. The selectivity indices of the amino-artemisinin ferrocene derivatives indicate there is overall an appreciably higher selectivity towards the malaria parasite than mammalian cells. Copyright © 2017. Published by Elsevier Ltd.

Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling.

PubMed

Abbott, Jason R; Hodges, Timothy R; Daniels, R Nathan; Patel, Pratiq A; Kennedy, Jack Phillip; Howes, Jennifer E; Akan, Denis T; Burns, Michael C; Sai, Jiqing; Sobolik, Tammy; Beesetty, Yugandhar; Lee, Taekyu; Rossanese, Olivia W; Phan, Jason; Waterson, Alex G; Fesik, Stephen W

2018-06-01

Deregulated RAS activity, often the result of mutation, is implicated in approximately 30% of all human cancers. Despite this statistic, no clinically successful treatment for RAS-driven tumors has yet been developed. One approach for modulating RAS activity is to target and affect the activity of proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report on structure-activity relationships (SAR) in an indole series of compounds. Using structure-based design, we systematically explored substitution patterns on the indole nucleus, the pendant amino acid moiety, and the linker unit that connects these two fragments. Best-in-class compounds activate the nucleotide exchange process at sub-micromolar concentrations in vitro, increase levels of active RAS-GTP in HeLa cells, and elicit signaling changes in the mitogen-activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway, resulting in a decrease in pERK1/2 T202/Y204 protein levels at higher compound concentrations.

Comparison of aryl hydrocarbon hydroxylase and acetanilide 4-hydroxylase induction by polycyclic aromatic compounds in human and mouse cell lines.

PubMed

Jaiswal, A K; Nebert, D W; Eisen, H W

1985-08-01

The human MCF-7 and the mouse Hepa-1 cell culture lines were compared for aryl hydrocarbon hydroxylase and acetanilide 4-hydroxylase inducibility by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and benzo[a]anthracene (BA) and TCDD- and BA-specific binding in the cytosol and nucleus. The effective concentration of BA in the growth medium required to induce either enzyme to 50% of its maximally inducible activity (EC50) was the same (5-11 microM) in both MCF-7 and Hepa-1 cells. On the other hand, the EC50 for TCDD in MCF-7 cells (5-25 nM) was more than 40-fold greater than that in Hepa-1 cells (0.4 to 0.6 nM). P1-450- and P3-450-specific mouse cDNA probes were used to quantitate mRNA induction in the Hepa-1 cell line. P1-450 mRNA was induced markedly by TCDD and benzo[a] anthracene, whereas P3-450 mRNA was induced negligibly. A P1-450-specific human cDNA probe was used to quantitate P1-450 mRNA induction in the MCF-7 cell line. Aryl hydrocarbon hydroxylase inducibility by TCDD or BA always paralleled P1-450 mRNA inducibility in either the mouse or human line. Although the cytosolic Ah receptor in Hepa-1 cells was easily detected by sucrose density gradient centrifugation, gel permeation chromatography, and anion-exchange high-performance liquid chromatography, the cytosolic receptor cannot be detected in MCF-7 cells. Following in vivo exposure of cultures to radiolabeled TCDD, the intranuclear concentration of inducer-receptor complex was at least fifty times greater in Hepa-1 than MCF-7 cultures. The complete lack of measurable cytosolic receptor and almost totally absent inducer-receptor complex in the nucleus of MCF-7 cells was, therefore, out of proportion to its capacity for aryl hydrocarbon hydroxylase and acetanilide 4-hydroxylase inducibility. This MCF-7 line should provide an interesting model for a better understanding of the mechanisms of drug-metabolizing enzyme induction by polycyclic aromatic compounds, including the Ah receptor-mediated mechanism.

Functional Fast Scan Cyclic Voltammetry Assay to Characterize Dopamine D2 and D3 Autoreceptors in the Mouse Striatum

PubMed Central

2010-01-01

Dopamine D2 and D3 autoreceptors are located on presynaptic terminals and are known to control the release and synthesis of dopamine. Dopamine D3 receptors have a fairly restricted pattern of expression in the mammalian brain. Their localization in the nucleus accumbens core and shell is of particular interest because of their association with the rewarding properties of drugs of abuse. Using background subtracted fast scan cyclic voltammetry, we investigated the effects of dopamine D2 and D3 agonists on electrically stimulated dopamine release and uptake rates in the mouse caudate putamen and nucleus accumbens core and shell. The dopamine D2 agonists (−)-quinpirole hydrochloride and 5,6,7,8-tetrahydro-6-(2-propen-1-yl)-4H-thiazolo[4,5-d]azepin-2-amine dihydrochloride (B-HT 920) had the same dopamine release inhibition effects on caudate putamen and nucleus accumbens (core and shell) on the basis of their EC50 values and efficacies. This suggests that the dopamine D2 autoreceptor functionality is comparable in all three striatal regions investigated. The dopamine D3 agonists (4aR,10bR)-3,4a,4,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride ((+)-PD 128907) and (±)-7-Hydroxy-2-dipropylaminotetralin hydrobromide (7-OH-DPAT) had a significantly greater effect on dopamine release inhibition in the nucleus accumbens shell than in the caudate putamen. This study confirms that, the dopamine D3 autoreceptor functionality is greater in the nucleus accumbens shell followed by the nucleus accumbens core, with the caudate putamen having the least. Neither dopamine D2 nor D3 agonists affected the uptake rates in nucleus accumbens but concentrations greater than 0.1 μM lowered the uptake rate in caudate putamen. To validate our method of evaluating dopamine D2 and D3 autoreceptors, sulpiride (D2 antagonist) and nafadotride (D3 antagonist) were used to reverse the effects of the dopamine agonists to approximately 100% of the preagonist dopamine release concentration. Finally, these results demonstrate a functional voltammetric assay that characterizes dopamine D2-like agonists as either D2- or D3-preferring agonists by taking advantage of the unique receptor density within the striatum. PMID:20567609

Alteration of glycine receptor immunoreactivity in the auditory brainstem of mice following three months of exposure to radiofrequency radiation at SAR 4.0 W/kg.

PubMed

Maskey, Dhiraj; Kim, Hyung Gun; Suh, Myung-Whan; Roh, Gu Seob; Kim, Myeung Ju

2014-08-01

The increasing use of mobile communication has triggered an interest in its possible effects on the regulation of neurotransmitter signals. Due to the close proximity of mobile phones to hearing-related brain regions during usage, its use may lead to a decrease in the ability to segregate sounds, leading to serious auditory dysfunction caused by the prolonged exposure to radiofrequency (RF) radiation. The interplay among auditory processing, excitation and inhibitory molecule interactions plays a major role in auditory function. In particular, inhibitory molecules, such a glycine, are predominantly localized in the auditory brainstem. However, the effects of exposure to RF radiation on auditory function have not been reported to date. Thus, the aim of the present study was to investigate the effects of exposure to RF radiation on glycine receptor (GlyR) immunoreactivity (IR) in the auditory brainstem region at 835 MHz with a specific absorption rate of 4.0 W/kg for three months using free-floating immunohistochemistry. Compared with the sham control (SC) group, a significant loss of staining intensity of neuropils and cells in the different subdivisions of the auditory brainstem regions was observed in the mice exposed to RF radiation (E4 group). A decrease in the number of GlyR immunoreactive cells was also noted in the cochlear nuclear complex [anteroventral cochlear nucleus (AVCN), 31.09%; dorsal cochlear nucleus (DCN), 14.08%; posteroventral cochlear nucleus (PVCN), 32.79%] and the superior olivary complex (SOC) [lateral superior olivary nucleus (LSO), 36.85%; superior paraolivary nucleus (SPN), 24.33%, medial superior olivary nucleus (MSO), 23.23%; medial nucleus of the trapezoid body (MNTB), 10.15%] of the mice in the E4 group. Auditory brainstem response (ABR) analysis also revealed a significant threshold elevation of in the exposed (E4) group, which may be associated with auditory dysfunction. The present study suggests that the auditory brainstem region is susceptible to chronic exposure to RF radiation, which may affect the function of the central auditory system.

Regulation of calcium signals in the nucleus by a nucleoplasmic reticulum

PubMed Central

Echevarría, Wihelma; Leite, M. Fatima; Guerra, Mateus T.; Zipfel, Warren R.; Nathanson, Michael H.

2013-01-01

Calcium is a second messenger in virtually all cells and tissues1. Calcium signals in the nucleus have effects on gene transcription and cell growth that are distinct from those of cytosolic calcium signals; however, it is unknown how nuclear calcium signals are regulated. Here we identify a reticular network of nuclear calcium stores that is continuous with the endoplasmic reticulum and the nuclear envelope. This network expresses inositol 1,4,5-trisphosphate (InsP3) receptors, and the nuclear component of InsP3-mediated calcium signals begins in its locality. Stimulation of these receptors with a little InsP3 results in small calcium signals that are initiated in this region of the nucleus. Localized release of calcium in the nucleus causes nuclear protein kinase C (PKC) to translocate to the region of the nuclear envelope, whereas release of calcium in the cytosol induces translocation of cytosolic PKC to the plasma membrane. Our findings show that the nucleus contains a nucleoplasmic reticulum with the capacity to regulate calcium signals in localized subnuclear regions. The presence of such machinery provides a potential mechanism by which calcium can simultaneously regulate many independent processes in the nucleus. PMID:12717445

The novel adenosine A(2A) antagonist prodrug MSX-4 is effective in animal models related to motivational and motor functions.

PubMed

Santerre, Jessica L; Nunes, Eric J; Kovner, Rotem; Leser, Chelsea E; Randall, Patrick A; Collins-Praino, Lyndsey E; Lopez Cruz, Laura; Correa, Merce; Baqi, Younis; Müller, Christa E; Salamone, John D

2012-10-01

Adenosine A(2A) and dopamine D2 receptors interact to regulate diverse aspects of ventral and dorsal striatal functions related to motivational and motor processes, and it has been suggested that adenosine A(2A) antagonists could be useful for the treatment of depression, parkinsonism and other disorders. The present experiments were performed to characterize the effects of MSX-4, which is an amino acid ester prodrug of the potent and selective adenosine A(2A) receptor antagonist MSX-2, by assessing its ability to reverse pharmacologically induced motivational and motor impairments. In the first group of studies, MSX-4 reversed the effects of the D2 antagonist eticlopride on a concurrent lever pressing/chow feeding task that is used as a measure of effort-related choice behavior. MSX-4 was less potent after intraperitoneal administration than the comparison compound, MSX-3, though both were equally efficacious. With this task, MSX-4 was orally active in the same dose range as MSX-3. MSX-4 also reversed the locomotor suppression induced by eticlopride in the open field, but did not induce anxiogenic effects as measured by the relative amount of interior activity. Behaviorally active doses of MSX-4 also attenuated the increase in c-Fos and pDARPP-32(Thr34) expression in nucleus accumbens core that was induced by injections of eticlopride. In addition, MSX-4 suppressed the oral tremor induced by the anticholinesterase galantamine, which is consistent with an antiparkinsonian profile. These actions of MSX-4 indicate that this compound could have potential utility as a treatment for parkinsonism, as well as some of the motivational symptoms of depression and other disorders. Copyright © 2012 Elsevier Inc. All rights reserved.

Lipid-binding proteins modulate ligand-dependent trans-activation by peroxisome proliferator-activated receptors and localize to the nucleus as well as the cytoplasm.

PubMed

Helledie, T; Antonius, M; Sorensen, R V; Hertzel, A V; Bernlohr, D A; Kølvraa, S; Kristiansen, K; Mandrup, S

2000-11-01

Peroxisome proliferator-activated receptors (PPARs) are activated by a variety of fatty acids, eicosanoids, and hypolipidemic and insulin-sensitizing drugs. Many of these compounds bind avidly to members of a family of small lipid-binding proteins, the fatty acid-binding proteins (FABPs). Fatty acids are activated to CoA esters, which bind with high affinity to the acyl-CoA-binding protein (ACBP). Thus, the availability of known and potential PPAR ligands may be regulated by lipid-binding proteins. In this report we show by transient transfection of CV-1 cells that coexpression of ACBP and adipocyte lipid-binding protein (ALBP) exerts a ligand- and PPAR subtype-specific attenuation of PPAR-mediated trans-activation, suggesting that lipid-binding proteins, when expressed at high levels, may function as negative regulators of PPAR activation by certain ligands. Expression of ACBP, ALBP, and keratinocyte lipid-binding protein (KLBP) is induced during adipocyte differentiation, a process during which PPARgamma plays a prominent role. We present evidence that endogenous ACBP, ALBP, and KLBP not only localize to the cytoplasm but also exhibit a prominent nuclear localization in 3T3-L1 adipocytes. In addition, forced expression of ACBP, ALBP, and KLBP in CV-1 cells resulted in a substantial accumulation of all three proteins in the nucleus. These results suggest that lipid-binding proteins, contrary to the general assumption, may exert their action in the nucleus as well as in the cytoplasm.

Antioxidative Dietary Compounds Modulate Gene Expression Associated with Apoptosis, DNA Repair, Inhibition of Cell Proliferation and Migration

PubMed Central

Wang, Likui; Gao, Shijuan; Jiang, Wei; Luo, Cheng; Xu, Maonian; Bohlin, Lars; Rosendahl, Markus; Huang, Wenlin

2014-01-01

Many dietary compounds are known to have health benefits owing to their antioxidative and anti-inflammatory properties. To determine the molecular mechanism of these food-derived compounds, we analyzed their effect on various genes related to cell apoptosis, DNA damage and repair, oxidation and inflammation using in vitro cell culture assays. This review further tests the hypothesis proposed previously that downstream products of COX-2 (cyclooxygenase-2) called electrophilic oxo-derivatives induce antioxidant responsive elements (ARE), which leads to cell proliferation under antioxidative conditions. Our findings support this hypothesis and show that cell proliferation was inhibited when COX-2 was down-regulated by polyphenols and polysaccharides. Flattened macrophage morphology was also observed following the induction of cytokine production by polysaccharides extracted from viili, a traditional Nordic fermented dairy product. Coix lacryma-jobi (coix) polysaccharides were found to reduce mitochondrial membrane potential and induce caspase-3- and 9-mediated apoptosis. In contrast, polyphenols from blueberries were involved in the ultraviolet-activated p53/Gadd45/MDM2 DNA repair system by restoring the cell membrane potential. Inhibition of hypoxia-inducible factor-1 by saponin extracts of ginsenoside (Ginsen) and Gynostemma and inhibition of S100A4 by coix polysaccharides inhibited cancer cell migration and invasion. These observations suggest that antioxidants and changes in cell membrane potential are the major driving forces that transfer signals through the cell membrane into the cytosol and nucleus, triggering gene expression, changes in cell proliferation and the induction of apoptosis or DNA repair. PMID:25226533

Abnormalities in hemispheric specialization of caudate nucleus connectivity in schizophrenia

PubMed Central

Mueller, Sophia; Wang, Danhong; Pan, Ruiqi; Holt, Daphne J.; Liu, Hesheng

2015-01-01

Importance Hemispheric specialization of the human brain is a marker of successful neurodevelopment. Altered brain asymmetry that has been repeatedly reported in schizophrenia may represent consequences of disrupted neurodevelopment in the disorder. However, a complete picture of functional specialization in the schizophrenic brain and its connectional substrates are yet to be unveiled. Objective We aimed to quantify intrinsic hemispheric specialization at a cortical and subcortical level and to reveal potential disease effects in schizophrenia. Design/Participants Resting-state functional connectivity MRI has been previously used to quantitatively measure hemispheric specialization in healthy subjects, in a reliable manner. Here we quantified the intrinsic hemispheric specialization at the whole brain level in 31 patients with schizophrenia and 37 demographically matched healthy control subjects using resting-state functional connectivity MRI. Results The caudate nucleus, and cortical regions with connections to the caudate nucleus, showed markedly abnormal hemispheric specialization in schizophrenia. Compared to healthy controls, patients exhibited weaker specialization in the left, but the opposite pattern in the right, caudate nucleus. Schizophrenia patients also displayed a disruption of the inter-hemispheric coordination among the cortical regions with connections to the caudate nucleus. A linear classifier based on the specialization of the caudate nucleus distinguished patients from controls with a classification accuracy of 74%. Conclusions and Relevance These data suggested that hemispheric specialization could serve as a potential imaging biomarker of schizophrenia that, compared to task-based fMRI measures, is less prone to the confounding effects of variation in task compliance, cognitive ability, and command of language. PMID:25830688

Abnormalities in hemispheric specialization of caudate nucleus connectivity in schizophrenia.

PubMed

Mueller, Sophia; Wang, Danhong; Pan, Ruiqi; Holt, Daphne J; Liu, Hesheng

2015-06-01

Hemispheric specialization of the human brain is a marker of successful neurodevelopment. Altered brain asymmetry that has been repeatedly reported in schizophrenia may represent consequences of disrupted neurodevelopment in the disorder. However, a complete picture of functional specialization in the schizophrenic brain and its connectional substrates is yet to be unveiled. To quantify intrinsic hemispheric specialization at cortical and subcortical levels and to reveal potential disease effects in schizophrenia. Resting-state functional connectivity magnetic resonance imaging has been previously used to quantitatively measure hemispheric specialization in healthy individuals in a reliable manner. We quantified the intrinsic hemispheric specialization at the whole brain level in 31 patients with schizophrenia and 37 demographically matched healthy controls from November 28, 2007, through June 29, 2010, using resting-state functional magnetic resonance imaging. The caudate nucleus and cortical regions with connections to the caudate nucleus had markedly abnormal hemispheric specialization in schizophrenia. Compared with healthy controls, patients exhibited weaker specialization in the left, but the opposite pattern in the right, caudate nucleus (P < .001). Patients with schizophrenia also had a disruption of the interhemispheric coordination among the cortical regions with connections to the caudate nucleus. A linear classifier based on the specialization of the caudate nucleus distinguished patients from controls with a classification accuracy of 74% (with a sensitivity of 68% and a specificity of 78%). These data suggest that hemispheric specialization could serve as a potential imaging biomarker of schizophrenia that, compared with task-based functional magnetic resonance imaging measures, is less prone to the confounding effects of variation in task compliance, cognitive ability, and command of language.

Thermal modeling of cometary nuclei

USGS Publications Warehouse

Weissman, P.R.; Kieffer, H.H.

1981-01-01

A new model of the sublimation of volatile ices from a cometary nucleus has been developed which includes the effects of diurnal heating and cooling, rotation period and pole orientation, and thermal properties of the ice and subsurface layers. The model also includes the contribution from coma opacity, scattering, and thermal emission, where the properties of the coma are derived from the integrated rate of volatile production by the nucleus. The model is applied to the specific case of the 1986 apparition of Halley's comet. It is found that the generation of a cometary dust coma actually increases the total energy reaching the Halley nucleus. This results because of the significantly greater geometrical cross section of the coma as compared with the bare nucleus, and because the coma provides an essentially isotropic source of multiply scattered sunlight and thermal emission over the entire nucleus surface. For Halley, the calculated coma opacity is approximately 0.2 at 1 AU from the Sun, and 1.2 at perihelion (0.587 AU). At 1 AU this has little effect on dayside temperatures (maximum ???200??K) but raises nightside temperatures (minimum ???150??K) by about 40??K. At perihelion the higher opacity results in a nearly isothermal nucleus with only small diurnal and latitudinal temperature variations. The general surface temperature is 205??K with a maximum of 209??K at local noon on the equator. Some possible consequences of the results with respect to the generation of nongravitational forces, observed volatile production rates for comets, and cometary lifetimes against sublimation are discussed. ?? 1981.

A fluorescent molecular rotor probes the kinetic process of degranulation of mast cells.

PubMed

Furuno, T; Isoda, R; Inagaki, K; Iwaki, T; Noji, M; Nakanishi, M

1992-08-01

A confocal fluorescence microscope was used to study the exocytotic secretory processes of mast cells in combination with an fluorescent molecular rotor, 9-(dicyanovinyl)julolidine (DCVJ). DCVJ is known to be an unique fluorescent dye which increases its quantum yield with decreasing intramolecular rotation. Here, DCVJ-loaded peritoneal rat mast cells were stimulated with compound 48/80 and their fluorescence images were compared with fluorescence calcium images of fluo-3-loaded mast cells. Subsequent to transient increases in intracellular free calcium ion concentration, DCVJ fluorescence increased dramatically in the cytoplasm and formed a ring-like structure around the nucleus, suggesting the possibility that the dye bound to the proteins composing the cytoskeletal architecture. Furthermore, the increases of DCVJ fluorescence intensities were mostly blocked in the presence of cytochalasin D (10 microM). However, fluo-3 fluorescence intensities still increased after addition of compound 48/80.

Honey bee (Hymenoptera: Apidae) foraging in response to preconditioning with onion flower scent compounds.

PubMed

Silva, Erin M; Dean, Bill B; Hiller, Larry K

2003-10-01

Onion (Allium cepa L.) seed production has long been plagued with yield problems because of lack of pollination by the honey bee, Apis mellifera L. To attempt to attract more pollinators to the onion seed production field, honey bees were conditioned to associate onion floral odor components with a reward. Isolated nucleus hives of honey bees were fed 30% sucrose solutions scented with a 0.2% solution of onion floral odor compounds. After feeding on these solutions for 6 wk, bees were not found to prefer onion flowers to two competing food sources, carrot and alfalfa flowers, at the 5% significance level. However, there was an overall trend indicating a change in honey bee behavior, with fewer "trained" bees visiting alfalfa and carrot and more visiting onion. Thus, it may be possible to alter honey bee behavior with preconditioning but probably not to a degree that would be economically significant.

Convergence of limb, visceral, and vertical semicircular canal or otolith inputs onto vestibular nucleus neurons

NASA Technical Reports Server (NTRS)

Jian, B. J.; Shintani, T.; Emanuel, B. A.; Yates, B. J.

2002-01-01

The major goal of this study was to determine the patterns of convergence of non-labyrinthine inputs from the limbs and viscera onto vestibular nucleus neurons receiving signals from vertical semicircular canals or otolith organs. A secondary aim was to ascertain whether the effects of non-labyrinthine inputs on the activity of vestibular nucleus neurons is affected by bilateral peripheral vestibular lesions. The majority (72%) of vestibular nucleus neurons in labyrinth-intact animals whose firing was modulated by vertical rotations responded to electrical stimulation of limb and/or visceral nerves. The activity of even more vestibular nucleus neurons (93%) was affected by limb or visceral nerve stimulation in chronically labyrinthectomized preparations. Some neurons received non-labyrinthine inputs from a variety of peripheral sources, including antagonist muscles acting at the same joint, whereas others received inputs from more limited sources. There was no apparent relationship between the spatial and dynamic properties of a neuron's responses to tilts in vertical planes and the non-labyrinthine inputs that it received. These data suggest that non-labyrinthine inputs elicited during movement will modulate the processing of information by the central vestibular system, and may contribute to the recovery of spontaneous activity of vestibular nucleus neurons following peripheral vestibular lesions. Furthermore, some vestibular nucleus neurons with non-labyrinthine inputs may be activated only during particular behaviors that elicit a specific combination of limb and visceral inputs.

Convergence of limb, visceral, and vertical semicircular canal or otolith inputs onto vestibular nucleus neurons.

PubMed

Jian, B J; Shintani, T; Emanuel, B A; Yates, B J

2002-05-01

The major goal of this study was to determine the patterns of convergence of non-labyrinthine inputs from the limbs and viscera onto vestibular nucleus neurons receiving signals from vertical semicircular canals or otolith organs. A secondary aim was to ascertain whether the effects of non-labyrinthine inputs on the activity of vestibular nucleus neurons is affected by bilateral peripheral vestibular lesions. The majority (72%) of vestibular nucleus neurons in labyrinth-intact animals whose firing was modulated by vertical rotations responded to electrical stimulation of limb and/or visceral nerves. The activity of even more vestibular nucleus neurons (93%) was affected by limb or visceral nerve stimulation in chronically labyrinthectomized preparations. Some neurons received non-labyrinthine inputs from a variety of peripheral sources, including antagonist muscles acting at the same joint, whereas others received inputs from more limited sources. There was no apparent relationship between the spatial and dynamic properties of a neuron's responses to tilts in vertical planes and the non-labyrinthine inputs that it received. These data suggest that non-labyrinthine inputs elicited during movement will modulate the processing of information by the central vestibular system, and may contribute to the recovery of spontaneous activity of vestibular nucleus neurons following peripheral vestibular lesions. Furthermore, some vestibular nucleus neurons with non-labyrinthine inputs may be activated only during particular behaviors that elicit a specific combination of limb and visceral inputs.

Increase in cocaine- and amphetamine-regulated transcript (CART) in specific areas of the mouse brain by acute caffeine administration.

PubMed

Cho, Jin Hee; Cho, Yun Ha; Kim, Hyo Young; Cha, Seung Ha; Ryu, Hyun; Jang, Wooyoung; Shin, Kyung Ho

2015-04-01

Caffeine produces a variety of behavioral effects including increased alertness, reduced food intake, anxiogenic effects, and dependence upon repeated exposure. Although many of the effects of caffeine are mediated by its ability to block adenosine receptors, it is possible that other neural substrates, such as cocaine- and amphetamine-regulated transcript (CART), may be involved in the effects of caffeine. Indeed, a recent study demonstrated that repeated caffeine administration increases CART in the mouse striatum. However, it is not clear whether acute caffeine administration alters CART in other areas of the brain. To explore this possibility, we investigated the dose- and time-dependent changes in CART immunoreactivity (CART-IR) after a single dose of caffeine in mice. We found that a high dose of caffeine (100 mg/kg) significantly increased CART-IR 2 h after administration in the nucleus accumbens shell (AcbSh), dorsal bed nucleus of the stria terminalis (dBNST), central nucleus of the amygdala (CeA), paraventricular hypothalamic nucleus (PVN), arcuate hypothalamic nucleus (Arc), and locus coeruleus (LC), and returned to control levels after 8 h. But this increase was not observed in other brain areas. In addition, caffeine administration at doses of 25 and 50 mg/kg appears to produce dose-dependent increases in CART-IR in these brain areas; however, the magnitude of increase in CART-IR observed at a dose of 50 mg/kg was similar or greater than that observed at a dose of 100 mg/kg. This result suggests that CART-IR in AcbSh, dBNST, CeA, PVN, Arc, and LC is selectively affected by caffeine administration. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cometary science. The organic-rich surface of comet 67P/Churyumov-Gerasimenko as seen by VIRTIS/Rosetta.

PubMed

Capaccioni, F; Coradini, A; Filacchione, G; Erard, S; Arnold, G; Drossart, P; De Sanctis, M C; Bockelee-Morvan, D; Capria, M T; Tosi, F; Leyrat, C; Schmitt, B; Quirico, E; Cerroni, P; Mennella, V; Raponi, A; Ciarniello, M; McCord, T; Moroz, L; Palomba, E; Ammannito, E; Barucci, M A; Bellucci, G; Benkhoff, J; Bibring, J P; Blanco, A; Blecka, M; Carlson, R; Carsenty, U; Colangeli, L; Combes, M; Combi, M; Crovisier, J; Encrenaz, T; Federico, C; Fink, U; Fonti, S; Ip, W H; Irwin, P; Jaumann, R; Kuehrt, E; Langevin, Y; Magni, G; Mottola, S; Orofino, V; Palumbo, P; Piccioni, G; Schade, U; Taylor, F; Tiphene, D; Tozzi, G P; Beck, P; Biver, N; Bonal, L; Combe, J-Ph; Despan, D; Flamini, E; Fornasier, S; Frigeri, A; Grassi, D; Gudipati, M; Longobardo, A; Markus, K; Merlin, F; Orosei, R; Rinaldi, G; Stephan, K; Cartacci, M; Cicchetti, A; Giuppi, S; Hello, Y; Henry, F; Jacquinod, S; Noschese, R; Peter, G; Politi, R; Reess, J M; Semery, A

2015-01-23

The VIRTIS (Visible, Infrared and Thermal Imaging Spectrometer) instrument on board the Rosetta spacecraft has provided evidence of carbon-bearing compounds on the nucleus of the comet 67P/Churyumov-Gerasimenko. The very low reflectance of the nucleus (normal albedo of 0.060 ± 0.003 at 0.55 micrometers), the spectral slopes in visible and infrared ranges (5 to 25 and 1.5 to 5% kÅ(-1)), and the broad absorption feature in the 2.9-to-3.6-micrometer range present across the entire illuminated surface are compatible with opaque minerals associated with nonvolatile organic macromolecular materials: a complex mixture of various types of carbon-hydrogen and/or oxygen-hydrogen chemical groups, with little contribution of nitrogen-hydrogen groups. In active areas, the changes in spectral slope and absorption feature width may suggest small amounts of water-ice. However, no ice-rich patches are observed, indicating a generally dehydrated nature for the surface currently illuminated by the Sun. Copyright © 2015, American Association for the Advancement of Science.

A Nucleus-Imaging Probe That Selectively Stabilizes a Minor Conformation of c-MYC G-quadruplex and Down-regulates c-MYC Transcription in Human Cancer Cells

PubMed Central

Panda, Deepanjan; Debnath, Manish; Mandal, Samir; Bessi, Irene; Schwalbe, Harald; Dash, Jyotirmayee

2015-01-01

The c-MYC proto-oncogene is a regulator of fundamental cellular processes such as cell cycle progression and apoptosis. The development of novel c-MYC inhibitors that can act by targeting the c-MYC DNA G-quadruplex at the level of transcription would provide potential insight into structure-based design of small molecules and lead to a promising arena for cancer therapy. Herein we report our finding that two simple bis-triazolylcarbazole derivatives can inhibit c-MYC transcription, possibly by stabilizing the c-MYC G-quadruplex. These compounds are prepared using a facile and modular approach based on Cu(I) catalysed azide and alkyne cycloaddition. A carbazole ligand with carboxamide side chains is found to be microenvironment-sensitive and highly selective for “turn-on” detection of c-MYC quadruplex over duplex DNA. This fluorescent probe is applicable to visualize the cellular nucleus in living cells. Interestingly, the ligand binds to c-MYC in an asymmetric fashion and selects the minor-populated conformer via conformational selection. PMID:26286633

Proton magnetic resonance imaging with para-hydrogen induced polarization.

PubMed

Dechent, Jan F; Buljubasich, Lisandro; Schreiber, Laura M; Spiess, Hans W; Münnemann, Kerstin

2012-02-21

A major challenge in imaging is the detection of small amounts of molecules of interest. In the case of magnetic resonance imaging (MRI) their signals are typically concealed by the large background signal of e.g. the body. This problem can be tackled by hyperpolarization which increases the NMR signals up to several orders of magnitude. However, this strategy is limited for (1)H, the most widely used nucleus in NMR and MRI, because the enormous number of protons in the body screens the small amount of hyperpolarized ones. Here, we describe a method giving rise to high (1)H MRI contrast for hyperpolarized molecules against a large background signal. The contrast is based on the J-coupling induced rephasing of the NMR signal of molecules hyperpolarized via PHIP and it can easily be implemented in common pulse sequences. We discuss several scenarios with different or equal dephasing times T(2)* for the hyperpolarized and thermally polarized compounds and verify our approach by experiments. This method may open up unprecedented opportunities to use the standard MRI nucleus (1)H for e.g. metabolic imaging in the future.

Advancing the Theory of Nuclear Reactions with Rare Isotopes: From the Laboratory to the Cosmos

DOE Office of Scientific and Technical Information (OSTI.GOV)

Elster, Charlotte

2015-06-01

The mission of the TORUS Topical Collaboration is to develop new methods that will advance nuclear reaction theory for unstable isotopes by using three-body techniques to improve direct-reaction calculations, and, by using a new partial-fusion theory, to integrate descriptions of direct and compound-nucleus reactions. Ohio University concentrates its efforts on the first part of the mission. Since direct measurements are often not feasible, indirect methods, e.g. (d,p) reactions, should be used. Those (d,p) reactions may be viewed as three-body reactions and described with Faddeev techniques. Faddeev equations in momentum space have a long tradition of utilizing separable interactions in ordermore » to arrive at sets of coupled integral equations in one variable. While there exist several separable representations for the nucleon-nucleon interaction, the optical potential between a neutron (proton) and a nucleus is not readily available in separable form. For this reason we first embarked in introducing a separable representation for complex phenomenological optical potentials of Woods-Saxon type.« less

Increased colonic propionate reduces anticipatory reward responses in the human striatum to high-energy foods.

PubMed

Byrne, Claire S; Chambers, Edward S; Alhabeeb, Habeeb; Chhina, Navpreet; Morrison, Douglas J; Preston, Tom; Tedford, Catriona; Fitzpatrick, Julie; Irani, Cherag; Busza, Albert; Garcia-Perez, Isabel; Fountana, Sofia; Holmes, Elaine; Goldstone, Anthony P; Frost, Gary S

2016-07-01

Short-chain fatty acids (SCFAs), metabolites produced through the microbial fermentation of nondigestible dietary components, have key roles in energy homeostasis. Animal research suggests that colon-derived SCFAs modulate feeding behavior via central mechanisms. In humans, increased colonic production of the SCFA propionate acutely reduces energy intake. However, evidence of an effect of colonic propionate on the human brain or reward-based eating behavior is currently unavailable. We investigated the effect of increased colonic propionate production on brain anticipatory reward responses during food picture evaluation. We hypothesized that elevated colonic propionate would reduce both reward responses and ad libitum energy intake via stimulation of anorexigenic gut hormone secretion. In a randomized crossover design, 20 healthy nonobese men completed a functional magnetic resonance imaging (fMRI) food picture evaluation task after consumption of control inulin or inulin-propionate ester, a unique dietary compound that selectively augments colonic propionate production. The blood oxygen level-dependent (BOLD) signal was measured in a priori brain regions involved in reward processing, including the caudate, nucleus accumbens, amygdala, anterior insula, and orbitofrontal cortex (n = 18 had analyzable fMRI data). Increasing colonic propionate production reduced BOLD signal during food picture evaluation in the caudate and nucleus accumbens. In the caudate, the reduction in BOLD signal was driven specifically by a lowering of the response to high-energy food. These central effects were partnered with a decrease in subjective appeal of high-energy food pictures and reduced energy intake during an ad libitum meal. These observations were not related to changes in blood peptide YY (PYY), glucagon-like peptide 1 (GLP-1), glucose, or insulin concentrations. Our results suggest that colonic propionate production may play an important role in attenuating reward-based eating behavior via striatal pathways, independent of changes in plasma PYY and GLP-1. This trial was registered at clinicaltrials.gov as NCT00750438.

Relative role of different radii in the dynamics of 8B+58Ni reaction

NASA Astrophysics Data System (ADS)

Kaur, Amandeep; Sandhu, Kirandeep; Sharma, Manoj K.

2018-05-01

In the present work, we intend to analyze the significance of three different radius terms in the framework of dynamical cluster-decay model (DCM) based calculations. In the majority of DCM based calculations the impact of mass- dependent radius R(A) is extensively analyzed. The other two factors on which the radius term may depend are, the neutron- proton asymmetry and the charge of the decaying fragments. Hence, the asymmetry dependent radius term R(I) and charge dependent radius term R(Z) are incorporated in DCM based calculations to investigate their effect on the reaction dynamics involved. Here, we present an extension of an earlier work based on the decay of 66As* compound nucleus by including R(I) and R(Z) radii in addition to the R(A) term. The effect of replacement of R(A) with R(I) and R(Z) is analyzed via fragmentation structure, tunneling probabilities (P) and other barrier characteristics like barrier height (VB), barrier position (RB), barrier turning point Ra etc. The role of temperature, deformations and angular momentum is duly incorporated in the present calculations.

Kavalactones and dihydrokavain modulate GABAergic activity in a rat gastric-brainstem preparation.

PubMed

Yuan, Chun-Su; Dey, Lucy; Wang, Anbao; Mehendale, Sangeeta; Xie, Jing-Tian; Aung, Han H; Ang-Lee, Michael K

2002-12-01

Using an in vitro neonatal rat gastric-brainstem preparation, the activity of majority neurons recorded in the nucleus tractus solitarius (NTS) of the brainstem were significantly inhibited by GABA A receptor agonist, muscimol (30 microM), and this inhibition was reversed by selective GABA A receptor antagonist, bicuculline (10 microM). Application of kavalactones (300 microg/ml) and dihydrokavain (300 microM) into the brainstem compartment of the preparation also significantly reduced the discharge rate of these NTS neurons (39 % and 32 %, respectively, compared to the control level), and this reduction was partially reversed by bicuculline (10 microM). Kavalactones or dihydrokavain induced inhibitory effects were not reduced after co-application of saclofen (10 microM; a selective GABA B receptor antagonist) or naloxone (100 nM; an opioid receptor antagonist). Pretreatment with kavalactones (300 microg/ml) or dihydrokavain (300 microM) significantly decreased the NTS inhibitory effects induced by muscimol (30 microM), approximately from 51 % to 36 %. Our results demonstrated modulation of brainstem GABAergic mechanism by kavalactones and dihydrokavain, and suggested that these compounds may play an important role in regulation of GABAergic neurotransmission.

False labelling of dopaminergic terminals in the rabbit caudate nucleus: uptake and release of [3H]-5-hydroxytryptamine.

PubMed

Feuerstein, T J; Hertting, G; Lupp, A; Neufang, B

1986-07-01

The effect of the catecholamine uptake inhibitor nomifensine and of the 5-hydroxytryptamine (5-HT) uptake blocker 6-nitroquipazine on the accumulation of [3H]-5-HT (0.1 microM, 60 min incubation) and [3H]-dopamine (0.1 microM, 30 min incubation) into slices of hippocampus and caudate nucleus of the rabbit was investigated. In addition, the influence of nomifensine on the electrically evoked [3H]-5-HT release from caudate nucleus slices and of nomifensine and 6-nitroquipazine on [3H]-5-HT released from caudate nucleus slices was analysed. In hippocampal slices, which contain practically no dopaminergic but densely distributed 5-hydroxytryptaminergic and noradrenergic nerve terminals (ratio of dopamine:5-HT:noradrenaline about 1:30:25), nomifensine (1, 10 microM) did not affect the accumulation of [3H]-5-HT; 6-nitroquipazine (1 microM) reduced [3H]-5-HT uptake to about 35% of controls. In the caudate nucleus, however, where dopamine is the predominant monoamine (ratio of dopamine:5-HT:noradrenaline about 400:25:15) nomifensine (1, 10 microM) reduced the tritium accumulation to 65% whereas 6-nitroquipazine (1 microM) was ineffective. The combination of both drugs (1 microM each) led to a further decrease to about 15%. The uptake of [3H]-dopamine into hippocampal slices was blocked by both nomifensine (1 microM) and 6-nitroquipazine (1 microM) whereas in caudate nucleus slices only nomifensine (1, 10 microM) reduced the accumulation of [3H]-dopamine. The combination of both drugs was not more effective than nomifensine alone. The different effects of both uptake inhibitors in the hippocampus and caudate nucleus suggest a neurone specific rather than a substrate specific mode of action. 4 In caudate nucleus slices incubated with [3H]-5-HT and superfused continuously the electrically evoked 5-HT release was diminished by the D2-dopamine receptor agonist LY 171555 and enhanced by the D2-receptor antagonist domperidone. If, however, the labelling of caudate nucleus slices was performed in the presence of I microM or 1O microM nomifensine, the modulation of 5-HT release via D2- receptors was reduced or abolished, respectively. In the hippocampus both LY 171555 and domperidone were completely ineffective in modulating 5-HT release regardless of the absence or presence of nomifensine. 5 The present results indicate that an inverse cross labelling of [3H]-5-HT into dopaminergic and of [3H]-dopamine into 5-hydroxytryptaminergic terminals may occur despite the low concentration (0.1 microM) oftritiated transmitters used. Such cross labelling, as demonstrated with the incubation period of 60 min in the caudate nucleus, may falsely indicate the existence of D2-dopamine receptors modulating [3H]-5-HT release. If both 5-hydroxytryptaminergic and dopaminergic terminals are present within the brain region under investigation false labelling can be corrected using neuronally specific uptake inhibitors.

Effects of morphine, physostigmine and raphe nuclei stimulation on 5-hydroxytryptamine release from the cerebral cortex of the cat.

PubMed Central

Aiello-Malmberg, P; Bartolini, A; Bartolini, R; Galli, A

1979-01-01

1. The release of 5-hydroxytryptamine (5-HT) from the cerebral cortex and caudate nucleus of brainstem-transected cats and from the cerebral cortex of rats anaesthetized with urethane was determined by radioenzymatic and biological assay. 2. The stimulation of nucleus linearis intermedius of raphe doubles the basal 5-HT release in the caudate nucleus and increases it 3 fold in the cerebral cortex. The effects of the electrical stimulation of the raphe are potentiated by chlorimipramine. 3. Brain 5-HT release is greatly increased by morphine hydrochloride (6 mg/kg i.v.) and by physostigmine (100 microgram/kg i.v.), but not by DL-DOPA (50 mg/kg i.v.). 4. It is suggested that the 5-HT releasing action of physostigmine can contribute to some of its pharmacological effects such as the analgesic effect so far attributed exclusively to its indirect cholinomimetic activity. 5. The 5-HT releasing action of physostigmine seems unrelated to its anticholinesterase activity. PMID:435680

A continuing controversy: Has the cometary nucleus been resolved?

NASA Technical Reports Server (NTRS)

Sekanina, Z.

1976-01-01

Evidence is presented for classifying cometary nuclei into two basic types, described by core mantle and coreless models. Mass loss related nongravitational effects in a comet's motion as a function of time are included in considering gradual evaporation of an icy envelope surrounding the meteoric matrix in the core of the nucleus.

Spiking Phineas Gage: A Neurocomputational Theory of Cognitive-Affective Integration in Decision Making

ERIC Educational Resources Information Center

Wagar, Brandon M.; Thagard, Paul

2004-01-01

The authors present a neurological theory of how cognitive information and emotional information are integrated in the nucleus accumbens during effective decision making. They describe how the nucleus accumbens acts as a gateway to integrate cognitive information from the ventromedial prefrontal cortex and the hippocampus with emotional…

Effect of Different Forms of Hypokinesia on the Ultrastructure of Limbic, Extrapyramidal and Neocortical Areas of the Rat Brain: Electron Microscopic Study

NASA Astrophysics Data System (ADS)

Zhvania, Mzia G.; Japaridze, Nadezhda J.; Ksovreli, Mariam G.

The effect of chronic restraint stress and chronic hypokinesia "without stress" on the ultrastructure of central and lateral nuclei of amygdala, CA1 and CA3 area of the hippocampus, cingular cortex, nucleus caudatus and motor cortex of adult male rats were elucidated. In some neurons and synapses of abovementioned regions pathological modifications were revealed. More significant alterations provokes chronic restraint stress. Alterations are mostly concentrated: first—in the nuclei of amygdala, then in the CA1 and CA3 areas. Moderate alterations were observed in cingular cortex and nucleus caudatus. In comparing with it, hypokinesia "without stress" provokes only moderate modifications: predominantly in the nucleus caudatus, in lesser degree—in the hippocampus and amygdalae.

Tracing the origin of azimuthal gluon correlations in the color glass condensate

DOE PAGES

Lappi, T.; Schenke, B.; Schlichting, S.; ...

2016-01-11

Here we examine the origins of azimuthal correlations observed in high energy proton-nucleus collisions by considering the simple example of the scattering of uncorrelated partons off color fields in a large nucleus. We demonstrate how the physics of fluctuating color fields in the color glass condensate (CGC) effective theory generates these azimuthal multiparticle correlations and compute the corresponding Fourier coefficients v n within different CGC approximation schemes. We discuss in detail the qualitative and quantitative differences between the different schemes. Lastly, we will show how a recently introduced color field domain model that captures key features of the observed azimuthalmore » correlations can be understood in the CGC effective theory as a model of non-Gaussian correlations in the target nucleus.« less

Cell Nucleus-Targeting Zwitterionic Carbon Dots.

PubMed

Jung, Yun Kyung; Shin, Eeseul; Kim, Byeong-Su

2015-12-22

An innovative nucleus-targeting zwitterionic carbon dot (CD) vehicle has been developed for anticancer drug delivery and optical monitoring. The zwitterionic functional groups of the CDs introduced by a simple one-step synthesis using β-alanine as a passivating and zwitterionic ligand allow cytoplasmic uptake and subsequent nuclear translocation of the CDs. Moreover, multicolor fluorescence improves the accuracy of the CDs as an optical code. The CD-based drug delivery system constructed by non-covalent grafting of doxorubicin, exhibits superior antitumor efficacy owing to enhanced nuclear delivery in vitro and tumor accumulation in vivo, resulting in highly effective tumor growth inhibition. Since the zwitterionic CDs are highly biocompatible and effectively translocated into the nucleus, it provides a compelling solution to a multifunctional nanoparticle for substantially enhanced nuclear uptake of drugs and optical monitoring of translocation.

Cell Nucleus-Targeting Zwitterionic Carbon Dots

PubMed Central

Jung, Yun Kyung; Shin, Eeseul; Kim, Byeong-Su

2015-01-01

An innovative nucleus-targeting zwitterionic carbon dot (CD) vehicle has been developed for anticancer drug delivery and optical monitoring. The zwitterionic functional groups of the CDs introduced by a simple one-step synthesis using β-alanine as a passivating and zwitterionic ligand allow cytoplasmic uptake and subsequent nuclear translocation of the CDs. Moreover, multicolor fluorescence improves the accuracy of the CDs as an optical code. The CD-based drug delivery system constructed by non-covalent grafting of doxorubicin, exhibits superior antitumor efficacy owing to enhanced nuclear delivery in vitro and tumor accumulation in vivo, resulting in highly effective tumor growth inhibition. Since the zwitterionic CDs are highly biocompatible and effectively translocated into the nucleus, it provides a compelling solution to a multifunctional nanoparticle for substantially enhanced nuclear uptake of drugs and optical monitoring of translocation. PMID:26689549

Effects of selective excitotoxic lesions of the nucleus accumbens core, anterior cingulate cortex, and central nucleus of the amygdala on autoshaping performance in rats.

PubMed

Cardinal, Rudolf N; Parkinson, John A; Lachenal, Guillaume; Halkerston, Katherine M; Rudarakanchana, Nung; Hall, Jeremy; Morrison, Caroline H; Howes, Simon R; Robbins, Trevor W; Everitt, Barry J

2002-08-01

The nucleus accumbens core (AcbC), anterior cingulate cortex (ACC), and central nucleus of the amygdala (CeA) are required for normal acquisition of tasks based on stimulus-reward associations. However, it is not known whether they are involved purely in the learning process or are required for behavioral expression of a learned response. Rats were trained preoperatively on a Pavlovian autoshaping task in which pairing a visual conditioned stimulus (CS+) with food causes subjects to approach the CS+ while not approaching an unpaired stimulus (CS-). Subjects then received lesions of the AcbC, ACC, or CeA before being retested. AcbC lesions severely impaired performance; lesioned subjects approached the CS+ significantly less often than controls, failing to discriminate between the CS+ and CS-. ACC lesions also impaired performance but did not abolish discrimination entirely. CeA lesions had no effect on performance. Thus, the CeA is required for learning, but not expression, of a conditioned approach response, implying that it makes a specific contribution to the learning of stimulus-reward associations.

The TRH neuron: a hypothalamic integrator of energy metabolism.

PubMed

Lechan, Ronald M; Fekete, Csaba

2006-01-01

Thyrotropin-releasing hormone (TRH) has an important role in the regulation of energy homeostasis not only through effects on thyroid function orchestrated through hypophysiotropic neurons in the hypothalamic paraventricular nucleus (PVN), but also through central effects on feeding behavior, thermogenesis, locomotor activation and autonomic regulation. Hypophysiotropic TRH neurons are located in the medial and periventricular parvocellular subdivisions of the PVN and receive direct monosynaptic projections from two, separate, populations of leptin-responsive neurons in the hypothalamic arcuate nucleus containing either alpha-melanocyte-stimulating hormone (alpha-MSH) and cocaine- and amphetamine-regulated transcript (CART), peptides that promote weight loss and increase energy expenditure, or neuropeptide Y (NPY) and agouti-related protein (AGRP), peptides that promote weight gain and reduce energy expenditure. During fasting, the reduction in TRH mRNA in hypophysiotropic neurons mediated by suppression of alpha-MSH/CART simultaneously with an increase in NPY/AGRP gene expression in arcuate nucleus neurons contributes to the fall in circulating thyroid hormone levels, presumably by increasing the sensitivity of the TRH gene to negative feedback inhibition by thyroid hormone. Endotoxin administration, however, has the paradoxical effect of increasing circulating levels of leptin and melanocortin signaling and CART gene expression in arcuate nucleus neurons, but inhibiting TRH gene expression in hypophysiotropic neurons. This may be explained by an overriding inhibitory effect of endotoxin to increase type 2 iodothyroine deiodinase (D2) in a population of specialized glial cells, tanycytes, located in the base and infralateral walls of the third ventricle. By increasing the conversion of T4 into T3, tanycytes may increase local tissue concenetrations of thyroid hormone, and thereby induce a state of local tissue hyperthyroidism in the region of hypophysisotrophic TRH neurons. Other regions of the brain may also serve as metabolic sensors for hypophysiostropic TRH neurons including the ventrolateral medulla and dorsomedial nucleus of the hypothalamus that have direct monosynaptic projections to the PVN. TRH also exerts a number of effects within the central nervous system that may contribute to the regulation of energy homeostasis. Included are an increase in core body temperature mediated through neurons in the anterior hypothalamic-preoptic area that coordinate a variety of autonomic responses; arousal and locomotor activation through cholinergic and dopaminergic mechanisms on the septum and nucleus accumbens, respectively; and regulation of the cephalic phase of digestion. While the latter responses are largely mediated through cholinergic mechanisms via TRH neurons in the brainstem medullary raphe and dorsal motor nucleus of the vagus, effects of TRH on autonomic loci in the hypothalamic PVN may also be important. Contrary to the actions of T3 to increase appetite, TRH has central effects to reduce food intake in normal, fasting and stressed animals. The precise locus where TRH mediates this response is unknown. However, evidence that an anatomically separate population of nonhypophysiotropic TRH neurons in the anterior parvocellular subdivision of the PVN is integrated into the leptin regulatory control system by the same arcuate nucleus neuronal populations that innervate hypophysiotropic TRH neurons, raises the possibility that anterior parvocellular TRH neurons may be involved, possibly through interactions with the limbic nervous system.

33S nuclear magnetic resonance spectroscopy of biological samples obtained with a laboratory model 33S cryogenic probe

NASA Astrophysics Data System (ADS)

Hobo, Fumio; Takahashi, Masato; Saito, Yuta; Sato, Naoki; Takao, Tomoaki; Koshiba, Seizo; Maeda, Hideaki

2010-05-01

S33 nuclear magnetic resonance (NMR) spectroscopy is limited by inherently low NMR sensitivity because of the quadrupolar moment and low gyromagnetic ratio of the S33 nucleus. We have developed a 10 mm S33 cryogenic NMR probe, which is operated at 9-26 K with a cold preamplifier and a cold rf switch operated at 60 K. The S33 NMR sensitivity of the cryogenic probe is as large as 9.8 times that of a conventional 5 mm broadband NMR probe. The S33 cryogenic probe was applied to biological samples such as human urine, bile, chondroitin sulfate, and scallop tissue. We demonstrated that the system can detect and determine sulfur compounds having SO42- anions and -SO3- groups using the S33 cryogenic probe, as the S33 nuclei in these groups are in highly symmetric environments. The NMR signals for other common sulfur compounds such as cysteine are still undetectable by the S33 cryogenic probe, as the S33 nuclei in these compounds are in asymmetric environments. If we shorten the rf pulse width or decrease the rf coil diameter, we should be able to detect the NMR signals for these compounds.

Structural variations on antitumour agents derived from bisacylimidoselenocarbamate. A proposal for structure-activity relationships based on the analysis of conformational behaviour.

PubMed

Font, María; Lizarraga, Elena; Ibáñez, Elena; Plano, Daniel; Sanmartín, Carmen; Palop, Juan A

2013-08-01

A molecular modelling study has been carried out on a previously reported series of symmetrically substituted bisacylimidoselenocarbamate (BSeC) derivatives that show remarkable antitumour activity in vitro against a panel of human tumour cell lines. These derivatives can be considered as a central scaffold constructed around a methyl carbamimidoselenoate nucleus in which two heteroarylacyl fragments are located on the scaffold nitrogen atoms, thus forming the different BSeCs. The results reveal that the nature of the selected heteroaryl ring has a marked influence on the antiproliferative activity of the compounds and this can be related, as a first approximation, to the ability to release methylselenol (MeSeH), a compound that, according to our initial hypothesis, is ultimately responsible for the antitumour activity of the compounds under investigation. The release of MeSeH from the active BSeCs has been confirmed by means of Head Space Gas Chromatography Mass Spectrometry techniques. The data that support this connection include the topography of the molecules, the conformational behaviour of the compounds, which influences the accessibility of the hydrolysis point, the interaction map obtained for an O2H type probe, and the location and energy of the HOMO/LUMO orbitals. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

The Effect of Chronic Antipsychotic Drug on Hypothalamic Expression of Neural Nitric Oxide Synthase and Dopamine D2 Receptor in the Male Rat

PubMed Central

Zhang, Zhi Jun; Li, Lei; Reynolds, Gavin P.

2012-01-01

Antipsychotic-induced sexual dysfunction is a common and serious clinical side effect. It has been demonstrated that both neuronal nitric oxide (nNOS) and dopamine D2 receptor (DRD2) in the medial preoptic area (MPOA) and the paraventricular nucleus (PVN) of the hypothalamus have important roles in the regulation of sexual behaviour. We investigated the influences of 21 days’ antipsychotic drug administration on expression of nNOS and DRD2 in the rat hypothalamus. Haloperidol (0.5 mg/kg/day i.p.) significantly decreased nNOS integrated optical density in a sub-nucleus of the MPOA, medial preoptic nucleus (MPN), and decreased the nNOS integrated optical density and cell density in another sub-nucleus of the MPOA, anterodorsal preoptic nucleus (ADP). Risperidone (0.25 mg/kg) inhibited the nNOS integrated optical density in the ADP. nNOS mRNA and protein in the MPOA but not the PVN was also significantly decreased by haloperidol. Haloperidol and risperidone increased DRD2 mRNA and protein expression in both the MPOA and the PVN. Quetiapine (20 mg/kg/day i.p.) did not influence the expression of nNOS and DRD2 in either the MPOA or the PVN. These findings indicate that hypothalamic nNOS and DRD2 are affected to different extents by chronic administration of risperidone and haloperidol, but are unaffected by quetiapine. These central effects might play a role in sexual dysfunction induced by certain antipsychotic drugs. PMID:22514604

Deep brain stimulation of the subthalamic nucleus enhances emotional processing in Parkinson disease.

PubMed

Schneider, Frank; Habel, Ute; Volkmann, Jens; Regel, Sabine; Kornischka, Jürgen; Sturm, Volker; Freund, Hans-Joachim

2003-03-01

High-frequency electrical stimulation of the subthalamic nucleus is a new and highly effective therapy for complications of long-term levodopa therapy and motor symptoms in advanced Parkinson disease (PD). Clinical observations indicate additional influence on emotional behavior. Electrical stimulation of deep brain nuclei with pulse rates above 100 Hz provokes a reversible, lesioning-like effect. Here, the effect of deep brain stimulation of the subthalamic nucleus on emotional, cognitive, and motor performance in patients with PD (n = 12) was examined. The results were compared with the effects of a suprathreshold dose of levodopa intended to transiently restore striatal dopamine deficiency. Patients were tested during medication off/stimulation off (STIM OFF), medication off/stimulation on (STIM ON), and during the best motor state after taking levodopa without deep brain stimulation (MED). More positive self-reported mood and an enhanced mood induction effect as well as improvement in emotional memory during STIM ON were observed, while during STIM OFF, patients revealed reduced emotional performance. Comparable effects were revealed by STIM ON and MED. Cognitive performance was not affected by the different conditions and treatments. Deep brain stimulation of the subthalamic nucleus selectively enhanced affective processing and subjective well-being and seemed to be antidepressive. Levodopa and deep brain stimulation had similar effects on emotion. This finding may provide new clues about the neurobiologic bases of emotion and mood disorders, and it illustrates the important role of the basal ganglia and the dopaminergic system in emotional processing in addition to the well-known motor and cognitive functions.

Orexin receptors in the developing piglet hypothalamus, and effects of nicotine and intermittent hypercapnic hypoxia exposures.

PubMed

Hunt, Nicholas J; Waters, Karen A; Machaalani, Rita

2013-05-01

Orexin and its receptors (OxR1 and OxR2) play a significant role in arousal and sleep regulation. Using developing piglets, we aimed to determine the effects of nicotine and Intermittent Hypercapnic Hypoxia (IHH), alone or in combination, on orexin receptor expression in the hypothalamus. Four piglet groups were studied: control (n=14), nicotine (n=14), IHH (n=10) and nic+IHH (n=14). Applying immunohistochemistry for OxR1 and OxR2 expression, eight nuclei/areas of the hypothalamus: dorsal medial nucleus (DMN), arcuate nucleus (ARC), perifornical area (PFA), paraventricular nucleus (PVN), lateral hypothalamic area (LHA), ventral medial nucleus (VMN), supraoptic nucleus, retrochiasmatic part (SONr) and tuberal mammillary nucleus (TMN), were studied. Compared to controls, OxR1 and OxR2 were increased due to exposures, however this was region dependent. Nicotine increased OxR1 in the DMN (P<0.001) and SONr (P=0.036), and OxR2 in the DMN (P<0.001), VMN (P=0.014) and the TMN (P=0.026). IHH increased OxR1 in the DMN, PVN, VMN and SONr (P<0.01 for all), and OxR2 in DMN (P<0.001), PFA (P=0.001), PVN (P=0.004), VMN (P=0.041) and the TMN (P<0.001). The nic+IHH exposure increased OxR1 expression in all nuclei (TMN excluded) however, the changes were not significantly different from IHH alone. For OxR2, the increased expression after nic+IHH was significant compared to IHH in the DMN, ARC and SONr. These results show that nicotine increases orexin receptor expression in a region dependent manner. IHH induced increases were specific to arousal and stress related regions and nic+IHH results suggest that for OxR1, nicotine has no additive effect whereas for OxR2 it does, and is region dependent. Copyright © 2013 Elsevier B.V. All rights reserved.

Rat Nucleus Accumbens Core Astrocytes Modulate Reward and the Motivation to Self-Administer Ethanol after Abstinence

PubMed Central

Bull, Cecilia; Freitas, Kelen CC; Zou, Shiping; Poland, Ryan S; Syed, Wahab A; Urban, Daniel J; Minter, Sabrina C; Shelton, Keith L; Hauser, Kurt F; Negus, S Stevens; Knapp, Pamela E; Bowers, M Scott

2014-01-01

Our understanding of the active role that astrocytes play in modulating neuronal function and behavior is rapidly expanding, but little is known about the role that astrocytes may play in drug-seeking behavior for commonly abused substances. Given that the nucleus accumbens is critically involved in substance abuse and motivation, we sought to determine whether nucleus accumbens astrocytes influence the motivation to self-administer ethanol following abstinence. We found that the packing density of astrocytes that were expressing glial fibrillary acidic protein increased in the nucleus accumbens core (NAcore) during abstinence from EtOH self-administration. No change was observed in the nucleus accumbens shell. This increased NAcore astrocyte density positively correlated with the motivation for ethanol. Astrocytes can communicate with one another and influence neuronal activity through gap-junction hemichannels. Because of this, the effect of blocking gap-junction hemichannels on the motivation for ethanol was examined. The motivation to self-administer ethanol after 3 weeks abstinence was increased following microinjection of gap-junction hemichannel blockers into the NAcore at doses that block both neuronal and astrocytic channels. In contrast, no effect was observed following microinjection of doses that are not thought to block astrocytic channels or following microinjection of either dose into the nucleus accumbens shell. Additionally, the motivation for sucrose after 3 weeks abstinence was unaffected by NAcore gap-junction hemichannel blockers. Next, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were selectively expressed in NAcore astrocytes to test the effect of astrocyte stimulation. DREADD activation increased cytosolic calcium in primary astrocytes, facilitated responding for rewarding brain stimulation, and reduced the motivation for ethanol after 3 weeks abstinence. This is the first work to modulate drug-seeking behavior with astrocyte-specific DREADDs. Taken together, our findings demonstrate that NAcore astrocytes can shape the motivation to self-administer ethanol; suggesting that the development of ligands which selectively stimulate astrocytes may be a successful strategy to abate ethanol-seeking behavior. PMID:24903651

Rat nucleus accumbens core astrocytes modulate reward and the motivation to self-administer ethanol after abstinence.

PubMed

Bull, Cecilia; Freitas, Kelen C C; Zou, Shiping; Poland, Ryan S; Syed, Wahab A; Urban, Daniel J; Minter, Sabrina C; Shelton, Keith L; Hauser, Kurt F; Negus, S Stevens; Knapp, Pamela E; Bowers, M Scott

2014-11-01

Our understanding of the active role that astrocytes play in modulating neuronal function and behavior is rapidly expanding, but little is known about the role that astrocytes may play in drug-seeking behavior for commonly abused substances. Given that the nucleus accumbens is critically involved in substance abuse and motivation, we sought to determine whether nucleus accumbens astrocytes influence the motivation to self-administer ethanol following abstinence. We found that the packing density of astrocytes that were expressing glial fibrillary acidic protein increased in the nucleus accumbens core (NAcore) during abstinence from EtOH self-administration. No change was observed in the nucleus accumbens shell. This increased NAcore astrocyte density positively correlated with the motivation for ethanol. Astrocytes can communicate with one another and influence neuronal activity through gap-junction hemichannels. Because of this, the effect of blocking gap-junction hemichannels on the motivation for ethanol was examined. The motivation to self-administer ethanol after 3 weeks abstinence was increased following microinjection of gap-junction hemichannel blockers into the NAcore at doses that block both neuronal and astrocytic channels. In contrast, no effect was observed following microinjection of doses that are not thought to block astrocytic channels or following microinjection of either dose into the nucleus accumbens shell. Additionally, the motivation for sucrose after 3 weeks abstinence was unaffected by NAcore gap-junction hemichannel blockers. Next, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were selectively expressed in NAcore astrocytes to test the effect of astrocyte stimulation. DREADD activation increased cytosolic calcium in primary astrocytes, facilitated responding for rewarding brain stimulation, and reduced the motivation for ethanol after 3 weeks abstinence. This is the first work to modulate drug-seeking behavior with astrocyte-specific DREADDs. Taken together, our findings demonstrate that NAcore astrocytes can shape the motivation to self-administer ethanol; suggesting that the development of ligands which selectively stimulate astrocytes may be a successful strategy to abate ethanol-seeking behavior.

Physical Properties of Cometary Nucleus Candidates

NASA Technical Reports Server (NTRS)

Jewitt, David; Hillman, John (Technical Monitor)

2003-01-01

In this proposal we aim to study the physical properties of the Centaurs and the dead comets, these being the precursors to, and the remnants from, the active cometary nuclei. The nuclei themselves are very difficult to study, because of the contaminating effects of near-nucleus coma. Systematic investigation of the nuclei both before they enter the zone of strong sublimation and after they have depleted their near-surface volatiles should neatly bracket the properties of these objects, revealing evolutionary effects.

Brain stem stimulation and the acetylcholine-evoked inhibition of neurones in the feline nucleus reticularis thalami

PubMed Central

Dingledine, Raymond; Kelly, J. S.

1977-01-01

1. In cats anaesthetized with halothane and nitrous oxide, the responses to iontophoretically applied acetylcholine (ACh) and to high-frequency stimulation of the mid-brain reticular formation (MRF) were tested on spontaneously active neurones in the nucleus reticularis thalami and underlying ventrobasal complex. 2. The initial response to MRF stimulation of 90% of the ACh-inhibited neurones found in the region of the dorsolateral nucleus reticularis was an inhibition. Conversely, the initial response of 82% of the ACh-excited neurones in the ventrobasal complex was an excitation. Neurones in the rostral pole of the nucleus reticularis were inhibited by both ACh and RMF stimulation. 3. The mean latency (and s.e. of mean) for the MRF-evoked inhibition was 13·7 ± 3·2 ms (n = 42) and that for the MRF-evoked excitation, 44.1 ± 4.2 ms (n = 35). 4. The ACh-evoked inhibitions were blocked by iontophoretic atropine, in doses that did not block amino acid-evoked inhibition. In twenty-four ACh-inhibited neurones the effect of iontophoretic atropine was tested on MRF-evoked inhibition. In all twenty-four neurones atropine had no effect on the early phase of MRF-evoked inhibition but weakly antagonized the late phase of inhibition in nine of fourteen neurones. 5. Interspike-interval histograms showed that the firing pattern of neurones in the nucleus reticularis was characterized by periods of prolonged, high-frequency bursting. Both the ACh-evoked inhibitions and the late phase of MRF-evoked inhibitions were accompanied by an increased burst activity. In contrast, iontophoretic atropine tended to suppress burst activity. 6. The possibility is discussed that electrical stimulation of the MRF activates an inhibitory cholinergic projection to the nucleus reticularis. Since neurones of the nucleus reticularis have been shown to inhibit thalamic relay cells, activation of this inhibitory pathway may play a role in MRF-evoked facilitation of thalamo-cortical relay transmission and the associated electrocortical desynchronization. PMID:915830

Hemisphere, gender and age-related effects on iron deposition in deep gray matter revealed by quantitative susceptibility mapping.

PubMed

Gong, Nan-Jie; Wong, Chun-Sing; Hui, Edward S; Chan, Chun-Chung; Leung, Lam-Ming

2015-10-01

The purpose of this work was to investigate the effects of hemispheric location, gender and age on susceptibility value, as well as the association between susceptibility value and diffusional metrics, in deep gray matter. Iron content was estimated in vivo using quantitative susceptibility mapping. Microstructure was probed using diffusional kurtosis imaging. Regional susceptibility and diffusional metrics were measured for the putamen, caudate nucleus, globus pallidus, thalamus, substantia nigra and red nucleus in 42 healthy adults (age range 25-78 years). Susceptibility value was significantly higher in the left than the right side of the caudate nucleus (P = 0.043) and substantia nigra (P < 0.001). Women exhibited lower susceptibility values than men in the thalamus (P < 0.001) and red nucleus (P = 0.032). Significant age-related increases of susceptibility were observed in the putamen (P < 0.001), red nucleus (P < 0.001), substantia nigra (P = 0.004), caudate nucleus (P < 0.001) and globus pallidus (P = 0.017). The putamen exhibited the highest rate of iron accumulation with aging (slope of linear regression = 0.73 × 10(-3) ppm/year), which was nearly twice those in substantia nigra (slope = 0.40 × 10(-3) ppm/year) and caudate nucleus (slope = 0.39 × 10(-3) ppm/year). Significant positive correlations between the susceptibility value and diffusion measurements were observed for fractional anisotropy (P = 0.045) and mean kurtosis (P = 0.048) in the putamen without controlling for age. Neither correlation was significant after controlling for age. Hemisphere, gender and age-related differences in iron measurements were observed in deep gray matter. Notably, the putamen exhibited the highest rate of increase in susceptibility with aging. Correlations between susceptibility value and microstructural measurements were inconclusive. These findings could provide new clues for unveiling mechanisms underlying iron-related neurodegenerative diseases. Copyright © 2015 John Wiley & Sons, Ltd.

Psychostimulants affect dopamine transmission through both dopamine transporter-dependent and independent mechanisms

PubMed Central

dela Peña, Ike; Gevorkiana, Ruzanna; Shi, Wei-Xing

2015-01-01

The precise mechanisms by which cocaine and amphetamine-like psychostimulants exert their reinforcing effects are not yet fully defined. It is widely believed, however, that these drugs produce their effects by enhancing dopamine neurotransmission in the brain, especially in limbic areas such as the nucleus accumbens, by inducing dopamine transporter-mediated reverse transport and/or blocking dopamine reuptake though the dopamine transporter. Here, we present the evidence that aside from dopamine transporter, non-dopamine transporter-mediated mechanisms also participate in psychostimulant-induced dopamine release and contribute to the behavioral effects of these drugs, such as locomotor activation and reward. Accordingly, psychostimulants could increase norepinephrine release in the prefrontal cortex, the latter then alters the firing pattern of dopamine neurons resulting in changes in action potential-dependent dopamine release. These alterations would further affect the temporal pattern of dopamine release in the nucleus accumbens, thereby modifying information processing in that area. Hence, a synaptic input to a nucleus accumbens neuron may be enhanced or inhibited by dopamine depending on its temporal relationship to dopamine release. Specific temporal patterns of dopamine release may also be required for certain forms of synaptic plasticity in the nucleus accumbens. Together, these effects induced by psychostimulants, mediated through a non-dopamine transporter-mediated mechanism involving norepinephrine and the prefrontal cortex, may also contribute importantly to the reinforcing properties of these drugs. PMID:26209364

Dependence of weak interaction rates on the nuclear composition during stellar core collapse

NASA Astrophysics Data System (ADS)

Furusawa, Shun; Nagakura, Hiroki; Sumiyoshi, Kohsuke; Kato, Chinami; Yamada, Shoichi

2017-02-01

We investigate the influences of the nuclear composition on the weak interaction rates of heavy nuclei during the core collapse of massive stars. The nuclear abundances in nuclear statistical equilibrium (NSE) are calculated by some equation of state (EOS) models including in-medium effects on nuclear masses. We systematically examine the sensitivities of electron capture and neutrino-nucleus scattering on heavy nuclei to the nuclear shell effects and the single-nucleus approximation. We find that the washout of the shell effect at high temperatures brings significant change to weak rates by smoothing the nuclear abundance distribution: the electron capture rate decreases by ˜20 % in the early phase and increases by ˜40 % in the late phase at most, while the cross section for neutrino-nucleus scattering is reduced by ˜15 % . This is because the open-shell nuclei become abundant instead of those with closed neutron shells as the shell effects disappear. We also find that the single-nucleus description based on the average values leads to underestimations of weak rates. Electron captures and neutrino coherent scattering on heavy nuclei are reduced by ˜80 % in the early phase and by ˜5 % in the late phase, respectively. These results indicate that NSE like EOS accounting for shell washout is indispensable for the reliable estimation of weak interaction rates in simulations of core-collapse supernovae.

Increased sucrose intake and corresponding c-Fos in amygdala and parabrachial nucleus of dietary obese rats.

PubMed

Li, Jinrong; Chen, Ke; Yan, Jianqun; Wang, Qian; Zhao, Xiaolin; Yang, Xuejuan; Yang, Dejun; Zhao, Shiru; Zhu, Guangjing; Sun, Bo

2012-09-13

The intake-excitatory effects of caloric foods are mainly due to the palatable taste and the ensuing positive postingestive effects. Dietary obese individuals are inclined to overeat high caloric foods. However, it is still unclear whether the taste or postingestive reinforcement mainly contributes to the excessive intake by obese individuals. In the present study, we measured 10- or 120-min sucrose solution drunk by dietary obese rats and measured c-Fos expression following 120-min tests in the central nucleus of amygdala (CeA), a forebrain nucleus involved in the hedonic reward and craving, and the parabrachial nucleus (PBN), a taste relay area responsive to positive postingestive effects. Dietary obese rats, compared with those fed normal chow, ingested larger amounts of sucrose solution (0.25 M) in the 120-min test, but not in the 10-min test. In addition, significantly more sucrose-induced c-Fos positive cells were found in the CeA, but much less in the external lateral subnucleus of the PBN of dietary obese rats. Our results demonstrate that increased sucrose intake in dietary obese rats is mainly due to the alteration of postingestive effects. The differences in these postingestive effects in obesity may involve greater positive/excitatory signals in which the CeA may play a role, and less negative/inhibitory signals in which the el-PBN may be involved. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Effect of the fluctuating proton size on the study of the chiral magnetic effect in proton-nucleus collisions

DOE PAGES

Kharzeev, Dmitri; Tu, Zhoudunming; Zhang, Aobo; ...

2018-02-12

High energy proton-nucleus (pA) collisions provide an important constraint on the study of the chiral magnetic effect in QCD matter. Naively, in pA collisions one expects no correlation between the orientation of event plane as reconstructed from the azimuthal distribution of produced hadrons and the orientation of magnetic field. If this is the case, any charge-dependent hadron correlations can only result from the background. Nevertheless, in this paper we point out that in high multiplicity pA collisions a correlation between the magnetic field and the event plane can appear. This is because triggering on the high hadron multiplicity amounts tomore » selecting Fock components of the incident proton with a large number of partons that are expected to have a transverse size much larger than the average proton size. We introduce the effect of the fluctuating proton size in the Monte Carlo Glauber model and evaluate the resulting correlation between the magnetic field and the second-order event plane in both pA and nucleus-nucleus (AA) collisions. The fluctuating proton size is found to result in a significant correlation between magnetic field and the event plane in pA collisions, even though the magnitude of the correlation is still much smaller than in AA collisions. Here, this result opens a possibility of studying the chiral magnetic effect in small systems.« less

Effect of the fluctuating proton size on the study of the chiral magnetic effect in proton-nucleus collisions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kharzeev, Dmitri; Tu, Zhoudunming; Zhang, Aobo

High energy proton-nucleus (pA) collisions provide an important constraint on the study of the chiral magnetic effect in QCD matter. Naively, in pA collisions one expects no correlation between the orientation of event plane as reconstructed from the azimuthal distribution of produced hadrons and the orientation of magnetic field. If this is the case, any charge-dependent hadron correlations can only result from the background. Nevertheless, in this paper we point out that in high multiplicity pA collisions a correlation between the magnetic field and the event plane can appear. This is because triggering on the high hadron multiplicity amounts tomore » selecting Fock components of the incident proton with a large number of partons that are expected to have a transverse size much larger than the average proton size. We introduce the effect of the fluctuating proton size in the Monte Carlo Glauber model and evaluate the resulting correlation between the magnetic field and the second-order event plane in both pA and nucleus-nucleus (AA) collisions. The fluctuating proton size is found to result in a significant correlation between magnetic field and the event plane in pA collisions, even though the magnitude of the correlation is still much smaller than in AA collisions. Here, this result opens a possibility of studying the chiral magnetic effect in small systems.« less

Shikonin extracted from medicinal Chinese herbs exerts anti-inflammatory effect via proteasome inhibition

PubMed Central

Lu, Li; Qin, Aiping; Huang, Hongbiao; Zhou, Ping; Zhang, Chuanyin; Liu, Ningning; Li, Shujue; Wen, Guanmei; Zhang, Change; Dong, Weihua; Wang, Xuejun; Dou, Q. Ping; Liu, Jinbao

2012-01-01

Shikonin, extracted from medicinal Chinese herb (Lithospermum erythrorhizo), was reported to exert anti-inflammatory and anti-cancer effects both in vitro and in vivo. We have found that proteasome was a molecular target of shikonin in tumor cells, but whether shikonin targets macrophage proteasome needs to be investigated. In the current study, we report that shikonin inhibited inflammation in mouse models as efficiently as dexamethasone. Shikonin at 4 μM reduced the Lipopolysaccharides (LPS)-mediated TNFα release in rat primary macrophage cultures, and blocked the translocation of p65-NF-κB from the cytoplasm to the nucleus, associated with decreased proteasomal activity. Consistently, shikonin accumulated IκB-α, an inhibitor of NF-κB, and ubiquitinated proteins in rat primary macrophage cultures, demonstrating that the proteasome is a target of shikonin under inflammatory conditions. Shikonin also induced macrophage cell apoptosis and cell death. These results demonstrate for the first time that proteasome inhibition by shikonin contributes to its anti-inflammatory effect. The novel finding about macrophage proteasome as a target of shikonin suggests that this medicinal compound has great potential to be developed into an anti-inflammatory agent. PMID:21392503

Shikonin extracted from medicinal Chinese herbs exerts anti-inflammatory effect via proteasome inhibition.

PubMed

Lu, Li; Qin, Aiping; Huang, Hongbiao; Zhou, Ping; Zhang, Chuanyin; Liu, Ningning; Li, Shujue; Wen, Guanmei; Zhang, Change; Dong, Weihua; Wang, Xuejun; Dou, Q Ping; Liu, Jinbao

2011-05-11

Shikonin, extracted from medicinal Chinese herb (Lithospermum erythrorhizo), was reported to exert anti-inflammatory and anti-cancer effects both in vitro and in vivo. We have found that proteasome was a molecular target of shikonin in tumor cells, but whether shikonin targets macrophage proteasome needs to be investigated. In the current study, we report that shikonin inhibited inflammation in mouse models as efficiently as dexamethasone. Shikonin at 4 μM reduced the Lipopolysaccharides (LPS)-mediated TNFα release in rat primary macrophage cultures, and blocked the translocation of p65-NF-κB from the cytoplasm to the nucleus, associated with decreased proteasomal activity. Consistently, shikonin accumulated IκB-α, an inhibitor of NF-κB, and ubiquitinated proteins in rat primary macrophage cultures, demonstrating that the proteasome is a target of shikonin under inflammatory conditions. Shikonin also induced macrophage cell apoptosis and cell death. These results demonstrate for the first time that proteasome inhibition by shikonin contributes to its anti-inflammatory effect. The novel finding about macrophage proteasome as a target of shikonin suggests that this medicinal compound has great potential to be developed into an anti-inflammatory agent. Copyright © 2011 Elsevier B.V. All rights reserved.

Perinatal asphyxia exerts lifelong effects on neuronal responsiveness to stress in specific brain regions in the rat.

PubMed

Salchner, Peter; Engidawork, Ephrem; Hoeger, Harald; Lubec, Barbara; Singewald, Nicolas

2003-09-01

Perinatal asphyxia (PA) causes irreversible damage to the brain of newborns and can produce neurologic and behavioral changes later in life. To identify neuronal substrates underlying the effects of PA, we investigated whether and how neuronal responsiveness to an established stress challenge is affected. We used Fos expression as a marker of neuronal activation and examined the pattern of Fos expression in response to acute swim stress in 24-month-old rats exposed to a 20-minute PA insult. Swim stress produced a similar pattern of Fos expression in control and asphyxiated rats in 34 brain areas. Asphyxiated rats displayed a higher number of stress-induced Fos-positive cells in the nucleus of the solitary tract, parabrachial nucleus, periaqueductal gray, paraventricular hypothalamic nucleus, nucleus accumbens, caudate-putamen, and prelimbic cortex. No differences in the Fos response to stress were observed in other regions, including the locus ceruleus, amygdala, hippocampus, or septum. These data provide functional anatomic evidence that PA has lifelong effects on neuronal communication and leads to an abnormal, augmented neuronal responsiveness to stress in specific brain areas, particularly in the main telencephalic target regions of the mesencephalic dopamine projections, as well as in a functionally related set of brain regions associated with autonomic and neuroendocrine regulation.

Effects of cabergoline and rotigotine on tacrine-induced tremulous jaw movements in rats.

PubMed

Koganemaru, Go; Abe, Hiroshi; Kuramashi, Aki; Ebihara, Kosuke; Matsuo, Hisae; Funahashi, Hideki; Yasuda, Kazuya; Ikeda, Tetsuya; Nishimori, Toshikazu; Ishida, Yasushi

2014-11-01

We examined the effects of two dopamine agonists, cabergoline and rotigotine, on tacrine-induced tremor and c-Fos expression in rats. Rats received intraperitoneal injection of cabergoline (0.5, 1.0, or 5.0mg/kg), rotigotine (1.0, 2.5, or 10.0mg/kg), or vehicle 30min before intraperitoneal injection of tacrine (5.0mg/kg). The number of tremulous jaw movements (TJMs) after tacrine administration was counted for 5min. Animals were sacrificed 2h later under deep anesthesia, and the brain sections were immunostained in order to evaluate the c-Fos expression. Induction of TJMs by tacrine was dose-dependently reduced by pretreatment with cabergoline and rotigotine. The number of c-Fos-positive cells was significantly enhanced in the medial striatum, nucleus accumbens core, and nucleus accumbens shell after tacrine administration, and the enhanced expression of c-Fos in these three regions was significantly attenuated by cabergoline, while rotigotine suppressed c-Fos expression in two regions except the nucleus accumbens core. These results suggest that tacrine-induced TJMs would be relieved by either cabergoline or rotigotine and that anticholinesterase-induced TJMs and the ameliorating effects of dopamine agonists would relate to neuronal activation in the striatum and nucleus accumbens. Copyright © 2014 Elsevier Inc. All rights reserved.

Test of level density models from reactions of Li6 on Fe58 and Li7 on Fe57

NASA Astrophysics Data System (ADS)

Oginni, B. M.; Grimes, S. M.; Voinov, A. V.; Adekola, A. S.; Brune, C. R.; Carter, D. E.; Heinen, Z.; Jacobs, D.; Massey, T. N.; O'Donnell, J. E.; Schiller, A.

2009-09-01

The reactions of Li6 on Fe58 and Li7 on Fe57 have been studied at 15 MeV beam energy. These two reactions produce the same compound nucleus, Cu64. The charged particle spectra were measured at backward angles. The data obtained have been compared with Hauser-Feshbach model calculations. The level density parameters of Ni63 and Co60 have been obtained from the particle evaporation spectra. We also find contributions from the break up of the lithium projectiles to the low energy region of the α spectra.

Crystal structure of 1,3-bis-(1H-benzotriazol-1-yl-meth-yl)benzene.

PubMed

Macías, Mario A; Nuñez-Dallos, Nelson; Hurtado, John; Suescun, Leopoldo

2016-06-01

The mol-ecular structure of the title compound, C20H16N6, contains two benzotriazole units bonded to a benzene nucleus in a meta configuration, forming dihedral angles of 88.74 (11) and 85.83 (10)° with the central aromatic ring and 57.08 (9)° with each other. The three-dimensional structure is controlled mainly by weak C-H⋯N and C-H⋯π inter-actions. The mol-ecules are connected in inversion-related pairs, forming the slabs of infinite chains that run along the [-110] and [110] directions.

Synthesis, structure and in vitro cytostatic activity of ferrocene-Cinchona hybrids.

PubMed

Kocsis, László; Szabó, Ildikó; Bősze, Szilvia; Jernei, Tamás; Hudecz, Ferenc; Csámpai, Antal

2016-02-01

Exploring copper(I)- and ruthenium(II)-catalyzed azide-alkyne cycloadditions and a Sonogashira protocol, novel cytostatic ferrocene-cinchona hybrids were synthetized displaying significant in vitro activity on HepG-2 and HT-29 cells. Preliminary SAR studies disclosed that compounds incorporating linkers with 1,2,3-triazole and chalchone residues can be considered as promising lead structures. According to the best of our knowledge this is the first letter on the incorporation of ferrocene nucleus in the reputed cinchona family via triazole and chalcone linkers with established pharmaceutical profile. Copyright © 2015 Elsevier Ltd. All rights reserved.

A Physiological Neural Network for Saccadic Eye Movement Control

DTIC Science & Technology

1994-04-01

cerebellum, substantia nigra, nucleus reticularis tegmenti pontis, the thalamus, the deep layers of the superior colliculus and the oculomotor plant...and pause cells), the vestibular nucleus , abducens nucleus , oculomotor nucleus , cerebellum, substantia nigra, nucleus reticularis tegmenti pontis, the...vestibular nucleus , abducens nucleus , oculomotor nucleus , cerebellum, substantia nigra, nucleus reticularis tegmenti pontis (NRTP), the thalamus, the

Statistical analysis of the distribution of chromosome aberrations in human lymphocytes induced by low and high energy heavy ions

NASA Astrophysics Data System (ADS)

Deperas-Standylo, Joanna; Lee, Ryonfa; Nasonova, Elena; Ritter, Sylvia; Gudowska-Nowak, Ewa; Kac, M.; Smoluchowski, M.

Differences in the track structure of high LET (Linear Energy Transfer) particles are clearly visible on chromosomal level, in particular in the number of lesions produced by an ion traversal through a cell nucleus and in the distribution of aberrations among the cells. In the present study we focus on the effects of low energy C-and Cr-ions (<10 MeV/u) in comparison with high energy C-ions (90 MeV/u). For the experiments human lymphocytes were exposed to 9.5 MeV/u C-ions, 4.1 MeV/u Cr-ions or 90 MeV/u C-ions with LET values of 175 keV/µm, 3160 keV/µm and 29 keV/µm, respectively. Chromosome aberrations were measured at several post-irradiation sampling times (48, 60, 72 and 84h) in first cycle metaphases following Giemsa-staining. For 90 MeV/u C-ions, where the track radius is larger than the cell nucleus, the distribution of aberrations did not change significantly with sampling time and has been well described by Poisson statistics. In contrast, for low energy C-ions, where the track radius is smaller than the cell nucleus, distribution of aberration strongly deviates from uni-modal and displays two peaks representative for subpopulations of non-hit and hit cells, respectively. Following this pattern, also damage-dependent cell cycle delay was observed. At 48 h after irradiation a high number of undamaged and probably unhit cells was found to reach mitosis. This number of undamaged cells decreased further with sampling time, while the frequencies of cells carrying aberrations (1-11 per cell) were increasing. All distributions were found to conform a compound Poisson (Neyman-type A) statistics which allows estimating the average number of particle traversals through a cell nucleus and the average number of aberrations induced by one particle traversal. Similar response has also been observed at 48h after Cr-ion exposure. In this case, however, non-aberrant cells have been found to dominate in the population even at later sampling times and a low number of heavily damaged cells up to 24 aberrations have been detected. Accordingly, the distribution of aberrations in cells collected at >48 h could not be then described by a standard Neyman statistics. Obtained results suggest that most cells hit by more than one Cr-ion do not reach mitosis. This observation was confirmed by parallel measurements showing that Cr-ion exposure produces a high fraction of apoptotic cells.

Changes of brain metabolite concentrations during maturation in different brain regions measured by chemical shift imaging.

PubMed

Bültmann, Eva; Nägele, Thomas; Lanfermann, Heinrich; Klose, Uwe

2017-01-01

We examined the effect of maturation on the regional distribution of brain metabolite concentrations using multivoxel chemical shift imaging. From our pool of pediatric MRI examinations, we retrospectively selected patients showing a normal cerebral MRI scan or no pathologic signal abnormalities at the level of the two-dimensional 1H MRS-CSI sequence and an age-appropriate global neurological development, except for focal neurological deficits. Seventy-one patients (4.5 months-20 years) were identified. Using LC Model, spectra were evaluated from voxels in the white matter, caudate head, and corpus callosum. The concentration of total N-acetylaspartate increased in all regions during infancy and childhood except in the right caudate head where it remained constant. The concentration of total creatine decreased in the caudate nucleus and splenium and minimally in the frontal white matter and genu. It remained largely constant in the parietal white matter. The concentration of choline-containing compounds had the tendency to decrease in all regions except in the parietal white matter where it remained constant. The concentration of myoinositol decreased slightly in the splenium and right frontal white matter, remained constant on the left side and in the caudate nucleus, and rose slightly in the parietal white matter and genu. CSI determined metabolite concentrations in multiple cerebral regions during routine MRI. The obtained data will be helpful in future pediatric CSI measurements deciding whether the ratios of the main metabolites are within the range of normal values or have to be considered as probably pathologic.

Correlation between the cumulative analgesic effect of electroacupuncture intervention and synaptic plasticity of hypothalamic paraventricular nucleus neurons in rats with sciatica☆

PubMed Central

Xu, Qiuling; Liu, Tao; Chen, Shuping; Gao, Yonghui; Wang, Junying; Qiao, Lina; Liu, Junling

2013-01-01

In the present study, a rat model of chronic neuropathic pain was established by ligation of the sciatic nerve and a model of learning and memory impairment was established by ovariectomy to investigate the analgesic effect of repeated electroacupuncture stimulation at bilateral Zusanli (ST36) and Yanglingquan (GB34). In addition, associated synaptic changes in neurons in the paraventricular nucleus of the hypothalamus were examined. Results indicate that the thermal pain threshold (paw withdrawal latency) was significantly increased in rats subjected to 2-week electroacupuncture intervention compared with 2-day electroacupuncture, but the analgesic effect was weakened remarkably in ovariectomized rats with chronic constrictive injury. 2-week electroacupuncture intervention substantially reversed the chronic constrictive injury-induced increase in the synaptic cleft width and thinning of the postsynaptic density. These findings indicate that repeated electroacupuncture at bilateral Zusanli and Yanglingquan has a cumulative analgesic effect and can effectively relieve chronic neuropathic pain by remodeling the synaptic structure of the hypothalamic paraventricular nucleus. PMID:25206591

The energy loss and nuclear absorption effects in semi-inclusive deep inelastic scattering on nucleus

NASA Astrophysics Data System (ADS)

Song, Li-Hua; Xin, Shang-Fei; Liu, Na

2018-02-01

Semi-inclusive deep inelastic lepton-nucleus scattering provides a good opportunity to investigate the cold nuclear effects on quark propagation and hadronization. Considering the nuclear modification of the quark energy loss and nuclear absorption effects in final state, the leading-order computations on hadron multiplicity ratios for both hadronization occurring outside and inside the medium are performed with the nuclear geometry effect of the path length L of the struck quark in the medium. By fitting the HERMES two-dimensional data on the multiplicity ratios for positively and negatively charged pions and kaons produced on neon, the hadron-nucleon inelastic cross section {σ }h for different identified hadrons is determined, respectively. It is found that our predictions obtained with the analytic parameterizations of quenching weights based on BDMPS formalism and the nuclear absorption factor {N}A(z,ν ) are in good agreement with the experimental measurements. This indicates that the energy loss and nuclear absorption are the main nuclear effects inducing a reduction of the hadron yield for quark hadronization occurring outside and inside the nucleus, respectively.

Tachykinin NK-1 and NK-3 selective agonists induce analgesia in the formalin test for tonic pain following intra-VTA or intra-accumbens microinfusions.

PubMed

Altier, N; Stewart, J

1997-12-01

Experiments were designed to examine the analgesic effects induced by selective tachykinin receptor agonists microinfused into either the ventral tegmental area (VTA) or nucleus accumbens septi (NAS). Rats were tested in the formalin test for tonic pain following an injection of 0.05 ml of 2.5% formalin into one hind paw immediately after bilateral intra-VTA infusions of either the NK-1 agonist, GR-73632 (0.005, 0.05 or 0.5 nmol/side), the NK-3 agonist, senktide (0.005, 0.5 or 1.5 nmol/side), or saline. Two weeks later, the saline-treated rats were assessed in the tail-flick test for phasic pain after infusions of the tachykinin agonists. Tail-flick latencies were recorded following immersion of the tail in 55 degrees C hot water at 10 min intervals for 1 h immediately after intra-VTA infusions of either GR-73632 (0.5 nmol/side), senktide (1.5 nmol/side) or saline. In a second group of rats, the same effects were studied after infusions into the nucleus accumbens (NAS) of GR-73632 (0.005, 0.5 or 1.5 nmol/side), senktide (0.005, 0.5 or 1.5 nmol/side), or saline. In both the VTA and NAS, the NK-1 and the NK-3 agonists caused significant analgesia in the formalin test, although the NK-1 agonist appeared to be more effective. Naltrexone (2.0 mg/kg) pretreatment failed to reverse the analgesic effects in the formalin test induced by intra-VTA infusions of the substance P (SP) analog, DiMe-C7 (3.0 microg/side), GR-73632 (0.5 nmol/side), or senktide (1.5 nmol/side). Neither compound given at either site was effective in the tail-flick test. These findings suggest that SP-dopamine (DA) interactions within the mesolimbic DA system play an important role in the inhibition of tonic pain. Furthermore, they support our earlier ideas that activation of midbrain DA systems by SP might play a role in stress- and/or pain-induced analgesia.

Therapeutic effects of naringin on degenerative human nucleus pulposus cells for discogenic low back pain.

PubMed

Li, Nianhu; Whitaker, Camden; Xu, Zhanwang; Heggeness, Michael; Yang, Shang-You

2016-10-01

Over half the population of the world will suffer from moderate or severe low back pain (LBP) during their life span. Studies have shown that naringin, a major flavonoid in grapefruit and an active compound extracted from a Chinese herbal medicine (Rhizoma Drynariae) possesses many pharmacological effects. The aim of this study was to evaluate the influence of naringin on the growth of degenerative human nucleus pulposus (NP) cells, and its repair effects on protein and gene expressions of the cells. This was an in vitro investigation of the human NP cells isolated from degenerated intervertebral discs that were interacted with various concentrated of naringin. This study was exempted by the institutional Human Subjects Committee-2, University of Kansas School of Medicine-Wichita. Degenerative human NP cells were isolated from intervertebral discs of patients with discogenic LBP and cultured at 37°C with 5% CO 2 . The proliferation of NP cells was determined following treatment with various concentrations of naringin. The protein expressions of tumor necrosis factor-α (TNF-α) and Bone morphogenetic protein 2 (BMP-2) were tested using enzyme-linked immunosorbent assay. Aggrecan and type II collagen levels were measured by immunohistological staining. Further examination of the gene expression of aggrecan, Sox6, and MMP3 was performed after intervention with naringin for 3 days. The human NP cells were successfully propagated in culture and stained positive with toluidine blue staining. Naringin effectively enhanced the cell proliferation at an optimal concentration of 20 µg/mL. Naringin treatment resulted in significant inhibition of TNF-α, but elevated protein expressions of BMP-2, collagen II, and aggrecan. Naringin also increased disc matrix gene activity including aggrecan and Sox6, and decreased the gene expression of MMP3. Naringin effectively promotes the proliferation of degenerative human NP cells and improves the recuperation of the cells from degeneration by increasing expression of aggrecan, BMP-2, and Sox6 while inhibiting the expression of TNF-α and MMP3. This study suggests that naringin may represent an alternative therapeutic agent for disc degeneration. Copyright © 2016 Elsevier Inc. All rights reserved.

Fluorescent nuclear track detectors for alpha radiation microdosimetry.

PubMed

Kouwenberg, J J M; Wolterbeek, H T; Denkova, A G; Bos, A J J

2018-06-07

While alpha microdosimetry dates back a couple of decades, the effects of localized energy deposition of alpha particles are often still unclear since few comparative studies have been performed. Most modern alpha microdosimetry studies rely for large parts on simulations, which negatively impacts both the simplicity of the calculations and the reliability of the results. A novel microdosimetry method based on the Fluorescent Nuclear Track Detector, a versatile tool that can measure individual alpha particles at sub-micron resolution, yielding accurate energy, fluence and dose rate measurements, was introduced to address these issues. Both the detectors and U87 glioblastoma cell cultures were irradiated using an external Am241 alpha source. The alpha particle tracks measured with a Fluorescent Nuclear Track Detector were used together with high resolution 3D cell geometries images to calculate the nucleus dose distribution in the U87 glioblastoma cells. The experimentally obtained microdosimetry parameters were thereafter applied to simulations of 3D U87 cells cultures (spheroids) with various spatial distributions of isotopes to evaluate the effect of the nucleus dose distribution on the expected cell survival. The new experimental method showed good agreement with the analytically derived nucleus dose distributions. Small differences (< 5%) in the relative effectiveness were found for isotopes in the cytoplasm and on the cell membrane versus external irradiation, while isotopes located in the nucleus or on the nuclear membrane showed a substantial increase in relative effectiveness (33 - 51%). The ease-of-use, good accuracy and use of experimentally derived characteristics of the radiation field make this method superior to conventional simulation-based microdosimetry studies. Considering the uncertainties found in alpha radionuclide carriers in-vivo and in-vitro, together with the large contributions from the relative biological effectiveness and the oxygen enhancement ratio, it is expected that only carriers penetrating or surrounding the cell nucleus will substantially benefit from microdosimetry.

Use of Monoclonal Antibodies to Study the Structural Basis of the Function of Nicotinic Acetylcholine Receptors on Electric Organ and Muscle and to Determine the Structure of Nicotinic Acetylcholine Receptors on Neurons

DTIC Science & Technology

1989-03-16

nucleus robustus archistriatalis 1 1 1 nucleus reticularis gigantocellularis 1 3 3 nucleus reticularis lateralis 1 3 3 nucleus ... reticularis pontis caudalis 1 1 3 nucleus reticularis parvocellularis 1 1 2 nucleus rotundus 1 1 1 nucleus tractus solitarii 1 3 3 nucleus semilunaris...Structure a-bungarotoxin mAb 35 inAb 270 nucleus accumbens 1 1 1 nucleus basalis 1 1 1 nucleus cerebelli intermedium 2 3 3

EPPS16: nuclear parton distributions with LHC data.

PubMed

Eskola, Kari J; Paakkinen, Petja; Paukkunen, Hannu; Salgado, Carlos A

2017-01-01

We introduce a global analysis of collinearly factorized nuclear parton distribution functions (PDFs) including, for the first time, data constraints from LHC proton-lead collisions. In comparison to our previous analysis, EPS09, where data only from charged-lepton-nucleus deep inelastic scattering (DIS), Drell-Yan (DY) dilepton production in proton-nucleus collisions and inclusive pion production in deuteron-nucleus collisions were the input, we now increase the variety of data constraints to cover also neutrino-nucleus DIS and low-mass DY production in pion-nucleus collisions. The new LHC data significantly extend the kinematic reach of the data constraints. We now allow much more freedom for the flavor dependence of nuclear effects than in other currently available analyses. As a result, especially the uncertainty estimates are more objective flavor by flavor. The neutrino DIS plays a pivotal role in obtaining a mutually consistent behavior for both up and down valence quarks, and the LHC dijet data clearly constrain gluons at large momentum fraction. Mainly for insufficient statistics, the pion-nucleus DY and heavy-gauge-boson production in proton-lead collisions impose less visible constraints. The outcome - a new set of next-to-leading order nuclear PDFs called EPPS16 - is made available for applications in high-energy nuclear collisions.

Kinetic theory of heterogeneous nucleation; effect of nonuniform density in the nuclei.

PubMed

Berim, Gersh O; Ruckenstein, Eli

2011-03-01

The heterogeneous nucleation of a liquid from a vapor in contact with a planar solid surface or a solid surface with cavities is examined on the basis of the kinetic theory of nucleation developed by Nowakowski and Ruckenstein [J. Phys. Chem. 96 (1992) 2313] which is extended to nonuniform fluid density distribution (FDD) in the nucleus. The latter is determined under the assumption that at each moment the FDD in the nucleus is provided by the density functional theory (DFT) for a nanodrop. As a result of this assumption, the theory does not require to consider that the contact angle which the nucleus makes with the solid surface and the density of the nucleus are independent parameters since they are provided by the DFT. For all considered cases, the nucleation rate is higher in the cavities than on a planar surface and increases with increasing strength of the fluid-solid interactions and decreasing cavity radius. The difference is small at high supersaturations (small critical nuclei), but becomes larger at low supersaturations when the critical nucleus has a size comparable with the size of the cavity. The nonuniformity of the FDD in the nucleus decreases the nucleation rate when compared to the uniform FDD. Copyright © 2010 Elsevier Inc. All rights reserved.

Aromatase inhibitor letrozole downregulates steroid receptor coactivator-1 in specific brain regions that primarily related to memory, neuroendocrine and integration.

PubMed

Bian, Chen; Zhao, Yangang; Guo, Qiang; Xiong, Ying; Cai, Wenqin; Zhang, Jiqiang

2014-05-01

As one of the third generation of aromatase inhibitors, letrozole is a favored drug for the treatment of hormone receptor-positive breast cancer with some adverse effects on the nervous system, but the knowledge is limited and the results are controversial, the mechanism underlying its central action is also unclear. Accumulated evidences have demonstrated that estrogens derived from androgens by aromatase play profound roles in the brain through their receptors, which needs coactivator for the transcription regulation, among which steroid receptor coactivator-1 (SRC-1) has been shown to be multifunctional potentials in the brain, but whether it is regulated by letrozole is currently unknown. In this study, we examined letrozole regulation on SRC-1 expression in adult mice brain using immunohistochemistry. The results showed that letrozole induced dramatic decrease of SRC-1 in the medial septal, hippocampus, medial habenular nucleus, arcuate hypothalamic nucleus and superior colliculus (p<0.01). Significant decrease was detected in the dorsal lateral septal nucleus, bed nucleus of stria terminalis, ventral taenia tecta, dorsomedial and ventromedial hypothalamic nuclei, dorsomedial periaqueductal gray, superior paraolivary nucleus and pontine nucleus (p<0.05). In the hippocampus, levels of estradiol content, androgen receptor, estrogen receptor α and β also decreased significantly after letrozole injection. The above results demonstrated letrozole downregulation of SRC-1 in specific regions that are primarily related to learning and memory, cognition and mood, neuroendocrine as well as information integration, indicating that SRC-1 may be one important downstream central target of letrozole. Furthermore, these potential central adverse effects of letrozole should be taken into serious considerations. Copyright © 2014 Elsevier Ltd. All rights reserved.

Desipramine and citalopram attenuate pretest swim-induced increases in prodynorphin immunoreactivity in the dorsal bed nucleus of the stria terminalis and the lateral division of the central nucleus of the amygdala in the forced swimming test.

PubMed

Chung, Sung; Kim, Hee Jeong; Kim, Hyun Ju; Choi, Sun Hye; Cho, Jin Hee; Cho, Yun Ha; Kim, Dong-Hoon; Shin, Kyung Ho

2014-10-01

Dynorphin in the nucleus accumbens shell plays an important role in antidepressant-like effect in the forced swimming test (FST), but it is unclear whether desipramine and citalopram treatments alter prodynorphin levels in other brain areas. To explore this possibility, we injected mice with desipramine and citalopram 0.5, 19, and 23 h after a 15-min pretest swim and observed changes in prodynorphin expression before the test swim, which was conducted 24 h after the pretest swim. The pretest swim increased prodynorphin immunoreactivity in the dorsal bed nucleus of the stria terminalis (dBNST) and lateral division of the central nucleus of the amygdala (CeL). This increase in prodynorphin immunoreactivity in the dBNST and CeL was blocked by desipramine and citalopram treatments. Similar changes in prodynorphin mRNA levels were observed in the dBNST and CeL, but these changes did not reach significance. To understand the underlying mechanism, we assessed changes in phosphorylated CREB at Ser(133) (pCREB) immunoreactivity in the dBNST and central nucleus of the amygdala (CeA). Treatment with citalopram but not desipramine after the pretest swim significantly increased pCREB immunoreactivity only in the dBNST. These results suggest that regulation of prodynorphin in the dBNST and CeL before the test swim may be involved in the antidepressant-like effect of desipramine and citalopram in the FST and suggest that changes in pCREB immunoreactivity in these areas may not play an important role in the regulation of prodynorphin in the dBNST and CeA. Copyright © 2014 Elsevier Ltd. All rights reserved.

Difference in Energy Metabolism of Annulus Fibrosus and Nucleus Pulposus Cells of the Intervertebral Disc

PubMed Central

Salvatierra, Jessica Czamanski; Yuan, Tai Yi; Fernando, Hanan; Castillo, Andre; Gu, Wei Yong; Cheung, Herman S.; Huant, C.-Y. Charles

2011-01-01

Low back pain is associated with intervertebral disc degeneration. One of the main signs of degeneration is the inability to maintain extracellular matrix integrity. Extracellular matrix synthesis is closely related to production of adenosine triphosphate (i.e. energy) of the cells. The intervertebral disc is composed of two major anatomical regions: annulus fibrosus and nucleus pulposus, which are structurally and compositionally different, indicating that their cellular metabolisms may also be distinct. The objective of this study was to investigate energy metabolism of annulus fibrosus and nucleus pulposus cells with and without dynamic compression, and examine differences between the two cell types. Porcine annulus and nucleus tissues were harvested and enzymatically digested. Cells were isolated and embedded into agarose constructs. Dynamically loaded samples were subjected to a sinusoidal displacement at 2 Hz and 15% strain for 4 h. Energy metabolism of cells was analyzed by measuring adenosine triphosphate content and release, glucose consumption, and lactate/nitric oxide production. A comparison of those measurements between annulus and nucleus cells was conducted. Annulus and nucleus cells exhibited different metabolic pathways. Nucleus cells had higher adenosine triphosphate content with and without dynamic loading, while annulus cells had higher lactate production and glucose consumption. Compression increased adenosine triphosphate release from both cell types and increased energy production of annulus cells. Dynamic loading affected energy metabolism of intervertebral disc cells, with the effect being greater in annulus cells. PMID:21625336

Effect of cochlear nerve electrocautery on the adult cochlear nucleus.

PubMed

Iseli, Claire E; Merwin, William H; Klatt-Cromwell, Cristine; Hutson, Kendall A; Ewend, Matthew G; Adunka, Oliver F; Fitzpatrick, Douglas C; Buchman, Craig A

2015-04-01

Electrocauterization and subsequent transection of the cochlear nerve induce greater injury to the cochlear nucleus than sharp transection alone. Some studies show that neurofibromatosis Type 2 (NF2) patients fit with auditory brainstem implants (ABIs) fail to achieve speech perception abilities similar to ABI recipients without NF2. Reasons for these differences remain speculative. One hypothesis posits poorer performance to surgically induced trauma to the cochlear nucleus from electrocautery. Sustained electrosurgical depolarization of the cochlear nerve may cause excitotoxic-induced postsynaptic nuclear injury. Equally plausible is that cautery in the vicinity of the cochlear nucleus induces necrosis. The cochlear nerve was transected in anesthetized adult gerbils sharply with or without bipolar electrocautery at varying intensities. Gerbils were perfused at 1, 3, 5, and 7 days postoperatively; their brainstem and cochleas were embedded in paraffin and sectioned at 10 μm. Alternate sections were stained with flourescent markers for neuronal injury or Nissl substance. In additional experiments, anterograde tracers were applied directly to a sectioned eighth nerve to verify that fluorescent-labeled profiles seen were terminating auditory nerve fibers. Cochlear nerve injury was observed from 72 hours postoperatively and was identical across cases regardless of surgical technique. Postsynaptic cochlear nucleus injury was not seen after distal transection of the nerve. By contrast, proximal transection was associated with trauma to the cochlear nucleus. Distal application of bipolar electrocautery seems safe for the cochlear nucleus. Application near the root entry zone must be used cautiously because this may compromise nuclear viability needed to support ABI stimulation.

Open Reading Frame 3 of Genotype 1 Hepatitis E Virus Inhibits Nuclear Factor-κappa B Signaling Induced by Tumor Necrosis Factor-α in Human A549 Lung Epithelial Cells

PubMed Central

Tian, Deying; Wang, Jingjing; Zheng, Zizheng; Xia, Ningshao

2014-01-01

Hepatitis E virus (HEV) is one of the primary causative agents of acute hepatitis, and represents a major cause of severe public health problems in developing countries. The pathogenesis of HEV is not well characterized, however, primarily due to the lack of well-defined cell and animal models. Here, we investigated the effects of genotype 1 HEV open reading frame 3 (ORF3) on TNF-α-induced nucleus factor-κappa B (NF-κB) signaling. Human lung epithelial cells (A549) were transiently transfected with ORF3 containing plasmids. These cells were then stimulated with TNF-α and the nucleus translocation of the p65 NF-κB subunit was assessed using western blot and laser confocal microscopy. DNA-binding activity of p65 was also examined using electrophoretic mobility shift assay (EMSA), and the suppression of NF-κB target genes were detected using real-time RT-PCR and ELISA. These results enabled us to identify the decreased phosphorylation levels of IKBα. We focused on the gene of negative regulation of NF-κB, represented by TNF-α-induced protein 3 (TNFAIP3, also known as A20). Reducing the levels of A20 with siRNAs significantly enhances luciferase activation of NF-κB. Furthermore, HEV ORF3 regulated A20 primarily via activating transcription factor 6 (ATF6), involved in unfolded protein response (UPR), resulting in the degradation or inactivation of the receptor interacting protein 1 (RIP1), a major upstream activator of IKB kinase compounds (IKKs). Consequently, the phosphorylation of IKBα and the nucleus translocation of p65 are blocked, which contributes to diminished NF-κB DNA-binding activation and NF-κB-dependent gene expression. The findings suggest that genotype 1 HEV, through ORF3, may transiently activate NF-κB through UPR in early stage, and subsequently inhibit TNF-α-induced NF-κB signaling in late phase so as to create a favorable virus replication environment. PMID:24959724

Osmosis and viscoelasticity both contribute to time-dependent behaviour of the intervertebral disc under compressive load: A caprine in vitro study.

PubMed

Emanuel, Kaj S; van der Veen, Albert J; Rustenburg, Christine M E; Smit, Theodoor H; Kingma, Idsart

2018-03-21

The mechanical behaviour of the intervertebral disc highly depends on the content and transport of interstitial fluid. It is unknown, however, to what extent the time-dependent behaviour can be attributed to osmosis. Here we investigate the effect of both mechanical and osmotic loading on water content, nucleus pressure and disc height. Eight goat intervertebral discs, immersed in physiological saline, were subjected to a compressive force with a pressure needle inserted in the nucleus. The loading protocol was: 10 N (6 h); 150 N (42 h); 10 N (24 h). Half-way the 150 N-phase (24 h), we eliminated the osmotic gradient by adding 26% poly-ethylene glycol to the surrounding fluid. For 62 additional discs, we determined the water content of both nucleus and annulus after 6, 24, 48, or 72 h. The compressive load was initially counterbalanced by the hydrostatic pressure in the nucleus. The load forced 4.3% of the water out of the nucleus, which reduced nucleus pressure by 44(±6)%. Reduction of the osmotic gradient disturbed the equilibrium disc height, and a significant loss of annulus water content was found. Remarkably, pressure and water content of the nucleus pulposus remained unchanged. This shows that annulus water content is important in the response to axial loading. After unloading, in the absence of an osmotic gradient, there was substantial viscoelastic recovery of 53(±11)% of the disc height, without a change in water content. However, for restoration of the nucleus pressure and for full restoration of disc height, restoration of the osmotic gradient was needed. Copyright © 2017 Elsevier Ltd. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nesterov, V. A., E-mail: archerix@ukpost.ua

On the basis of the energy-density method, the effect of simultaneously taking into account the Pauli exclusion principle and the monopole and quadrupole polarizations of interacting nuclei on their interaction potential is considered for the example of the {sup 16}O + {sup 16}O system by using the wave function for the two-center shell model. The calculations performed in the adiabatic approximation reveal that the inclusion of the Pauli exclusion principle and the polarization of interacting nuclei, especially their quadrupole polarization, has a substantial effect on the potential of the nucleus-nucleus interaction.

Design, synthesis and evaluation of some N-methylenebenzenamine derivatives as selective acetylcholinesterase (AChE) inhibitor and antioxidant to enhance learning and memory.

PubMed

Shrivastava, Sushant K; Srivastava, Pavan; Upendra, T V R; Tripathi, Prabhash Nath; Sinha, Saurabh K

2017-02-15

Series of some 3,5-dimethoxy-N-methylenebenzenamine and 4-(methyleneamino)benzoic acid derivatives comprising of N-methylenebenzenamine nucleus were designed, synthesized, characterized, and assessed for their acetylcholinesterase (AChE), butyrylcholinesterase (BChE) inhibitory, and antioxidant activity thereby improving learning and memory in rats. The IC 50 values of all the compound along with standard were determined on AChE and BChE enzyme. The free radical scavenging activity was also assessed by in vitro DPPH (2,2-diphenyl-1-picryl-hydrazyl) and hydrogen peroxide radical scavenging assay. The selective inhibitions of all compounds were observed against AChE in comparison with standard donepezil. The enzyme kinetic study of the most active compound 4 indicated uncompetitive AChE inhibition. The docking studies of compound 4 exhibited the worthy interaction on active-site gorge residues Phe330 and Trp279 responsible for its high affinity towards AChE, whereas lacking of the BChE inhibition was observed due to a wider gorge binding site and absence of important aromatic amino acids interactions. The ex vivo study confirmed AChE inhibition abilities of compound 4 at brain site. Further, a considerable decrease in escape latency period of the compound was observed in comparison with standard donepezil through in vivo Spatial Reference Memory (SRM) and Spatial Working Memory (SWM) models which showed the cognition-enhancing potential of compound 4. The in vivo reduced glutathione (GSH) estimation on rat brain tissue homogenate was also performed to evaluate free radical scavenging activity substantiated the antioxidant activity in learning and memory. Copyright © 2017 Elsevier Ltd. All rights reserved.

Evaluation of Pterin, a Promising Drug Candidate from Cyanide Degrading Bacteria.

PubMed

Mahendran, Ramasamy; Thandeeswaran, Murugesan; Kiran, Gopikrishnan; Arulkumar, Mani; Ayub Nawaz, K A; Jabastin, Jayamanoharan; Janani, Balraj; Anto Thomas, Thomas; Angayarkanni, Jayaraman

2018-06-01

Pterin is a member of the compounds known as pteridines. They have the same nucleus of 2-amino-4-hydroxypteridine (pterin); however, the side-chain is different at the position 6, and the state of oxidation of the ring may exist in different form viz. tetrahydro, dihydro, or a fully oxidized form. In the present study, the microorganisms able to utilize cyanide, and heavy metals have been tested for the efficient production of pterin compound. The soil samples contaminated with cyanide and heavy metals were collected from Salem steel industries, Tamil Nadu, India. Out of 77 isolated strains, 40 isolates were found to utilize sodium cyanate as nitrogen source at different concentrations. However, only 13 isolates were able to tolerate maximum concentration (60 mM) of sodium cyanate and were screened for pterin production. Among the 13 isolates, only 1 organism showed maximum production of pterin, and the same was identified as Bacillus pumilus SVD06. The compound was extracted and purified by preparative high-performance liquid chromatography and analyzed by UV/visible, FTIR, and fluorescent spectrum. The antioxidant property of the purified pterin compound was determined by cyclic voltammetry. In addition, antimicrobial activity of pterin was also studied which was substantiated by antagonistic activity against Escherichia coli, and Pseudomonas aeruginosa. Besides that the pterin compound was proved to inhibit the formation of biofilm. The extracted pterin compounds could be proposed further not only for antioxidant and antimicrobial but also for its potency to aid as anticancer and psychotic drugs in future.

Heterogeneities of 67P nucleus seen by CONSERT in the vicinity of Abydos

NASA Astrophysics Data System (ADS)

Ciarletti, Valerie; Lasue, Jéremie; Hérique, Alain; Kofman, Wlodek; Levasseur-Regourd, Anny-Chantal; Lemmonier, Florentin; Guiffaut, Christophe; Plettemeier, Dirk

2016-04-01

Since their arrival at comet 67P in August 2014, a number of instruments onboard Rosetta's main spacecraft and Philae lander have been observing the surface of the nucleus and have revealed details of amazing structures. This information was complemented by information about the nucleus internal structure collected by the CONSERT (Comet Nucleus Sounding Experiment by Radiowave Transmission) experiment in order to constrain the nucleus formation and evolution. The CONSERT experiment is a bistatic radar with receivers and transmitters on-board both Rosetta's main spacecraft and Philae lander. The instrument makes use of electromagnetic waves at 90 MHz that propagated, during the First Science Sequence, between Philae and Rosetta through the small lobe of 67P over distances ranging from approximately 200 to 800 m depending on the spacecraft location. The data used here have been collected at depths that reach a maximum of about one hundred of meters nucleus in the vicinity of Abydos. The data collected by CONSERT provide an estimate of the permittivity mean value and information about its spatial variability inside the sounded volume. Thanks to the 10 MHz frequency bandwidth of the signal used by the instrument a spatial resolution around 10m is obtained inside the sounded volume of the nucleus. In this paper, we specifically focus on local variations in the nucleus subsurface permittivity. A number of electromagnetic simulations corresponding to the CONSERT operations have been performed for a variety of subsurface permittivity models. The effect of local vertical and horizontal large scale variations as well as smaller scale random fractal structure of the permittivity values around the landing site will be presented and discussed in comparison with CONSERT's experimental data collected in the same configurations. Possible interpretations of the results will be presented as well as potential consequences for the nucleus structure in connection with observations made available by other instruments.

GABAB Receptor Positive Modulation Decreases Selective Molecular and Behavioral Effects of Cocaine

PubMed Central

Lhuillier, Loic; Mombereau, Cedric; Cryan, John F.; Kaupmann, Klemens

2006-01-01

Exposure to cocaine induces selective behavioral and molecular adaptations. In rodents, acute cocaine induces increased locomotor activity whereas prolonged drug exposure results in behavioral locomotor sensitization, which is thought to be a consequence of drug–induced neuroadaptive changes. Recent attention has been given to compounds activating GABAB receptors as potential anti-addictive therapies. In particular the principle of allosteric positive GABAB receptor modulators is very promising in this respect, as positive modulators lack the sedative and muscle relaxant properties of full GABAB receptor agonists such as baclofen. Here we investigated the effects of systemic application of the GABAB receptor positive modulator GS39783 in animals treated with acute and chronic cocaine administration. Both GS39783 and baclofen dose-dependently attenuated acute cocaine-induced hyperlocomotion. Furthermore, both compounds also efficiently blocked cocaine-induced Fos induction in the striatal complex. In chronic studies GS39783 induced a modest attenuation of cocaine-induced locomotor sensitization. Chronic cocaine induces the accumulation of the transcription factor ΔFosB and up regulates cAMP-response-element-binding-protein (CREB) and dopamine-and-cAMP-regulated-phosphoprotein of 32 kd (DARPP-32). GS39783 blocked the induction/activation of DARPP-32 and CREB in the nucleus accumbens and dorsal striatum and partially inhibited ΔFosB accumulation in the dorsal striatum. In summary our data provide evidence that GS39783 attenuates the acute behavioral effects of cocaine exposure in rodents and in addition prevents the induction of selective long-term adaptive changes in dopaminergic signaling pathways. Further investigation of GABAB receptor positive modulation as a novel therapeutic strategy for the treatment of cocaine dependence and possibly other drugs of abuse is therefore warranted. PMID:16710312

RUNX3 is involved in caspase-3-dependent apoptosis induced by a combination of 5-aza-CdR and TSA in leukaemia cell lines.

PubMed

Zhai, Feng-Xian; Liu, Xiang-Fu; Fan, Rui-Fang; Long, Zi-Jie; Fang, Zhi-Gang; Lu, Ying; Zheng, Yong-Jiang; Lin, Dong-Jun

2012-03-01

Epigenetic therapy has had a significant impact on the management of haematologic malignancies. The aim of this study was to assess whether 5-aza-CdR and TSA inhibit the growth of leukaemia cells and induce caspase-3-dependent apoptosis by upregulating RUNX3 expression. K562 and Reh cells were treated with 5-aza-CdR, TSA or both compounds. RT-PCR and Western blot analyses were used to examine the expression of RUNX3 at the mRNA and protein levels, respectively. Immunofluorescence microscopy was used to detect the cellular location of RUNX3. Additionally, after K562 cells were transfected with RUNX3, apoptosis and proliferation were studied using Annexin V staining and MTT assays. The expression of RUNX3 in leukaemia cell lines was markedly less than that in the controls. Demethylating drug 5-aza-CdR could induce RUNX3 expression, but the combination of TSA and 5-aza-CdR had a greater effect than did treatment with a single compound. The combination of 5-aza-CdR and TSA induced the translocation of RUNX3 from the cytoplasm into the nucleus. TSA enhanced apoptosis induced by 5-aza-CdR, and Annexin V and Hoechst 33258 staining showed that the combination induced apoptosis but not necrosis. Furthermore, apoptosis was dependent on the caspase-3 pathway. RUNX3 overexpression in K562 cells led to growth inhibition and apoptosis and potentiated the effects of 5-aza-CdR induction. RUNX3 plays an important role in leukaemia cellular functions, and the induction of RUNX3-mediated effects may contribute to the therapeutic value of combination TSA and 5-aza-CdR treatment.

Pure uptake blockers of dopamine can reduce prolactin secretion: studies with diclofensine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Di Renzo, G.; Amoroso, S.; Taglialatela, M.

1988-01-01

The effects of diclofensine, a pure dopamine (DA) uptake inhibitor on 1) /sup 3/H-DA uptake in rat arcuate-periventricular nucleus-median eminence synaptosomes, 2) basal and K+-evoked endogenous DA release from tuberoinfundibular dopaminergic (TIDA) neurons and 3) in vivo prolactin (PRL) secretion were studied. Diclofensine, in concentrations of 0.01, 0.1 and 1 ..mu..M caused a marked decrease of /sup 3/H-DA uptake. In addition, it was unable to stimulate basal endogenous DA release which, on the contrary, was elicited by d-amphetamine in the same concentration. On the other hand, diclofensine caused a 3 fold enhancement on K+-evoked DA release. Finally, the compound, whenmore » administered in vivo to male rats, significantly reduced basal serum PRL levels. The results of the present study seem to indicate that the pharmacological blockade of DA uptake in TIDA neurons is a condition sufficient to cause a reduction of PRL release.« less

Steroid 11-Alpha-Hydroxylation by the Fungi Aspergillus nidulans and Aspergillus ochraceus.

PubMed

Ríos, Lidia Ortega-de Los; Luengo, José M; Fernández-Cañón, José M

2017-01-01

Steroids are a group of natural compounds derived from the cyclopentane-perhydro-phenantrene nucleus that have a great interest for the pharmaceutical industries as a consequence of their physiological effects. Among their functions are anti-inflammatory, immunosuppressive, or contraceptive activities. Nowadays, microbial transformation of steroid precursors is winning relevance opposite to the chemical synthesis, since it allows for decreasing time, expenses, and environmental pollution. Pharmaceutical industry tends to use cholesterol and phytosterols as starting materials due to their low cost. Aspergillus ochraceus and Aspergillus nidulans, a fungus whose biochemistry and genetics are well known, have been chosen because of their capacity of 11-α-hydroxylation over some steroids which confers on them their anti-inflammatory properties. We have cloned the genes encoding the 11-α-hydroxylase enzymatic activities with the aim to introduce them in other microorganisms, such as Mycobacterium smegmatis, used in the industry to split the side chain of phytosterols, and thus creating recombinant microorganisms able to generate useful steroids from cheap precursors in just one-step fermentation.

In Vivo Dentate Nucleus Gamma-aminobutyric Acid Concentration in Essential Tremor vs. Controls.

PubMed

Louis, Elan D; Hernandez, Nora; Dyke, Jonathan P; Ma, Ruoyun E; Dydak, Ulrike

2018-04-01

Despite its high prevalence, essential tremor (ET) is among the most poorly understood neurological diseases. The presence and extent of Purkinje cell (PC) loss in ET is the subject of controversy. PCs are a major storehouse of central nervous system gamma-aminobutyric acid (GABA), releasing GABA at the level of the dentate nucleus. It is therefore conceivable that cerebellar dentate nucleus GABA concentration could be an in vivo marker of PC number. We used in vivo 1 H magnetic resonance spectroscopy (MRS) to quantify GABA concentrations in two cerebellar volumes of interest, left and right, which included the dentate nucleus, comparing 45 ET cases to 35 age-matched controls. 1 H MRS was performed using a 3.0-T Siemens Tim Trio scanner. The MEGA-PRESS J-editing sequence was used for GABA detection in two cerebellar volumes of interest (left and right) that included the dentate nucleus. The two groups did not differ with respect to our primary outcome of GABA concentration (given in institutional units). For the right dentate nucleus, [GABA] in ET cases = 2.01 ± 0.45 and [GABA] in controls = 1.86 ± 0.53, p = 0.17. For the left dentate nucleus, [GABA] in ET cases = 1.68 ± 0.49 and [GABA] controls = 1.80 ± 0.53, p = 0.33. The controls had similar dentate nucleus [GABA] in the right vs. left dentate nucleus (p = 0.52); however, in ET cases, the value on the right was considerably higher than that on the left (p = 0.001). We did not detect a reduction in dentate nucleus GABA concentration in ET cases vs. One interpretation of the finding is that it does not support the existence of PC loss in ET; however, an alternative interpretation is the observed pattern could be due to the effects of terminal sprouting in ET (i.e., collateral sprouting from surviving PCs making up for the loss of GABA-ergic terminals from PC degeneration). Further research is needed.

Elliptic and triangular flow in p-Pb and peripheral Pb-Pb collisions from parton scatterings

DOE PAGES

Bzdak, Adam; Ma, Guo-Liang

2014-12-15

Using a multiphase transport model (AMPT) we calculate the elliptic v₂ and triangular v₃ Fourier coefficients of the two-particle azimuthal correlation function in proton-nucleus (p-Pb) and peripheral nucleus-nucleus (Pb-Pb) collisions. Our results for v₃ are in a good agreement with the CMS data collected at the Large Hadron Collider. The v₂ coefficient is very well described in p-Pb collisions and is underestimated for higher transverse momenta in Pb-Pb interactions. The characteristic mass ordering of v₂ in p-Pb is reproduced, whereas for v₃, this effect is not observed. We further predict the pseudorapidity dependence of v₂ and v₃ in p-Pb andmore » observe that both are increasing when going from a proton side to a Pb-nucleus side. Predictions for the higher-order Fourier coefficients, v₄ and v₅, in p-Pb are also presented.« less

Photo nuclear energy loss term for muon-nucleus interactions based on xi scaling model of QCD

NASA Technical Reports Server (NTRS)

Roychoudhury, R.

1985-01-01

Extensive air showers (EMC) experiments discovered a significant deviation of the ratio of structure functions of iron and deuteron from unity. It was established that the quark parton distribution in nuclei are different from the corresponding distribution in the nucleus. It was examined whether these results have an effect on the calculation of photo nucleus energy loss term for muon-nucleus nuclear interaction. Though the EMC and SLAC data were restricted to rather large q sq region it is expected that the derivation would persist even in the low q sq domain. For the ratio of iron and deuteron structure function a rather naive least square fit of the form R(x) = a + bx was taken and it is assumed that the formula is valid for the whole q sq region the absence of any knowledge of R(x) for small q sq.

Orofacial inflammatory pain affects the expression of MT1 and NADPH-d in rat caudal spinal trigeminal nucleus and trigeminal ganglion

PubMed Central

Huang, Fang; He, Hongwen; Fan, Wenguo; Liu, Yongliang; Zhou, Hongyu; Cheng, Bin

2013-01-01

Very little is known about the role of melatonin in the trigeminal system, including the function of melatonin receptor 1. In the present study, adult rats were injected with formaldehyde into the right vibrissae pad to establish a model of orofacial inflammatory pain. The distribution of melatonin receptor 1 and nicotinamide adenine dinucleotide phosphate diaphorase in the caudal spinal trigeminal nucleus and trigeminal ganglion was determined with immunohistochemistry and histochemistry. The results show that there are significant differences in melatonin receptor 1 expression and nicotinamide adenine dinucleotide phosphate diaphorase expression in the trigeminal ganglia and caudal spinal nucleus during the early stage of orofacial inflammatory pain. Our findings suggest that when melatonin receptor 1 expression in the caudal spinal nucleus is significantly reduced, melatonin's regulatory effect on pain is attenuated. PMID:25206619

meso-4,4′-Dimeth­oxy-2,2′-{[(3aR,7aS)-2,3,3a,4,5,6,7,7a-octa­hydro-1H-benz­imidazole-1,3-di­yl]bis­(methyl­ene)}diphenol

PubMed Central

Rivera, Augusto; Quiroga, Diego; Ríos-Motta, Jaime; Kučeraková, Monika; Dušek, Michal

2013-01-01

The title compound, C23H30N2O4, a di-Mannich base derived from 4-meth­oxy­phenol and cis-1,2-di­amine­cyclo­hexane, has a perhydro­benzimidazolidine nucleus, in which the cyclo­hexane ring adopts a chair conformation and the heterocyclic ring has a half-chair conformation with a C—N—C—C torsion angles of −48.14 (15) and −14.57 (16)°. The mean plane of the heterocycle makes dihedral angles of 86.29 (6) and 78.92 (6)° with the pendant benzene rings. The mol­ecular structure of the title compound shows the presence of two inter­actions between the N atoms of the imidazolidine ring and the hydroxyl groups through intra­molecular O—H⋯N hydrogen bonds with graph-set motif S(6). The unobserved lone pairs of the N atoms are presumed to be disposed in a syn conformation, being only the second example of an exception to the typical ‘rabbit-ears’ effect in 1,2-di­amines. PMID:24046631

The behavioral effects of the destruction of the magnocellular basal nucleus of the forebrain of cats.

PubMed

Nabieva, T N

1993-01-01

Behavioral experiments were carried out in cats following methodology which simulates complexly organized, nonautomatized behavior with elements of generalization and abstraction. A conclusion was reached regarding the participation of this formation in the structural-functional support of complex integrative forms of activity, cognitive and gnostic processes, was reached on the basis of the results of the performance of test tasks by the animals with partial destruction of the magnocellular basal nucleus. The proposed mechanism of the involvement of the basal nucleus in gnostic and cognitive processes is the nonspecific support of the system of structures which participate directly in thinking and learning.

Universal Parameterization of Absorption Cross Sections

NASA Technical Reports Server (NTRS)

Tripathi, R. K.; Cucinotta, Francis A.; Wilson, John W.

1997-01-01

This paper presents a simple universal parameterization of total reaction cross sections for any system of colliding nuclei that is valid for the entire energy range from a few AMeV to a few AGeV. The universal picture presented here treats proton-nucleus collision as a special case of nucleus-nucleus collision, where the projectile has charge and mass number of one. The parameters are associated with the physics of the collision system. In general terms, Coulomb interaction modifies cross sections at lower energies, and the effects of Pauli blocking are important at higher energies. The agreement between the calculated and experimental data is better than all earlier published results.

Projections of the nucleus of the optic tract to the nucleus reticularis tegmenti pontis and prepositus hypoglossi nucleus in the pigmented rat as demonstrated by anterograde and retrograde transport methods.

PubMed

Korp, B G; Blanks, R H; Torigoe, Y

1989-01-01

The visual pathways from the nucleus of the optic tract (NOT) to the nucleus reticularis tegmenti pontis (NRTP) and prepositus hypoglossi nucleus (ph) were studied following injections of tritiated leucine into the NOT of pigmented rats. The cell bodies of origin of the pretectal-NRTP, NRTP-ph, and pretectal-ph projections were determined using retrograde horseradish peroxidase (HRP) technique. The pretectum projects strongly to the rostral two-thirds of the central and pericentral subdivisions of the NRTP and sends a remarkably smaller projection to the ph. Both are entirely ipsilateral. The fibers destined for the ph travel with the NOT-NRTP bundle, pass through the NRTP, traverse the medial longitudinal fasciculus, and are distributed to the rostral one-half of the ph. The retrograde HRP studies confirm these pathways. The pretectal projections to the NRTP arise from neurons in the rostromedial NOT; those to the ph are located primarily in the rostral NOT although small numbers are found within the anterior, posterior, and olivary pretectal nuclei. Of major importance is the fact that the ph injections retrogradely label neurons within the NRTP and the adjacent paramedian pontine reticular formation. This NRTP-ph projection is entirely bilateral and arises from parts of both subdivisions of the nucleus targeted by NOT afferents. Both the direct NOT-ph and indirect NOT-NRTP-ph connections provide the anatomical basis for the relay of visual (optokinetic) information to the perihypoglossal complex and, presumably, by virtue of reciprocal ph-vestibular nuclear connections, to the vestibular nuclei itself. Such pathways confirm previous physiological studies in rat and, in particular, clarify the contrasting effects of electrolytic lesions of NRTP in rat which completely abolishes optokinetic nystagmus (OKN) (Cazin et al., 1980a) vs kainic acid lesions which produce only minor effects on OKN slow velocity (Hess et al., 1988). Given these differential effects, one concludes that the critical pathway for OKN passes in relation to, but is not significantly relayed by, the neurons of the NRTP or adjacent pontine tegmentum. The present studies suggest that one such fiber system is the NOT-ph bundle. How this relatively small projection compares to other possible fiber of passage systems remains to be determined electrophysiologically.

Kynurenine Metabolites and Migraine: Experimental Studies and Therapeutic Perspectives

PubMed Central

Fejes, Annamária; Párdutz, Árpád; Toldi, József; Vécsei, László

2011-01-01

Migraine is one of the commonest neurological disorders. Despite intensive research, its exact pathomechanism is still not fully understood and effective therapy is not always available. One of the key molecules involved in migraine is glutamate, whose receptors are found on the first-, second- and third-order trigeminal neurones and are also present in the migraine generators, including the dorsal raphe nucleus, nucleus raphe magnus, locus coeruleus and periaqueductal grey matter. Glutamate receptors are important in cortical spreading depression, which may be the electrophysiological correlate of migraine aura. The kynurenine metabolites, endogenous tryptophan metabolites, include kynurenic acid (KYNA), which exerts a blocking effect on ionotropic glutamate and α7-nicotinic acetylcholine receptors. Thus, KYNA and its derivatives may act as modulators at various levels of the pathomechanism of migraine. They can give rise to antinociceptive effects at the periphery, in the trigeminal nucleus caudalis, and may also act on migraine generators and cortical spreading depression. The experimental data suggest that KYNA or its derivatives might offer a novel approach to migraine therapy. PMID:22131946

Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses.

PubMed

Scott, David J; Stohler, Christian S; Egnatuk, Christine M; Wang, Heng; Koeppe, Robert A; Zubieta, Jon-Kar

2008-02-01

Placebo and nocebo effects, the therapeutic and adverse effects, respectively, of inert substances or sham procedures, represent serious confounds in the evaluation of therapeutic interventions. They are also an example of cognitive processes, particularly expectations, capable of influencing physiology. To examine the contribution of 2 different neurotransmitters, the endogenous opioid and the dopaminergic (DA) systems, to the development of placebo and nocebo effects. Using a within-subject design, subjects twice underwent a 20-minute standardized pain challenge, in the absence and presence of a placebo with expected analgesic properties. Studies were conducted in a university hospital setting. Twenty healthy men and women aged 20 to 30 years recruited by advertisement. Activation of DA and opioid neurotransmission by a pain stressor with and without placebo (changes in the binding potential of carbon 11 [11C]-labeled raclopride and [11C] carfentanil with positron emission tomography) and ratings of pain, affective state, and anticipation and perception of analgesia. Placebo-induced activation of opioid neurotransmission was detected in the anterior cingulate, orbitofrontal and insular cortices, nucleus accumbens, amygdala, and periaqueductal gray matter. Dopaminergic activation was observed in the ventral basal ganglia, including the nucleus accumbens. Regional DA and opioid activity were associated with the anticipated and subjectively perceived effectiveness of the placebo and reductions in continuous pain ratings. High placebo responses were associated with greater DA and opioid activity in the nucleus accumbens. Nocebo responses were associated with a deactivation of DA and opioid release. Nucleus accumbens DA release accounted for 25% of the variance in placebo analgesic effects. Placebo and nocebo effects are associated with opposite responses of DA and endogenous opioid neurotransmission in a distributed network of regions. The brain areas involved in these phenomena form part of the circuit typically implicated in reward responses and motivated behavior.

Differential effects of centrally-administered oestrogen antagonist ICI-182,780 on oestrogen-sensitive functions in the hypothalamus.

PubMed

Steyn, F J; Anderson, G M; Grattan, D R

2007-01-01

Oestrogen actions within the hypothalamus are essential for a range of reproductive functions. In this study, we sought to develop a method for suppressing central oestrogen action without affecting peripheral oestrogenic effects. We administered the oestrogen receptor antagonist ICI-182,780 (ICI) via crystalline implants into the left lateral ventricle or the arcuate nucleus and measured the effectiveness of this drug on three endpoints known to be regulated by oestrogen: gonadotrophin-releasing hormone (GnRH) pulse frequency, progesterone receptor expression and the generation of a sustained prolactin surge during late pregnancy. To confirm that central ICI administration had no effect on peripheral actions of oestrogen, we monitored changes in uterine weight. Intracerebroventricular ICI treatment reversed the inhibitory effects of oestrogen on GnRH pulse frequency, as measured by plasma luteinising hormone pulse frequency. No effect on the oestrogenic induction of progesterone receptors within the arcuate nucleus or ventromedial hypothalamus was observed; however, a small yet significant reduction in progesterone receptor expression within dopaminergic neurones in the arcuate nucleus was observed. Intracerebroventricular or direct crystalline ICI administration to the arcuate nucleus did not change the serum prolactin level during late pregnancy. Central administration of ICI did not affect uterine weight, and thus did not have a peripheral effect. These data suggest that central administration of ICI can overcome some actions of oestrogen in the brain, such as GnRH pulse frequency, but does not affect other oestrogen mediated actions, including the induction of progesterone receptors or the antepartum prolactin surge. Thus, it appears that there is a differential sensitivity to the inhibition of central oestrogen actions by ICI.

Chronic methamphetamine exposure significantly decreases microglia activation in the arcuate nucleus.

PubMed

Lloyd, Steven A; Corkill, Beau; Bruster, Matthew C; Roberts, Rick L; Shanks, Ryan A

2017-07-01

Methamphetamine is a powerful psychostimulant drug and its use and abuse necessitates a better understanding of its neurobiobehavioral effects. The acute effects of binge dosing of methamphetamine on the neurons in the CNS are well studied. However, the long-term effects of chronic, low-dose methamphetamine are less well characterized, especially in other cell types and areas outside of the major dopamine pathways. Mice were administered 5mg/kg/day methamphetamine for ten days and brain tissue was analyzed using histochemistry and image analysis. Increased microglia activity in the striatum confirmed toxic effects of methamphetamine in this brain region using this dosing paradigm. A significant decrease in microglia activity in the arcuate nucleus of the hypothalamus was observed with no effect noted on dopamine neurons in the arcuate nucleus. Given the importance of this area in homeostatic and neuroendocrine regulation, the current study highlights the need to more fully understand the systemic effects of chronic, low-dose methamphetamine use. The novel finding of microglia downregulation after chronic methamphetamine could lead to advances in understanding neuroinflammatory responses towards addiction treatment and protection from psychostimulant-induced neurotoxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

Intensive Voice Treatment (LSVT[R]LOUD) for Parkinson's Disease Following Deep Brain Stimulation of the Subthalamic Nucleus

ERIC Educational Resources Information Center

Spielman, Jennifer; Mahler, Leslie; Halpern, Angela; Gilley, Phllip; Klepitskaya, Olga; Ramig, Lorraine

2011-01-01

Purpose: Intensive voice therapy (LSVT[R]LOUD) can effectively manage voice and speech symptoms associated with idiopathic Parkinson disease (PD). This small-group study evaluated voice and speech in individuals with and without deep brain stimulation of the subthalamic nucleus (STN-DBS) before and after LSVT LOUD, to determine whether outcomes…