Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal dopaminergic pathway damage similar to that observed in Parkinson disease (PD). To study the role of NO radical in MPTP-induced neurotoxicity, we injected MPTP into mice in which nitric oxide synthase (NOS) was inhibited by 7-nitroindazole (7-NI) in a time- and dose-dependent fashion. 7-NI dramatically protected MPTP-injected mice against indices of severe injury to the nigrostriatal dopaminergic pathway, including reduction in striatal dopamine contents, decreases in numbers of nigral tyrosine hydroxylase-positive neurons, and numerous silver-stained degenerating nigral neurons. The resistance of 7-NI-injected mice to MPTP is not due to alterations in striatal pharmacokinetics or content of 1-methyl-4-phenylpyridinium ion (MPP+), the active metabolite of MPTP. To study specifically the role of neuronal NOS (nNOS), MPTP was administered to mutant mice lacking the nNOS gene. Mutant mice are significantly more resistant to MPTP-induced neurotoxicity compared with wild-type littermates. These results indicate that neuronally derived NO mediates, in part, MPTP-induced neurotoxicity. The similarity between the MPTP model and PD raises the possibility that NO may play a significant role in the etiology of PD.

Milwaukee and vicinity, Wisconsin, 1962 (Image 1 of 4) (Raster Image)

This layer is a georeferenced raster image of the historic, topographic paper map entitled: Milwaukee and vicinity, Wisconsin, 1959, mapped, edited and published by the Geological Survey. It was published by U.S. Dept. of the Interior, Geological Survey in 1962. Scale 1:24,000. Compiled from 1:24,000-scale maps of Thiensville, Menomonee Falls, Wauwatosa, Milwaukee, South Milwaukee, Greendale 1958, and Hales Corners 1959 7.5 minute quadrangles. Selected hydrographic data compiled from U.S. Lake Survey Charts 74 and 743 (1957). This layer is image 1 of 4 total images of the four sheet source map representing the northwest portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Wisconsin South State Plane NAD 1927 coordinate system (Fipszone 4803). All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This is a typical topographic map portraying both natural and manmade features. It shows and names works of nature, such as mountains, valleys, lakes, rivers, vegetation, etc. It also identify the principal works of humans, such as roads, railroads, boundaries, transmission lines, major buildings, etc. Relief shown by contours (interval 10 feet) and spot heights. Depths shown by contours and soundings. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection as part of the Imaging the Urban Environment project. Maps selected for this project represent major urban areas and cities of the world, at various time periods. These maps typically portray both natural and manmade features at a large scale. The selection represents a range of regions, originators, ground condition dates, scales, and purposes.

General Statistics 1977, No. 4-7

The monthly Bulletin of general statistics contains the principal data on short term economic trends in the European Community, by subject and by country.

Operator, organizational, direct and general support maintenance manual : delousing outfit, power driven; gasoline engine, 4-cycle, air-cooled, 3600 RPM, 4.7 HP; 10 dusting guns, (Curtis Automotive Devices, Inc. model CDR 70000), FSN 4230-078-5455, (Curtis Dyna-Products Corporation model CDR 70000B), FSN 4230-935-9361.

Includes index.

Organizational, direct, and general support maintenance repair parts and special tools list : delousing outfit, power driven, gasoline engine, 4 cycle, air cooled, 3600 rpm, 4.7 hp, 10 dusting guns (Curtis Automotive Devices, Inc model CDR 70,000), FSN 4230-078-5455 ....

"December 1970."

Macrocyclic systems containing 2,6,9-trioxabicyclo[3.3.1]-nona-3,7-dienes as chiral spacer groups: Synthesis, stereochemical features and preliminary complexation properties

Novel 2:2-macrocycles bearing bridged concave 2,6,9-trioxabicyclo[3.3.1]nona-3,7-dienes as chiral spacer units were obtained by cyclocondensation reaction of the chiral bisacid chloride and the corresponding diols, while use of methylene diamines instead of diols afforded 1:1 macrocycles only. Applying the same, but now template-assisted, experimental procedure to the reaction of the bisacid chloride with triethylene glycol brought about a significant increase in yield as well as a suitable simplification of the work-up during preparation and separation of the corresponding 1:1 as well as 2:2 macrocycles, when compared to results reported previously. HPLC separation on chiral columns revealed the presence of diastereoisomers [RR(S,S)- and RS-(meso)-forms] for all 2:2 macrocycles, which was further evidenced by the CD spectrum of one of those species as an example. Preliminary ESI-MS experiments indicated strong complexation abilities of the sulphur-containing ligand towards Ag(I), Cu(II) and Au(III) ions.

Subthalamic nucleus neurones in slices from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mice show irregular, dopamine-reversible firing pattern changes, but without synchronous activity

The loss of dopamine in idiopathic or animal models of Parkinson's disease induces synchronized low-frequency oscillatory burst-firing in subthalamic nucleus neurones. We sought to establish whether these firing patterns observed in vivo were preserved in slices taken from dopamine-depleted animals, thus establishing a role for the isolated subthalamic-globus pallidus complex in generating the pathological activity. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) showed significant reductions of over 90% in levels of dopamine as measured in striatum by high pressure liquid chromatography. Likewise, significant reductions in tyrosine hydroxylase immunostaining within the striatum (>90%) and tyrosine hydroxylase positive cell numbers (65%) in substantia nigra were observed. Compared with slices from intact mice, neurones in slices from MPTP-lesioned mice fired significantly more slowly (mean rate of 4.2 Hz, cf. 7.2 Hz in control) and more irregularly (mean coefficient of variation of inter-spike interval of 94.4%, cf. 37.9% in control). Application of ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2-amino-5-phosphonopentanoic acid (AP5) and the GABAA receptor antagonist picrotoxin caused no change in firing pattern. Bath application of dopamine significantly increased cell firing rate and regularized the pattern of activity in cells from slices from both MPTP-treated and control animals. Although the absolute change was more modest in control slices, the maximum dopamine effect in the two groups was comparable. Indeed, when taking into account the basal firing rate, no differences in the sensitivity to dopamine were observed between these two cohorts. Furthermore, pairs of subthalamic nucleus cells showed no correlated activity in slices from either control (21 pairs) or MPTP-treated animals (20 pairs). These results indicate that the isolated but interconnected subthalamic-globus pallidus network is not itself sufficient to generate the aberrant firing patterns in dopamine-depleted animals. More likely, inputs from other regions, such as the cortex, are needed to generate pathological oscillatory activity. © 2006 IBRO.

N-terminal His7-modification of glucagon-like peptide-1(7-36) amide generates dipeptidyl peptidase IV-stable analogues with potent antihyperglycaemic activity

Glucagon-like peptide-1(7-36)amide (GLP-1) possesses several unique and beneficial effects for the potential treatment of type 2 diabetes. However, the rapid inactivation of GLP-1 by dipeptidyl peptidase IV (DPP IV) results in a short half-life in vivo (less than 2 min) hindering therapeutic development. In the present study, a novel His7-modified analogue of GLP-1, N-pyroglutamyl-GLP-1 as well as N-acetyl-GLP-1 were synthesised and tested for DPP IV stability and biological activity. Incubation of GLP-1 with either DPP IV or human plasma resulted in rapid degradation of native GLP-1 to GLP-1(9-36)amide, while N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 were completely resistant to degradation. N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 bound to the GLP-1 receptor but had reduced affinities (IC50 values 32.9 and 6.7 nM, respectively) compared with native GLP-1 (IC50-37 nM). Similarly, both analogues stimulated cAMP production with EC50 values of 16.3 and 27 nM respectively compared with GLP-1 (EC50 4.7 nM). However, N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 exhibited potent insulinotropic activity in vitro at 5.6 mM glucose (P< 0.05 to P< 0.001) similar to native GLP-1. Both analogues (25 nM/kg body weight) lowered plasma glucose and increased plasma insulin levels when administered in conjunction with glucose (18 nM/kg body weight) to adult obese diabetic (ob/ob) mice. N-pyroglutamyl-GLP-1 was substantially better at lowering plasma glucose compared with the native peptide, while N-acetyl-GLP-1 was significantly more potent at stimulating insulin secretion. These studies indicate that N-terminal modification of GLP-1 results in DPP IV-resistant and biologically potent forms of GLP-1. The particularly powerful antihyperglycaemic action of N-pyroglutamyl-GLP-1 shows potential for the treatment of type 2 diabetes. © 2004 Society for Endocrinology.

Complexation in composite solutions of melanin with 2,4,7-trinitrofluorenone

A feasibility of formation of donor-acceptor charge-transfer (CT) complexes between melanin and 2,4,7-trinitrofluorenone (TNF) being good electron acceptor has been studied in solutions by means of the absorption and photoluminescence (PL) spectra. The model of electronic transitions in a melanin-TNF composite solution has been proposed. © 2014 Copyright Taylor & Francis Group, LLC.

Mechanistic studies on the degradation of gasoline oxygenates by advanced oxidation technologies and the reaction of 4-methyl-1,2,4-triazoline-3,5-dione with tetracyclopropylethylene

Gasoline oxygenates (MTBE, methyl tert-butyl ether; DIPE, di-isopropyl ether; ETBE, ethyl tert-butyl ether; TAME, tert-amyl ether) are added to gasoline to boost octane and enhance combustion. The combination of large scale use, high water solubility and only minor biodegradability has now resulted in a significant gasoline oxygenate contamination occurring in surface, ground, and drinking water systems. Combination of hydroxyl radical formation and the pyrolytic environment generated by ultrasonic irradiation (665 kHz) leads to the rapid degradation of MTBE and other gasoline oxygenates in aqueous media. ^ The presence of oxygen promotes the degradation processes by rapid reaction with carbon centered radicals indicating radical processes involving O 2 are significant pathways. A number of the oxidation products were identified. The formation of products (alcohols, ketones, aldehydes, esters, peroxides, etc) could be rationalized by mechanisms which involve hydrogen abstraction by OH radical and/or pyrolysis to form carboncentered radicals which react with oxygen and follow standard oxidation chain processes. ^ The reactions of N-substituted R-triazolinediones (RTAD; R = CH 3 or phenyl) have attracted considerable interest because they exhibit a number of unusual mechanistic characteristics that are analogous to the reactions of singlet oxygen (1O2) and offer an easy way to provide C-N bond(s) formation. The reactions of triazolinedione with olefins have been widely studied and aziridinium imides are generally accepted to be the reactive intermediates. ^ We observed the rapid formation of an unusual intermediate upon mixing tetracyclopropylethylene with 4-methyl-1,2,4-triazoline-3,5-dione in CDCl 3. Detailed characterization by NMR (proton, 13C, 2-D NMRs) indicates the intermediate is 5,5,6,6-tetracyclopropyl-3-methyl-5,6-dihydro-oxazolo[3,2- b][1,2,4]-triazolium-2-olate. Such products are extremely rare and have not been studied. Upon warming the intermediate is converted to 2 + 2 diazetidine (major) and ene product (minor). ^ To further explore the kinetics and dynamics of the reaction activation energies were obtained using Arrhenius plots. Activation energies for the formation of the intermediate from reactants, and 2+2 adduct from the intermediate were determined as 7.48 kcal moll and 19.8 kcal mol−1 with their pre-exponential values of 2.24 × 105 dm 3 mol−1 sec−1 and 2.75 × 108 sec−1, respectively, meaning net slow reactions because of low pre-exponential values caused by steric hindrance. ^

Oxygen, pH and calcium dynamics and fluxes at the thallus surface under ambient (8.1) and low (7.8) seawater pH and across a range of irradiances

Presently, an incomplete mechanistic understanding of tropical reef macroalgae photosynthesis and calcification restricts predictions of how these important autotrophs will respond to global change. Therefore, we investigated the mechanistic link between inorganic carbon uptake pathways, photosynthesis and calcification in a tropical crustose coralline alga (CCA) using microsensors. We measured pH, oxygen (O2), and calcium (Ca2+) dynamics and fluxes at the thallus surface under ambient (8.1) and low (7.8) seawater pH (pHSW) and across a range of irradiances. Acetazolamide (AZ) was used to inhibit extracellular carbonic anhydrase (CAext), which mediates hydrolysis of HCO3-, and 4,4' diisothiocyanatostilbene-2,2'-disulphonate (DIDS) that blocks direct HCO3- uptake by anion exchange transport. Both inhibited photosynthesis, suggesting both diffusive uptake of CO2 via HCO3- hydrolysis to CO2 and direct HCO3- ion transport are important in this CCA. Surface pH was raised approximately 0.3 units at saturating irradiance, but less when CAext was inhibited. Surface pH was lower at pHSW 7.8 than pHSW 8.1 in the dark, but not in the light. The Ca2+ fluxes were large, complex and temporally variable, but revealed net Ca2+ uptake under all conditions. The temporal variability in Ca2+ dynamics was potentially related to localized dissolution during epithallial cell sloughing, a strategy of CCA to remove epiphytes. Simultaneous Ca2+ and pH dynamics suggest the presence of Ca2+/H+ exchange. Rapid light-induced H+ surface dynamics that continued after inhibition of photosynthesis revealed the presence of a light-mediated, but photosynthesis-independent, proton pump. Thus, the study indicates metabolic control of surface pH can occur in CCA through photosynthesis and light-inducible H+ pumps. Our results suggest that complex light-induced ion pumps play an important role in biological processes related to inorganic carbon uptake and calcification in CCA.

Particle positions of numerical experiments 1 to 4

In mixed sediment beds, erosion resistance can change relative to that of beds composed of a uniform sediment because of varying textural and/or other grain-size parameters, with effects on pore water flow that are difficult to quantify by means of analogue techniques. To overcome this difficulty, a three-dimensional numerical model was developed using a finite difference method (FDM) flow model coupled with a distinct element method (DEM) particle model. The main aim was to investigate, at a high spatial resolution, the physical processes occurring during the initiation of motion of single grains at the sediment-water interface and in the shallow subsurface of simplified sediment beds under different flow velocities. Increasing proportions of very fine sand (D50=0.08 mm) were mixed into a coarse sand matrix (D50=0.6 mm) to simulate mixed sediment beds, starting with a pure coarse sand bed in experiment 1 (0 wt% fines), and proceeding through experiment 2 (6.5 wt% fines), experiment 3 (10.5 wt% fines), and experiment 4 (28.7 wt% fines). All mixed beds were tested for their erosion behavior at predefined flow velocities varying in the range of U 1-5=10-30 cm/s. The experiments show that, with increasing fine content, the smaller particles increasingly fill the spaces between the larger particles. As a consequence, pore water inflow into the sediment is increasingly blocked, i.e., there is a decrease in pore water flow velocity and, hence, in the flow momentum available to entrain particles. These findings are portrayed in a new conceptual model of enhanced sediment bed stabilization.

(E)-2-[2-(2-Aminofenil)vinil]-1-metilquinolin-4(1H)-ona como precursor de novos compostos heterociclicos

Esta dissertação reporta a síntese de novos derivados de 4-quinolonas com potencial atividade biológica e está dividida em 3 capítulos. No primeiro capítulo é feita uma breve introdução aos compostos do tipo 4quinolona, azepina e indol, focando a nomenclatura, atividade biológica e métodos de síntese mais comuns deste tipo de compostos, e é apresentada a nomenclatura dos compostos sintetizados ao longo deste trabalho. No segundo capítulo são descritas as metodologias desenvolvidas para obtenção dos compostos pretendidos. Foram sintetizados novos derivados de 4-quinolonas via reações de N-metilação seguida de ciclização in situ da (E)-N(2-acetilfenil)-3-(2-nitrofenil)acrilamida, via reações de redução da 1-metil-2-[2(2-nitrofenil)vinil]quinolin-4(1H)-ona e reações de halogenação da 1-metil-2-[2(2-nitrofenil)vinil]quinolin-4(1H)-ona e da 2-[2-(2-aminofenil)vinil]-1metilquinolin-4(1H)-ona. Posteriormente, fizeram-se estudos de reatividade da 1-metil-2-[2-(2-nitrofenil)vinil]quinolin-4(1H)-ona e da 2-[2-(2-aminofenil)vinil]-3bromo-1-metilquinolin-4(1H)-ona. Na reação de redução in situ seguida de ciclização intramolecular da 1-metil-2-[2-(2-nitrofenil)vinil]quinolin-4(1H)-ona obteve-se a 2-(1H-indol-2-il)-1-metilquinolin-4(1H)-ona. Partindo da 2-[2-(2aminofenil)vinil]-3-bromo-1-metilquinolin-4(1H)-ona via reações de BuchwaldHartwig obteve-se a 11-metil-5H-benzo[6,7]azepino[3,2-b]quinolin-6(11H)-ona. Novas N-[2-(2-(3-bromo-1-metil-4-oxo-1,4-di-hidroquinolin-2il)vinil)fenil]alquilamidas foram obtidas via reações de acilação da 2-[2-(2aminofenil)vinil]-3-bromo-1-metilquinolin-4(1H)-ona em piridina seca usando diferentes cloretos de acilo. Numa tentativa de ciclização intramolecular da N[2-(2-(3-bromo-1-metil-4-oxo-1,4-di-hidroquinolin-2-il)vinil)fenil]-hexanamida via reação de Ullmann intramolecular foi obtida a 2-(1-hexanoil-1H-indol-2-il)-1metilquinolin-4(1H)-ona. Após a descrição detalhada das metodologias de síntese são apresentadas as principais conclusões deste trabalho e perspectivas futuras. Por último, no terceiro capítulo, são apresentados os procedimentos experimentais usados para obtenção dos compostos sintetizados e os dados relativos à sua caracterização estrutural, que foi sendo discutida ao longo do segundo capítulo. Os compostos sintetizados foram caracterizados por espetroscopia de ressonância magnética nuclear monodimensional (1H e 13C) e bidimensional (HSQC, HMBC) e por espetrometria de massa e sempre que possível por espetrometria de massa de alta resolução.

Synthesis and antibacterial study of some s-substituted aliphatic analogues of 2-mercapto-5-(1-(4-toluenesulfonyl) piperidin-4-yl)-1,3,4-oxadiazole

Purpose: To synthesize a series of analogues of 1,3,4-oxadiazole and to evaluate their antibacterial activity. Methods: Ethyl piperidin-4-carboxylate (1) was mixed with 4-toluenesulfonyl chloride (2) in benignant conditions to yield ethyl 1-(4-toluenesulfonyl)piperidin-4-carboxylate (3) and then 1-(4- toluenesulfonyl)piperidin-4-carbohydrazide (4). Intermolecular cyclization of 4 into 2-mercapto-5-(1-(4- toluenesulfonyl) piperidin-4-yl)-1,3,4-oxadiazole (5) was obtained on reflux with CS2 in the presence of KOH. Molecule 5 was stirred with alkyl halides, 6a-i, in DMF in the presence of LiH to synthesize the final compounds, 7a-i. The structures of these molecules were elucidated by Fourier transform infra-red (FTIR) spectroscopy, proton nuclear magnetic resonance (1H-NMR) and electron impact mass spectrometry (EI-MS). Antibacterial activity was evaluated against five bacterial strains, namely, Salmonella typhi, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis, with ciprofloxacin used as standard antibacterial agent. Results: Out of nine synthesized derivatives, compound 7a was the most active against three bacterial strains, S. typhi, E. coli and P. aeruginosa, with minimum inhibitory concentration (MIC) of 9.11 ± 0.40, 9.89 ± 0.45 and 9.14 ± 0.72 μM, respectively, compared with 7.45 ± 0.58, 7.16 ± 0.58 and 7.14 ± 0.18 μM, respectively, for the reference standard (ciprofloxacin). Similarly, compounds 7a - 7c showed relatively good antibacterial activity against B. subtilis strain while compound 7e - 7g revealed good results against S. typhi bacterial strain. Conclusion: The results indicate that S-substituted derivatives of the parent compound are more effective antibacterial agents than the parent compound, even with minor differences in substituents