Multigram synthesis and in vivo efficacy studies of a novel multitarget anti-Alzheimer's compound

We describe the multigram synthesis and in vivo efficacy studies of a donepezil‒huprine hybrid that has been found to display a promising in vitro multitarget profile of interest for the treatment of Alzheimer's disease (AD). Its synthesis features as the key step a novel multigram preparative chromatographic resolution of intermediate racemic huprine Y by chiral HPLC. Administration of this compound to transgenic CL4176 and CL2006 Caenorhabditis elegans strains expressing human Aβ42, here used as simplified animal models of AD, led to a significant protection from the toxicity induced by Aβ42. However, this protective effect was not accompanied, in CL2006 worms, by a reduction of amyloid deposits. Oral administration for 3 months to transgenic APPSL mice, a well-established animal model of AD, improved short-term memory, but did not alter brain levels of Aβ peptides nor cortical and hippocampal amyloid plaque load. Despite the clear protective and cognitive effects of AVCRI104P4, the lack of Aβ lowering effect in vivo might be related to its lower in vitro potency toward Aβ aggregation and formation as compared with its higher anticholinesterase activities. Further lead optimization in this series should thus focus on improving the anti-amyloid/anticholinesterase activity ratio.

Adsorptive removal of harmful organic compound from aqueous solutions

Adsorption is one of the most commonly used methods in water treatment processes. It is attractive due to it easy operation and the availability of a wide variety of commercial adsorbents. This doctoral thesis focuses on investigating and explaining the influence of external phase conditions (temperature, pH, ionic strength, acidity, presence of cosolutes) on adsorption phenomena. In order to cover a wide range of factors and phenomena, case studies were chosen from various fields where adsorption is applied. These include the adsorptive removal of surface active agents (used in cleaning chemicals, for example) from aqueous effluents, the removal of hormones (estradiol) from drinking water, and the adsorption of antibiotics onto silica. The latter can beused to predict the diffusion of antibiotics in the aquatic system if they are released into the environment. Also the adsorption of living cells on functionalized polymers to purify infected water streams was studied. In addition to these examples, the adsorptive separation of harmful compounds from internal water streams within a chemical process was investigated. The model system was removal of fermentation inhibitors from lignocelluloses hydrolyzates. The detoxification of the fermentation broth is an important step in the manufacture of bioethanol from wood, but has not been studied previously in connection with concentrated acid hydrolyzates. New knowledge on adsorption phenomena was generated for all of the applications investigated. In most cases, the results could be explained by combining classical theories for individual phenomena. As an example, it was demonstrated how liquid phase aggregation could explain abnormal-looking adsorption equilibrium data. In addition to the fundamental phenomena, also process performance was of interest. This aspect is often neglected in adsorption studies. It was demonstrated that adsorbents should not be selected for a target application based on their adsorption properties only, but regeneration of the spent adsorbent must be considered. It was found that using a suitable amount of organic co-solvent in the regeneration can significantly improve the productivity of the process.

Chemical quality parameters and bioactive compound content of brazilian berries

There is a growing consumer demand for higher healthy foods such as berries which are a rich source of phenolic compounds. The current work evaluated blackberry cultivars: Cherokee, Tupy and Xavante; raspberry cultivars: Heritage, Fallgold and Black; and the hybrid Boysenberry. All berries were grown under homogenous subtropical conditions in Brazil. Black raspberry, Cherokee and Tupy blackberry cultivars showed the highest ratio between soluble solid contents and titratable acidity, and Fallgold and Heritage raspberry showed the highest titratable acidity. Total phenolic content ranged from 2.03 to 5.33 g kg–1 fresh weight and total anthocyanin content registered values from 0.41 to 1.81 g kg–1 fresh weight. The most common phenolic acids were gallic, p-coumaric and ellagic, and for anthocyanins: cyanidin-3-glucoside and malvinidin-3-glucoside. Antioxidant capacity ranged from 14.13 to 21.51 mol equivalent trolox kg–1 fresh weight. Black raspberry, all blackberry cultivars and the Boysenberry hybrid are appropriate to be consumed fresh, while Fallgold and Heritage raspberries are recommended to the food industry. Due to their phenolic richness and antioxidant properties, these fruits are of great interest to the fresh fruit market and to pharmaceutical industries. These results could help breeders and growers when planning the cultivar selection according to their foreseeable destination.

N-nitroso compound exposure-associated transcriptomic profiles are indicative of an increased risk for colorectal cancer

Endogenous formation of N-nitroso compounds (NOCs), which are known animal carcinogens, could contribute to human carcinogenesis but definitive evidence is still lacking. To investigate the relevance of NOCs in human colorectal cancer (CRC) development, we analyzed whole genome gene expression modifications in human colon biopsies in relation to fecal NOC exposure. We had a particular interest in patients suffering from intestinal inflammation as this may stimulate endogenous NOC formation, and consequently predispose to CRC risk. Inflammatory bowel disease (IBD) patients diagnosed with ulcerative colitis and irritable bowel syndrome patients without inflammation, serving as controls, were therefore recruited. Fecal NOC were demonstrated in the majority of subjects. By associating gene expression levels of all subjects to fecal NOC levels, we identified a NOC exposure-associated transcriptomic response that suggests that physiological NOC concentrations may potentially induce genotoxic responses and chromatin modifications in human colon tissue, both of which are linked to carcinogenicity. In a network analysis, chromatin modifications were linked to 11 significantly modulated histone genes, pointing towards a possible epigenetic mechanism that may be relevant in comprehending NOC-induced carcinogenesis. In addition, pro-inflammatory transcriptomic modifications were identified in visually non-inflamed regions of the IBD colon. However, fecal NOC levels were slightly but not significantly increased in IBD patients, suggesting that inflammation did not strongly stimulate NOC formation. We conclude that NOC exposure is associated with gene expression modifications in the human colon that may suggest a potential role of these compounds in CRC development.

Magnetic tunneling junctions with the Heusler compound Co 2 Cr 0.6 Fe 0.4 Al

Materialen mit sehr hoher Spinpolarisation werden für Anwendungen im Bereich der Spin-Elektronik benötigt. Deshalb werden große Forschungsanstrengungen zur Untersuchung der Eigenschaften von Verbindungen mit potentiell halbmetallischem Charakter, d. h.mit 100% Spinpolarisation, unternommen. In halbmetallischen Verbindungen, erwartet man eine Lücke in der Zustandsdichte an der Fermi Energie für Ladungsträger einer Spinrichtung, wahrend die Ladungsträger mit der anderen Spinrichtung sich metallisch verhalten. Eine Konsequenz davon ist, dass ein Strom, der durch solche Verbindung fließt, voll spinpolarisiert ist. Die hohe Curie-Temperatur Tc (800 K) und der theoretisch vorhergesagte halbmetallische Charakter machen Co2Cr0.6Fe0.4Al (CCFA) zu einem guten Kandidaten für Spintronik-Anwendungen wie magnetische Tunnelkontakte (MTJs = Magnetic Tunneling Junctions). In dieser Arbeit werden die Ergebnisse der Untersuchung der elektronischen und strukturellen Eigenschaften von dünnen CCFA Schichten dargestellt. Diese Schichten wurden in MTJs integriert und der Tunnel-Magnetowiderstands-Effekt untersucht. Hauptziele waren die Messung der Spinpolarisation und Untersuchungen der elektronischen Struktur von CCFA. Der Einfluss verschiedener Depositionsparameter auf die Eigenschaften der Schichten, speziell auf der Oberflächenordnung und damit letztlich auf den Tunnel-Magnetowiderstand (TMR), wurde bestimmt. Epitaktische d¨unne CCFA Schichten mit zwei verschiedenen Wachstumsrichtungen wurden auf verschiedene Substrate und Pufferschichten deponiert. Ein Temperverfahren wurde eingesetzt um die strukturelle Eigenschaften der dünnen Schichten zu verbessern. Für die MTJs wurde Al2O3 als Barrierenmaterial verwendet und Co als Gegenelektrode gewählt. Die Mehrschicht-Systeme wurden in Mesa-Geometrie mit lithographischen Methoden strukturiert. Eine maximal Jullière Spinpolarisation von 54% wurde an Tunnelkontakte mit epitaktischen CCFA Schichten gemessen. Ein starker Einfluss der Tempernbedingungen auf dem TMR wurde festgestellt. Eine Erhörung des TMR wurde mit einer Verbesserung der Oberflächenordung der CCFA Schichten korreliert. Spektroskopische Messungen wurden an den MTJs durchgeführt. Diesen Messungen liefern Hinweise auf inelastische Elektron-Magnon und Elektron-Phonon Stossprozesse an den Grenzflächen. Einige der beobachteten Strukturen konnten mit der berechneten elektronischen Struktur von CCFA korreliert worden.

Analysis and compound of carbon sequestration and serpentinization from the Iberian Margin and the Northern Apennine

Fluid circulation in peridotite-hosted hydrothermal systems influences the incorporation of carbon into the oceanic crust and its long-term storage. At low to moderate temperatures, serpentinization of peridotite produces alkaline fluids that are rich in CH4 and H2. Upon mixing with seawater, these fluids precipitate carbonate, forming an extensive network of calcite veins in the basement rocks, while H2 and CH4 serve as an energy source for microorganisms. Here, we analyzed the carbon geochemistry of two ancient peridotite-hosted hydrothermal systems: 1) ophiolites cropping out in the Northern Apennines, and 2) calcite-veined serpentinites from the Iberian Margin (Ocean Drilling Program (ODP) Legs 149 and 173), and compare them to active peridotite-hosted hydrothermal systems such as the Lost City hydrothermal field (LCHF) on the Atlantis Massif near the Mid-Atlantic Ridge (MAR). Our results show that large amounts of carbonate are formed during serpentinization of mantle rocks exposed on the seafloor (up to 9.6 wt.% C in ophicalcites) and that carbon incorporation decreases with depth. In the Northern Apennine serpentinites, serpentinization temperatures decrease from 240 °C to < 150 °C, while carbonates are formed at temperatures decreasing from ~ 150 °C to < 50 °C. At the Iberian Margin both carbonate formation and serpentinization temperatures are lower than in the Northern Apennines with serpentinization starting at ~ 150 °C, followed by clay alteration at < 100 °C and carbonate formation at < 19-44 °C. Comparison with various active peridotite-hosted hydrothermal systems on the MAR shows that the serpentinites from the Northern Apennines record a thermal evolution similar to that of the basement of the LCHF and that tectonic activity on the Jurassic seafloor, comparable to the present-day processes leading to oceanic core complexes, probably led to formation of fractures and faults, which promoted fluid circulation to greater depth and cooling of the mantle rocks. Thus, our study provides further evidence that the Northern Apennine serpentinites host a paleo-stockwork of a hydrothermal system similar to the basement of the LCHF. Furthermore, we argue that the extent of carbonate uptake is mainly controlled by the presence of fluid pathways. Low serpentinization temperatures promote microbial activity, which leads to enhanced biomass formation and the storage of organic carbon. Organic carbon becomes dominant with increasing depth and is the principal carbon phase at more than 50-100 m depth of the serpentinite basement at the Iberian Margin. We estimate that annually 1.1 to 2.7 × 1012 g C is stored within peridotites exposed to seawater, of which 30-40% is fixed within the uppermost 20-50 m mainly as carbonate. Additionally, we conclude that alteration of oceanic lithosphere is an important factor in the long-term global carbon cycle, having the potential to store carbon for millions of years.

Investigation of electrically active defects at the interface of high-k dielectrics and compound semiconductors

As silicon based devices in integrated circuits reach the fundamental limits of dimensional scaling there is growing research interest in the use of high electron mobility channel materials, such as indium gallium arsenide (InGaAs), in conjunction with high dielectric constant (high-k) gate oxides, for Metal-Oxide-Semiconductor Field Effect Transistor (MOSFET) based devices. The motivation for employing high mobility channel materials is to reduce power dissipation in integrated circuits while also providing improved performance. One of the primary challenges to date in the field of III-V semiconductors has been the observation of high levels of defect densities at the high-k/III-V interface, which prevents surface inversion of the semiconductor. The work presented in this PhD thesis details the characterization of MOS devices incorporating high-k dielectrics on III-V semiconductors. The analysis examines the effect of modifying the semiconductor bandgap in MOS structures incorporating InxGa1-xAs (x: 0, 0.15. 0.3, 0.53) layers, the optimization of device passivation procedures designed to reduce interface defect densities, and analysis of such electrically active interface defect states for the high-k/InGaAs system. Devices are characterized primarily through capacitance-voltage (CV) and conductance-voltage (GV) measurements of MOS structures both as a function of frequency and temperature. In particular, the density of electrically active interface states was reduced to the level which allowed the observation of true surface inversion behavior in the In0.53Ga0.47As MOS system. This was achieved by developing an optimized (NH4)2S passivation, minimized air exposure, and atomic layer deposition of an Al2O3 gate oxide. An extraction of activation energies allows discrimination of the mechanisms responsible for the inversion response. Finally a new approach is described to determine the minority carrier generation lifetime and the oxide capacitance in MOS structures. The method is demonstrated for an In0.53Ga0.47As system, but is generally applicable to any MOS structure exhibiting a minority carrier response in inversion.

Compound Heterozygous Rag2 Mutations Mimicking Hyper Igm Syndrome.

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Preparação do (+)-±-terpineol a partir do (+)-limoneno: monoterpenos de odor agradável em um projeto para química orgânica experimental

A synthesis of (+)-±-terpineol from (+)-limonene was proposed as a project for undergraduate organic laboratory course. Terpineol is a useful flavor and fragrance compound, and several aspects of this preparation are suited for experimental organic classes, including basic techniques for extraction and analyses of essential oils, different reaction types and the possibility of a high degree of student interest.

EPR and magnetic studies of a carboxylate-bridged dinuclear copper(II) compound: [cu2(flu)4(dmf)2]

We report magnetic and EPR (electron paramagnetic resonance) spectroscopy studies of [Cu2(flu)4(dmf)2] (flu = flufenamate and dmf = dimethylformamide), which has CuII ions in tetracarboxylate "paddle wheel" dinuclear units. Susceptibility measurements at 10 < T < 275 K allowed the evaluation of an antiferromagnetic intradinuclear exchange coupling J0 = -294 ± 5 cm-1 between CuII ions (Hex = "J0 S1·S2). EPR experiments at 300 K in powder and single-crystals at 9.5 and 34.4 GHz indicated g// = 2.373, g⊥ = 2.073 and zero field splitting parameters D = (-0.334 ± 0.001) cm"1 and E ca. 0. EPR signal intensity measurements at X-band in the range 4 < T < 295 K indicated that J0 = "283 ± 5 cm"1. A higher limit |J´| < 5×10-3 cm-1 for the interdinuclear exchange coupling between neighbor units at ca.14.24 Å was estimated from the angular variation of the single crystal spectra around the magic angles. The results are discussed in terms of the structure of the dinuclear unit and the bridges connecting CuII ions and compared with values reported for similar compounds.

A Novel Organotellurium Compound (RT-01) as a New Antileishmanial Agent

Leishmaniasis is a neglected disease and endemic in developing countries. A lack of adequate and definitive chemotherapeutic agents to fight against this infection has led to the investigation of numerous compounds. The aim of this study was to investigate the effect of RT-01, an organotellurane compound presenting biological activities, in 2 experimental systems against Leishmania amazonensis. The in vitro system consisted of promastigotes and amastigotes forms of the parasite, and the in vivo system consisted of L. amazonensis infected BALB/c mice, an extremely susceptible mouse strain. The compound proved to be toxic against promastigotes and amastigotes. The study also showed that treatment with RT-01 produces an effect similar to that treatment with the reference antimonial drug, Glucantime, in L. amazonensis infected mice. The best results were obtained following RT-01 intralesional administration (720 mu g/kg/day); mice showed significant delay in the development of cutaneous lesions and decreased numbers of parasites obtained from the lesions. Significant differences in tissue pathology consisted mainly of no expressive accumulation of inflammatory cells and well-preserved structures in the skin tissue of RT-01-treated mice compared with expressive infiltration of infected cells replacing the skin tissue in lesions of untreated mice. These findings highlight the fact that the apparent potency of organotellurane compounds, together with their relatively simple structure, may represent a new avenue for the development of novel drugs to combat parasitic diseases.

Isotropic and anisotropic spin-spin interactions and a quantum phase transition in a dinuclear Cu(II) compound

We report electron-paramagnetic resonance (EPR) studies at similar to 9.5 GHz (X band) and similar to 34 GHz (Q band) of powder and single-crystal samples of the compound Cu(2)[TzTs](4) [N-thiazol-2-yl-toluenesulfonamidatecopper(II)], C(40)H(36)Cu(2)N(8)O(8)S(8), having copper(II) ions in dinuclear units. Our data allow determining an antiferromagnetic interaction J(0)=(-113 +/- 1) cm(-1) (H(ex)=-J(0)S(1)center dot S(2)) between Cu(II) ions in the dinuclear unit and the anisotropic contributions to the spin-spin coupling matrix D (H(ani)=S(1)center dot D center dot S(2)), a traceless symmetric matrix with principal values D/4=(0.198 +/- 0.003) cm(-1) and E/4=(0.001 +/- 0.003) cm(-1) arising from magnetic dipole-dipole and anisotropic exchange couplings within the units. In addition, the single-crystal EPR measurements allow detecting and estimating very weak exchange couplings between neighbor dinuclear units, with an estimated magnitude parallel to J(')parallel to=(0.060 +/- 0.015) cm(-1). The interactions between a dinuclear unit and the ""environment"" of similar units in the structure of the compound produce a spin dynamics that averages out the intradinuclear dipolar interactions. This coupling with the environment leads to decoherence, a quantum phase transition that collapses the dipolar interaction when the isotropic exchange coupling with neighbor dinuclear units equals the magnitude of the intradinuclear dipolar coupling. Our EPR experiments provide a new procedure to follow the classical exchange-narrowing process as a shift and collapse of the line structure (not only as a change of the resonance width), which is described with general (but otherwise simple) theories of magnetic resonance. Using complementary procedures, our EPR measurements in powder and single-crystal samples allow measuring simultaneously three types of interactions differing by more than three orders of magnitude (between 113 cm(-1) and 0.060 cm(-1)).

Facies, delta(13)C, delta(15)N and C/N analyses in a late Quaternary compound estuarine fill, northern Brazil and relation to sea level

The present work integrates sedimentary facies, (14)C dating, delta(13)C, delta(15)N, and C/N with geologic and geomorphologic data available from literature. The aim was to characterize the depositional settings of a late Quaternary estuary in northeastern Marajo Island and analyze its evolution within the context of relative sea level fluctuations. The data derive from four continuous cores along a proximal-to-distal transect of a paleoestuary, previously recognized using remote sensing information. Fifteen sediment samples recorded ages ranging from 42,580 +/- 1430 to 3184 +/- 37 (14)C yr B.P. Fades analysis indicated fine- to coarse-grained sands with parallel lamination or cross stratification, massive or laminated muds and heterolithic deposits. delta(13)C (-28.1 parts per thousand to -19.7 parts per thousand, mean = -23.0 parts per thousand), delta(15)N (+ 14.8 parts per thousand to + 4.7 parts per thousand, mean = + 9.2 parts per thousand) and C/N (14.5 to 1.5, mean = 7.9) indicate mostly marine and freshwater phytoplankton sources for the organic matter. The results confirm a large late Quaternary paleoestuary in northeastern Marajo Island. The distribution of delta(13)C, delta(15)N, and C/N, together with fades associations, led to identify depositional settings related to fluvial channel, floodplain, tidal channel/tidal flat, central basin, tidal delta, and tidal inlet/sand barrier. These deposits are consistent with a wave-dominated estuary. Variations in stratigraphy and geochemistry are controlled by changes in relative sea level, revealing a main transgression from an undetermined time around 42,000 (14)C yr B.P. and 29,340 (+/- 200) (14)C yr B.P., which is synchronous to the overall drop in sea level after the last interglacial. Following this period, and probably until 9110 +/- 37 (14)C yr B.P., i.e., during a time interval encompassing two glacial episodes including the Last Glacial and the Younger Dryas, there was a pronounced drop in sea level, recorded by the development of a major erosional discontinuity due to valley re-incision. Sea level rose again until 5464 +/- 40 (14)C yr B.P, just before the main worldwide mid-Holocene transgressive peak. Mid to late Holocene coastal progradation ended the Marajo paleoestuarine history, and promoted the establishment of continental conditions throughout the island. The divergence comparing the Marajo sea level behavior with the eustatic curve allows hypothesizing that post-rifting tectonics along the Brazilian Equatorial margin influenced the sedimentary evolution of the studied paleoestuary. Considering that sedimentary facies in estuarine settings are highly variable both laterally and vertically, the present integration of facies with isotope and elemental analyses was crucial to provide a more precise interpretation of the Late Pleistocene and Holocene Marajo paleoestuary, and analyze its sea level history within the eustatic and tectonic context. (C) 2010 Elsevier B.V. All rights reserved.

Comparative study of the biochemical changes and volatile compound formations during the production of novel whey-based kefir beverages and traditional milk kefir

Cheese whey (CW) and deproteinised cheese whey (DCW) were investigated for their suitability as novel substrates for the production of kefir-like beverages. Lactose consumption, ethanol production, as well as organic acids and volatile compounds formation, were determined during CW and DCW fermentation by kefir grains and compared with values obtained during the production of traditional milk kefir. The results showed that kefir grains were able to utilise lactose from CW and DCW and produce similar amounts of ethanol (7.8-8.3 g/l), lactic acid (5.0 g/l) and acetic acid (0.7 g/l) to those obtained during milk fermentation. In addition, the concentration of higher alcohols (2-methyl-1-butanol, 3-methyl-1-butanol, 1-hexanol, 2-methyl-1-propanol, and 1-propanol), ester (ethyl acetate) and aldehyde (acetaldehyde) in cheese whey-based kefir and milk kefir beverages were also produced in similar amounts. Cheese whey and deproteinised cheese whey may therefore serve as substrates for the production of kefir-like beverages similar to milk kefir. (C) 2010 Elsevier Ltd. All rights reserved.

Inhibitory action of toxic compounds present in lignocellulosic hydrolysates on xylose to xylitol bioconversion by Candida guilliermondii

The inhibitory action of acetic acid, ferulic acid, and syringaldehyde on metabolism of Candida guilliermondii yeast during xylose to xylitol bioconversion was evaluated. Assays were performed in buffered and nonbuffered semidefined medium containing xylose as main sugar (80.0 g/l), supplemented or not with acetic acid (0.8-2.6 g/l), ferulic acid (0.2-0.6 g/l), and/or syringaldehyde (0.3-0.8 g/l), according to a 2(3) full factorial design. Since only individual effects of the variables were observed, assays were performed in a next step in semidefined medium containing different concentrations of each toxic compound individually, for better understanding of their maximum concentration that can be present in the fermentation medium without affecting yeast metabolism. It was concluded that acetic acid, ferulic acid, and syringaldehyde are compounds that may affect Candida guilliermondii metabolism (mainly cell growth) during bioconversion of xylose to xylitol. Such results are of interest and reveal that complete removal of toxic compounds from the fermentation medium is not necessary to obtain efficient conversion of xylose to xylitol by Candida guilliermondii. Fermentation in buffered medium was also considered as an alternative to overcome the inhibition caused by these toxic compounds, mainly by acetic acid.