Novel Magnetic Materials Based on Macrocyclic Ligands: Towards High Relaxivity Contrast Agents and Mononuclear Single-Molecule Magnets

The preparation and characterization of coordination complexes of Schiff-base and crown ether macrocycles is presented, for application as contrast agents for magnetic resonance imaging, Project 1; and single-molecule magnets (SMMs), Projects 2 and 3. In Project 1, a family of eight Mn(II) and Gd(III) complexes of N3X2 (X = NH, O) and N3O3 Schiff-base macrocycles were synthesized, characterized, and evaluated as potential contrast agents for MRI. In vitro and in vivo (rodent) studies indicate that the studied complexes display efficient contrast behaviour, negligible toxicity, and rapid excretion. In Project 2, DyIII complexes of Schiff-base macrocycles were prepared with a view to developing a new family of mononuclear Ln-SMMs with pseudo-D5h geometries. Each complex displayed slow relaxation of magnetization, with magnetically-derived energy barriers in the range Ueff = 4 – 24 K. In Project 3, coordination complexes of selected later lanthanides with various crown ether ligands were synthesized. Two families of complexes were structurally and magnetically analyzed: ‘axial’ or sandwich-type complexes based on 12-crown-4 and 15-crown-5; and ‘equatorial’ complexes based on 18-crown-6. Magnetic data are supported by ab initio calculations and luminescence measurements. Significantly, the first mononuclear Ln-SMM prepared from a crown ether ligand is described.

Développement d'une nouvelle méthode de caractérisation tissulaire basée sur l'élastographie ultrasonore : application pour le dépistage précoce du cancer du sein

Le cancer du sein est le cancer le plus fréquent chez la femme. Il demeure la cause de mortalité la plus importante chez les femmes âgées entre 35 et 55 ans. Au Canada, plus de 20 000 nouveaux cas sont diagnostiqués chaque année. Les études scientifiques démontrent que l'espérance de vie est étroitement liée à la précocité du diagnostic. Les moyens de diagnostic actuels comme la mammographie, l'échographie et la biopsie comportent certaines limitations. Par exemple, la mammographie permet de diagnostiquer la présence d’une masse suspecte dans le sein, mais ne peut en déterminer la nature (bénigne ou maligne). Les techniques d’imagerie complémentaires comme l'échographie ou l'imagerie par résonance magnétique (IRM) sont alors utilisées en complément, mais elles sont limitées quant à la sensibilité et la spécificité de leur diagnostic, principalement chez les jeunes femmes (< 50 ans) ou celles ayant un parenchyme dense. Par conséquent, nombreuses sont celles qui doivent subir une biopsie alors que leur lésions sont bénignes. Quelques voies de recherche sont privilégiées depuis peu pour réduire l`incertitude du diagnostic par imagerie ultrasonore. Dans ce contexte, l’élastographie dynamique est prometteuse. Cette technique est inspirée du geste médical de palpation et est basée sur la détermination de la rigidité des tissus, sachant que les lésions en général sont plus rigides que le tissu sain environnant. Le principe de cette technique est de générer des ondes de cisaillement et d'en étudier la propagation de ces ondes afin de remonter aux propriétés mécaniques du milieu via un problème inverse préétabli. Cette thèse vise le développement d'une nouvelle méthode d'élastographie dynamique pour le dépistage précoce des lésions mammaires. L'un des principaux problèmes des techniques d'élastographie dynamiques en utilisant la force de radiation est la forte atténuation des ondes de cisaillement. Après quelques longueurs d'onde de propagation, les amplitudes de déplacement diminuent considérablement et leur suivi devient difficile voir impossible. Ce problème affecte grandement la caractérisation des tissus biologiques. En outre, ces techniques ne donnent que l'information sur l'élasticité tandis que des études récentes montrent que certaines lésions bénignes ont les mêmes élasticités que des lésions malignes ce qui affecte la spécificité de ces techniques et motive la quantification de d'autres paramètres mécaniques (e.g.la viscosité). Le premier objectif de cette thèse consiste à optimiser la pression de radiation acoustique afin de rehausser l'amplitude des déplacements générés. Pour ce faire, un modèle analytique de prédiction de la fréquence de génération de la force de radiation a été développé. Une fois validé in vitro, ce modèle a servi pour la prédiction des fréquences optimales pour la génération de la force de radiation dans d'autres expérimentations in vitro et ex vivo sur des échantillons de tissu mammaire obtenus après mastectomie totale. Dans la continuité de ces travaux, un prototype de sonde ultrasonore conçu pour la génération d'un type spécifique d'ondes de cisaillement appelé ''onde de torsion'' a été développé. Le but est d'utiliser la force de radiation optimisée afin de générer des ondes de cisaillement adaptatives, et de monter leur utilité dans l'amélioration de l'amplitude des déplacements. Contrairement aux techniques élastographiques classiques, ce prototype permet la génération des ondes de cisaillement selon des parcours adaptatifs (e.g. circulaire, elliptique,…etc.) dépendamment de la forme de la lésion. L’optimisation des dépôts énergétiques induit une meilleure réponse mécanique du tissu et améliore le rapport signal sur bruit pour une meilleure quantification des paramètres viscoélastiques. Il est aussi question de consolider davantage les travaux de recherches antérieurs par un appui expérimental, et de prouver que ce type particulier d'onde de torsion peut mettre en résonance des structures. Ce phénomène de résonance des structures permet de rehausser davantage le contraste de déplacement entre les masses suspectes et le milieu environnant pour une meilleure détection. Enfin, dans le cadre de la quantification des paramètres viscoélastiques des tissus, la dernière étape consiste à développer un modèle inverse basé sur la propagation des ondes de cisaillement adaptatives pour l'estimation des paramètres viscoélastiques. L'estimation des paramètres viscoélastiques se fait via la résolution d'un problème inverse intégré dans un modèle numérique éléments finis. La robustesse de ce modèle a été étudiée afin de déterminer ces limites d'utilisation. Les résultats obtenus par ce modèle sont comparés à d'autres résultats (mêmes échantillons) obtenus par des méthodes de référence (e.g. Rheospectris) afin d'estimer la précision de la méthode développée. La quantification des paramètres mécaniques des lésions permet d'améliorer la sensibilité et la spécificité du diagnostic. La caractérisation tissulaire permet aussi une meilleure identification du type de lésion (malin ou bénin) ainsi que son évolution. Cette technique aide grandement les cliniciens dans le choix et la planification d'une prise en charge adaptée.

Understanding land-sea warming contrast in response to increasing greenhouse gases. Part I: Transient adjustment

Climate model simulations consistently show that surface temperature over land increases more rapidly than over sea in response to greenhouse gas forcing. The enhanced warming over land is not simply a transient effect caused by the land–sea contrast in heat capacities, since it is also present in equilibrium conditions. This paper elucidates the transient adjustment processes over time scales of days to weeks of the surface and tropospheric climate in response to a doubling of CO2 and to changes in sea surface temperature (SST), imposed separately and together, using ensembles of experiments with an atmospheric general circulation model. These adjustment processes can be grouped into three stages: immediate response of the troposphere and surface processes (day 1), fast adjustment of surface processes (days 2–5), and adjustment of the whole troposphere (days 6–20). Some land surface warming in response to doubled CO2 (with unchanged SSTs) occurs immediately because of increased downward longwave radiation. Increased CO2 also leads to reduced plant stomatal resistance and hence restricted evaporation, which increases land surface warming in the first day. Rapid reductions in cloud amount lead in the next few days to increased downward shortwave radiation and further warming, which spreads upward from the surface, and by day 5 the surface and tropospheric response is statistically consistent with the equilibrium value. Land surface warming in response to imposed SST change (with unchanged CO2) is slower. Tropospheric warming is advected inland from the sea, and over land it occurs at all levels together rather than spreading upward from the surface. The atmospheric response to prescribed SST change in about 20 days is statistically consistent with the equilibrium value, and the warming is largest in the upper troposphere over both land and sea. The land surface warming involves reduction of cloud cover and increased downward shortwave radiation, as in the experiment with CO2 change, but in this case it is due to the restriction of moisture supply to the land (indicated by reduced soil moisture), whereas in the CO2 forcing experiment it is due to restricted evaporation despite increased moisture supply (indicated by increased soil moisture). The warming over land in response to SST change is greater than over the sea and is the dominant contribution to the land–sea warming contrast under enhanced CO2 forcing.

The basic ingredients of the North Atlantic storm track. Part I: land-sea contrast and orography

Understanding and predicting changes in storm tracks over longer time scales is a challenging problem, particularly in the North Atlantic. This is due in part to the complex range of forcings (land–sea contrast, orography, sea surface temperatures, etc.) that combine to produce the structure of the storm track. The impact of land–sea contrast and midlatitude orography on the North Atlantic storm track is investigated through a hierarchy of GCM simulations using idealized and “semirealistic” boundary conditions in a high-resolution version of the Hadley Centre atmosphere model (HadAM3). This framework captures the large-scale essence of features such as the North and South American continents, Eurasia, and the Rocky Mountains, enabling the results to be applied more directly to realistic modeling situations than was possible with previous idealized studies. The physical processes by which the forcing mechanisms impact the large-scale flow and the midlatitude storm tracks are discussed. The characteristics of the North American continent are found to be very important in generating the structure of the North Atlantic storm track. In particular, the southwest–northeast tilt in the upper tropospheric jet produced by southward deflection of the westerly flow incident on the Rocky Mountains leads to enhanced storm development along an axis close to that of the continent’s eastern coastline. The approximately triangular shape of North America also enables a cold pool of air to develop in the northeast, intensifying the surface temperature contrast across the eastern coastline, consistent with further enhancements of baroclinicity and storm growth along the same axis.

A supramolecular polymer based on tweezer-type pi-pi stacking interactions: molecular design for healability and enhanced toughness

An elastomeric, healable, supramolecular polymer blend comprising a chain-folding polyimide and a telechelic polyurethane with pyrenyl end groups is compatibilized by aromatic pi-pi stacking between the pi-electron-deficient diimide groups and the pi-electron-rich pyrenyl units. This interpolymer interaction is the key to forming a tough, healable, elastomeric material. Variable-temperature FTIR analysis of the bulk material also conclusively demonstrates the presence of hydrogen bonding, which complements the pi-pi stacking interactions. Variable-temperature SAXS analysis shows that the healable polymeric blend has a nanophase-separated morphology and that the X-ray contrast between the two types of domain increases with increasing temperature, a feature that is repeatable over several heating and cooling cycles. A fractured sample of this material reproducibly regains more than 95% of the tensile modulus, 91% of the elongation to break, and 77% of the modulus of toughness of the pristine material.

Enhanced sensitivity to rapamycin following long-term oestrogen deprivation in MCF-7, T-47-D and ZR-75-1 human breast cancer cells

Human breast cancer cells (MCF-7, T-47-D and ZR-75-1) can adapt to circumvent any reduced growth rate during long-term oestrogen deprivation, and this provides three model systems to investigate mechanisms of endocrine resistance in breast cancer. In this paper we report consistent differences in the effects of three growth inhibitors following long-term oestrogen deprivation in all three cell models. Long-term oestrogen deprivation of MCF-7, T-47-D and ZR-75-1 cells resulted in reduced growth inhibition by PD98059 (2–10 µg/ml), implying a loss of dependence on mitogen-activated protein kinase pathways for growth. The growth inhibitor LY294002 (2–10 µM) inhibited growth of both oestrogen-maintained and oestrogen-deprived cells with similar dose–responses, implying continued similar dependence on phosphoinositide 3-kinase (PI3K) pathways with no alteration after adaptation to oestrogen independent growth. However, by contrast, long-term oestrogen deprivation resulted in an increased sensitivity to growth inhibition by rapamycin, which was not reduced by readdition of oestradiol. The enhanced inhibition of long-term oestrogen-deprived MCF-7-ED, T-47-D-ED and ZR-75-1-ED cell growth by combining rapamycin with LY294002 at concentrations where each alone had little effect, offers preclinical support to the development of therapeutic combinations of rapamycin analogues with other PI3K inhibitors in endocrine-resistant breast cancer.

Is prospective memory enhanced by cue-action semantic relatedness and enactment at encoding?

Benefits and costs on prospective memory performance, of enactment at encoding and a semantic association between a cue-action word pair, were investigated in two experiments. Findings revealed superior performance for both younger and older adults following enactment, in contrast to verbal encoding, and when cue-action semantic relatedness was high. Although younger adults outperformed older adults, age did not moderate benefits of cue-action relatedness or enactment. Findings from a second experiment revealed that the inclusion of an instruction to perform a prospective memory task led to increments in response latency to items from the ongoing activity in which that task was embedded, relative to latencies when the ongoing task only was performed. However, this task interference ‘cost’ did not differ as a function of either cue-action relatedness or enactment. We argue that the high number of cue-action pairs employed here influenced meta-cognitive consciousness, hence determining attention allocation, in all experimental conditions.

Toll-Like Receptor 4 Signaling Leads to Severe Fungal Infection Associated with Enhanced Proinflammatory Immunity and Impaired Expansion of Regulatory T Cells

Toll-like receptors (TLRs) present in innate immune cells recognize pathogen molecular patterns and influence immunity to control the host-parasite interaction. The objective of this study was to characterize the involvement of TLR4 in the innate and adaptive immunity to Paracoccidioides brasiliensis, the most important primary fungal pathogen of Latin America. We compared the responses of C3H/HeJ mice, which are naturally defective in TLR4 signaling, with those of C3H/HePas mice, which express functional receptors, after in vitro and in vivo infection with P. brasiliensis. Unexpectedly, we verified that TLR4-defective macrophages infected in vitro with P. brasiliensis presented decreased fungal loads associated with impaired synthesis of nitric oxide, interleukin-12 (IL-12), and macrophage chemotactic protein 1 (MCP-1). After intratracheal infection with 1 million yeasts, TLR4-defective mice developed reduced fungal burdens and decreased levels of pulmonary nitric oxide, proinflammatory cytokines, and antibodies. TLR4-competent mice produced elevated levels of IL-12 and tumor necrosis factor alpha (TNF-alpha), besides cytokines of the Th17 pattern, indicating a proinflammatory role for TLR4 signaling. The more severe infection of TLR4-normal mice resulted in increased influx of activated macrophages and T cells to the lungs and progressive control of fungal burdens but impaired expansion of regulatory T cells (Treg cells). In contrast, TLR4-defective mice were not able to clear their diminished fungal burdens totally, a defect associated with deficient activation of T-cell immunity and enhanced development of Treg cells. These divergent patterns of immunity, however, resulted in equivalent mortality rates, indicating that control of elevated fungal growth mediated by vigorous inflammatory reactions is as deleterious to the hosts as low fungal loads inefficiently controlled by limited inflammatory reactions.

Enhanced classification of Chagas serologic results and epidemiologic characteristics of seropositive donors at three large blood centers in Brazil

BACKGROUND: A major problem in Chagas disease donor screening is the high frequency of samples with inconclusive results. The objective of this study was to describe patterns of serologic results among donors to the three Brazilian REDS-II blood centers and correlate with epidemiologic characteristics. STUDY DESIGN AND METHODS: The centers screened donor samples with one Trypanosoma cruzi lysate enzyme immunoassay (EIA). EIA-reactive samples were tested with a second lysate EIA, a recombinant-antigen based EIA, and an immunfluorescence assay. Based on the serologic results, samples were classified as confirmed positive (CP), probable positive (PP), possible other parasitic infection (POPI), and false positive (FP). RESULTS: In 2007 to 2008, a total of 877 of 615,433 donations were discarded due to Chagas assay reactivity. The prevalences (95% confidence intervals [CIs]) among first-time donors for CP, PP, POPI, and FP patterns were 114 (99-129), 26 (19-34), 10 (5-14), and 96 (82-110) per 100,000 donations, respectively. CP and PP had similar patterns of prevalence when analyzed by age, sex, education, and location, suggesting that PP cases represent true T. cruzi infections; in contrast the demographics of donors with POPI were distinct and likely unrelated to Chagas disease. No CP cases were detected among 218,514 repeat donors followed for a total of 718,187 person-years. CONCLUSION: We have proposed a classification algorithm that may have practical importance for donor counseling and epidemiologic analyses of T. cruzi-seroreactive donors. The absence of incident T. cruzi infections is reassuring with respect to risk of window phase infections within Brazil and travel-related infections in nonendemic countries such as the United States.

New insights on surface-enhanced Raman scattering based on controlled aggregation and spectroscopic studies, DFT calculations and symmetry analysis for 3,6-bi-2-pyridyl-1,2,4,5-tetrazine adsorbed onto citrate-stabilized gold nanoparticles

Asystematic study on the surface-enhanced Raman scattering (SERS) for 3,6-bi-2-pyridyl-1,2,4,5-tetrazine (bptz) adsorbed onto citrate-modified gold nanoparticles (cit-AuNps) was carried out based on electronic and vibrational spectroscopy and density functional methods. The citrate/bptz exchange was carefully controlled by the stepwise addition of bptz to the cit-AuNps, inducing flocculation and leading to the rise of a characteristic plasmon coupling band in the visible region. Such stepwise procedure led to a uniform decrease of the citrate SERS signals and to the rise of characteristic peaks of bptz, consistent with surface binding via the N heterocyclic atoms. In contrast, single addition of a large amount of bptz promoted complete aggregation of the nanoparticles, leading to a strong enhancement of the SERS signals. In this case, from the distinct Raman profiles involved, the formation of a new SERS environment became apparent, conjugating the influence of the local hot spots and charge-transfer (CT) effects. The most strongly enhanced vibrations belong to a(1) and b(2) representations, and were interpreted in terms of the electromagnetic and the CT mechanisms: the latter involving significant contribution of vibronic coupling in the system. Copyright (C) 2010 John Wiley & Sons, Ltd.

Technique to combine images produced by different propagation modes of guided waves for damage detection and contrast improvement in plate-like structures

This paper describes an image compounding technique based on the use of different apodization functions, the evaluation of the signals phases and information from the interaction of different propagation modes of Lamb waves with defects for enhanced damage detection, resolution and contrast. A 16 elements linear array is attached to a 1 mm thickness isotropic aluminum plate with artificial defects. The array can excite the fundamental A0 and S0 modes at the frequencies of 100 kHz and 360 kHz, respectively. For each mode two synthetic aperture (SA) images with uniform and Blackman apodization and one image of Coherence Factor Map (CFM) are obtained. The specific interaction between each propagation mode and the defects and the characteristics of acoustic radiation patterns due to different apodization functions result in images with different resolution and contrast. From the phase information one of the SA images is selected at each pixel to compound the final image. The SA images are multiplied by the CFM image to improve contrast and for the dispersive A0 mode it is used a technique for dispersion compensation. There is a contrast improvement of 47.5 dB, reducing the dead zone and improving resolution and damage detection. © 2012 IEEE.

A magnetically drivable nanovehicle for curcumin with antioxidant capacity and MRI relaxation properties

Curcumin possesses wide-ranging anti-inflammatory and anti-cancer properties and its biological activity can be linked to its potent antioxidant capacity. Superparamagnetic maghemite (gamma-Fe2O3), called surface-active maghemite nanoparticles (SAMNs) were surface-modified with curcumin molecules, due to the presence of under-coordinated Fe-III atoms on the nanoparticle surface. The so-obtained curcumin-modified SAMNs (SAMN@curcumin) had a mean size of 13 +/- 4 nm. SAMN@curcumin was characterized by transmission and scanning electron microscopy, UV/Vis, FTIR, and Mossbauer spectroscopy, X-ray powder diffraction, bulk susceptibility (SQUID), and relaxometry measurements (MRI imaging). The high negative contrast proclivity of SAMN@curcumin to act as potential contrast agent in MRI screenings was also tested. Moreover, the redox properties of bound curcumin were probed by electrochemistry. SAMN@curcumin was studied in the presence of different electroactive molecules, namely hydroquinone, NADH and ferrocyanide, to assess its redox behavior. Finally, SAMN@curcumin was electrochemically probed in the presence of hydrogen peroxide, demonstrating the stability and reactivity of bound curcumin.

Silver Molybdate and Silver Tungstate Nanocomposites with Enhanced Photoluminescence

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Effects of diazepam on BOLD activation during the processing of aversive faces

This study aimed to measure, using fMRI, the effect of diazepam on the haemodynamic response to emotional faces. Twelve healthy male volunteers (mean age = 24.83 +/- 3.16 years), were evaluated in a randomized, balanced-order, double-blind, placebo-controlled crossover design. Diazepam (10 mg) or placebo was given 1 h before the neuroimaging acquisition. In a blocked design covert face emotional task, subjects were presented with neutral (A) and aversive (B) (angry or fearful) faces. Participants were also submitted to an explicit emotional face recognition task, and subjective anxiety was evaluated throughout the procedures. Diazepam attenuated the activation of right amygdala and right orbitofrontal cortex and enhanced the activation of right anterior cingulate cortex (ACC) to fearful faces. In contrast, diazepam enhanced the activation of posterior left insula and attenuated the activation of bilateral ACC to angry faces. In the behavioural task, diazepam impaired the recognition of fear in female faces. Under the action of diazepam, volunteers were less anxious at the end of the experimental session. These results suggest that benzodiazepines can differentially modulate brain activation to aversive stimuli, depending on the stimulus features and indicate a role of amygdala and insula in the anxiolytic action of benzodiazepines.

Longitudinal follow-up of cavum septum pellucidum and adhesio interthalamica alterations in first-episode psychosis: a population-based MRI study

Background. Neurodevelopmental alterations have been described inconsistently in psychosis probably because of lack of standardization among studies. The aim of this study was to conduct the first longitudinal and population-based magnetic resonance imaging (MRI) evaluation of the presence and size of the cavum septum pellucidum (CSP) and adhesio interthalamica (AI) in a large sample of patients with first-episode psychosis (FEP). Method. FEP patients (n=122) were subdivided into schizophrenia (n=62), mood disorders (n=46) and other psychosis (n=14) groups and compared to 94 healthy next-door neighbour controls. After 13 months, 80 FEP patients and 52 controls underwent a second MRI examination. Results. We found significant reductions in the AI length in schizophrenia FEP in comparison with the mood disorders and control subgroups (longer length) at the baseline assessment, and no differences in any measure of the CSP. By contrast, there was a diagnosis x time interaction for the CSP length, with a more prominent increase for this measure in the psychosis group. There was an involution of the AI length over time for all groups but no diagnosis x time interaction. Conclusions. Our findings suggest that the CSP per se may not be linked to the neurobiology of emerging psychotic disorders, although it might be related to the progression of the disease. However, the fact that the AI length was shown to be shorter at the onset of the disorder supports the neurodevelopmental model of schizophrenia and indicates that an alteration in this grey matter junction may be a risk factor for developing psychosis.