Design, synthesis, and biological activity of rhodium metalloinsertors

Deficiencies in the mismatch repair (MMR) pathway are associated with several types of cancers, as well as resistance to commonly used chemotherapeutics. Rhodium metalloinsertors have been found to bind DNA mismatches with high affinity and specificity in vitro, and also exhibit cell-selective cytotoxicity, targeting MMR-deficient cells over MMR-proficient cells.

Here we examine the biological fate of rhodium metalloinsertors bearing dipyridylamine ancillary ligands. These complexes are shown to exhibit accelerated cellular uptake which permits the observation of various cellular responses, including disruption of the cell cycle and induction of necrosis, which occur preferentially in the MMR-deficient cell line. These cellular responses provide insight into the mechanisms underlying the selective activity of this novel class of targeted anti-cancer agents.

In addition, ten distinct metalloinsertors with varying lipophilicities are synthesized and their mismatch binding affinities and biological activities studied. While they are found to have similar binding affinities, their cell-selective antiproliferative and cytotoxic activities vary significantly. Inductively coupled plasma mass spectrometry (ICP-MS) experiments show that all of these metalloinsertors localize in the nucleus at sufficient concentrations for binding to DNA mismatches. Furthermore, metalloinsertors with high rhodium localization in the mitochondria show toxicity that is not selective for MMR-deficient cells. This work supports the notion that specific targeting of the metalloinsertors to nuclear DNA gives rise to their cytotoxic and antiproliferative activities that are selective for cells deficient in MMR.

To explore further the basis of the unique selectivity of the metlloinsertors in targeting MMR-deficient cells, experiments were conducted using engineered NCI-H23 lung adenocarcinoma cells that contain a doxycycline-inducible shRNA which suppresses the expression of the MMR gene MLH1. Here we use this new cell line to further validate rhodium metalloinsertors as compounds capable of differentially inhibiting the proliferation of MMR-deficient cancer cells over isogenic MMR-proficient cells. General DNA damaging agents, such as cisplatin and etoposide, in contrast, are less effective in the induced cell line defective in MMR.

Finally, we describe a new subclass of metalloinsertors with enhanced potency and selectivity, in which the complexes show Rh-O coordination. In particular, it has been found that both Δ and Λ enantiomers of [Rh(chrysi)(phen)(DPE)]²⁺ bind to DNA with similar affinities, suggesting a possible different binding conformation than previous metalloinsertors. Remarkably, all members of this new family of compounds have significantly increased potency in a range of cellular assays; indeed, all are more potent than the FDA-approved anticancer drugs cisplatin and MNNG. Moreover, these activities are coupled with high levels of selectivity for MMR-deficient cells.

Avaliação da qualidade da assistência perinatal : um exercício

A relação da qualidade da prática médica assistencial com os indicadores de saúde tem sido objeto de controvérsia. A possibilidade de avaliar o estado de saúde do recém-nascido em função do cuidado recebido, facilita o estudo desta relação, principalmente na área perinatal onde a expectativa é o nascimento de um bebê saudável ao final de uma gestação sem fatores de riscos acompanhados segundo as normas obstétricas vigentes. Neste estudo, examina-se a adequação do acompanhamento do trabalho de parto em uma maternidade pública do Estado do Rio de Janeiro, sob a ótica de avaliação de qualidade pela abordagem de processos e resultados através de critérios explícitos supondo que os fatores selecionados como componentes do processo de assistência ao trabalho de parto determinariam o resultado. Observa-se tais relações através da metodologia epidemiológica optando por um estudo caso-referente ou um estudo caso-controle, com definição primária da base. Selecionou-se como determinantes da qualidade da prática obstétrica intraparto a duração do trabalho de parto, percepção de alterações durante o trabalho de parto, prontidão para intervenção, número de exames realizados e intervalo entre o último exame e hora do parto. O resultado neonatal adverso caracterizou-se por óbito intra-útero, óbito neonatal e presença de um conjunto de sinais clínicos anormais no período neonatal imediato, com alto valor preditivo para o futuro dano neurológico. O risco de um resultado adverso foi estimado pela razão dos produtos cruzados aodds ratio (OR) numa população de 34 casos e 124 controles. A duração do trabalho de parto maior que doze horas esteve associada a um OR igual a 3,48 (1,28-9,43), idade da gestante, dilatação cervical do colo uterino à admissão e peso ao nascer modificaram o efeito desta associação, que também foi confundida pela paridade e pelo uso da ocitocina contrariando hipótese inicial. A percepção de alterações resultou num OR= 14,73 (4.24-54,27) e, à medida que o tempo de intervenção se prolongava os riscos aumentavam obedecendo a uma tendência linear. Discutem-se as dificuldades de aplicação metodologia epidemiológica ao campo da avaliação da qualidade, essencialmente no que se refere as exigências quantitativas, para garantir precisão e confiabilidade. A observação da interação e o controle do confundimento apontam o cuidado necessário nos trabalhos desta natureza para alcançar consistência e validade.

Fluctuations in a tokamak plasma

An experimental investigation of low frequency floating potential fluctuations (f ≤ 200 kHz) in a research tokamak plasma using two spatially separated electrostatic probes has been performed. The spectra, correlation length, and the phase velocity of the fluctuations in both the radial and azimuthal direction have been determined. The propagation velocity in the toroidal direction was also measured and was found to be in the direction of electron current flow. The waves traveled azimuthally in the ion diamagnetic drift direction, even after the usual E x B rotation was taken into account. The electron density fluctuations associated with these oscillations were large, δn/n ≃ 0.35 - 0.50.

The spectra were found to have regularly spaced peaks which seemed to be related to specific azimuthal modes (m =1,2,3,...,etc. ) A parametric study was made to determine what effect plasma parameters had on these peaks. During periods of high electron density in the first 2 msec of the plasma lifetime, strong sawtooth type oscillations were observed. These oscillations typically had frequencies of approximately 10 kHz and were also present when large amounts of neutral gas were added during the discharge by a process called "gas puffing."

The results are compared with experimental observations made on other plasma devices with electric and magnetic probes and with microwave and CO₂ laser scattering techniques. (The scattering measurements are complimentary to the probe measurements since, in the former case, the wavelength is fixed by the scattering angle, but the oscillations could not be spatially localized.) The oscillations in the Caltech torus were probably related to a drift-tearing type instability which is thought to play a major role in the anomalous particle and energy flux observed in tokamaks. Comparisons are made between current theory and the experimental results. However, the theory for the observed oscillations is still in a rudimentary stage of development, and it is hoped that the present investigation will stimulate future analytical work.

Measurement of the galactic cosmic ray antiproton flux from 0.25 gev to 3.11 gev with the isotope matter antimatter experiment (imax)

The intensities and relative abundances of galactic cosmic ray protons and antiprotons have been measured with the Isotope Matter Antimatter Experiment (IMAX), a balloon-borne magnet spectrometer. The IMAX payload had a successful flight from Lynn Lake, Manitoba, Canada on July 16, 1992. Particles detected by IMAX were identified by mass and charge via the Cherenkov-Rigidity and TOP-Rigidity techniques, with measured rms mass resolution ≤0.2 amu for Z=1 particles.

Cosmic ray antiprotons are of interest because they can be produced by the interactions of high energy protons and heavier nuclei with the interstellar medium as well as by more exotic sources. Previous cosmic ray antiproton experiments have reported an excess of antiprotons over that expected solely from cosmic ray interactions.

Analysis of the flight data has yielded 124405 protons and 3 antiprotons in the energy range 0.19-0.97 GeV at the instrument, 140617 protons and 8 antiprotons in the energy range 0.97-2.58 GeV, and 22524 protons and 5 antiprotons in the energy range 2.58-3.08 GeV. These measurements are a statistical improvement over previous antiproton measurements, and they demonstrate improved separation of antiprotons from the more abundant fluxes of protons, electrons, and other cosmic ray species.

When these results are corrected for instrumental and atmospheric background and losses, the ratios at the top of the atmosphere are p/p=3.21(+3.49, -1.97)x10^(-5) in the energy range 0.25-1.00 GeV, p/p=5.38(+3.48, -2.45) x10^(-5) in the energy range 1.00-2.61 GeV, and p/p=2.05(+1.79, -1.15) x10^(-4) in the energy range 2.61-3.11 GeV. The corresponding antiproton intensities, also corrected to the top of the atmosphere, are 2.3(+2.5, -1.4) x10^(-2) (m^2 s sr GeV)^(-1), 2.1(+1.4, -1.0) x10^(-2) (m^2 s sr GeV)^(-1), and 4.3(+3.7, -2.4) x10^(-2) (m^2 s sr GeV)^(-1) for the same energy ranges.

The IMAX antiproton fluxes and antiproton/proton ratios are compared with recent Standard Leaky Box Model (SLBM) calculations of the cosmic ray antiproton abundance. According to this model, cosmic ray antiprotons are secondary cosmic rays arising solely from the interaction of high energy cosmic rays with the interstellar medium. The effects of solar modulation of protons and antiprotons are also calculated, showing that the antiproton/proton ratio can vary by as much as an order of magnitude over the solar cycle. When solar modulation is taken into account, the IMAX antiproton measurements are found to be consistent with the most recent calculations of the SLBM. No evidence is found in the IMAX data for excess antiprotons arising from the decay of galactic dark matter, which had been suggested as an interpretation of earlier measurements. Furthermore, the consistency of the current results with the SLBM calculations suggests that the mean antiproton lifetime is at least as large as the cosmic ray storage time in the galaxy (~10^7 yr, based on measurements of cosmic ray ^(10)Be). Recent measurements by two other experiments are consistent with this interpretation of the IMAX antiproton results.

Fabrication, Characterization, And Deformation of 3D Structural Meta-Materials

Current technological advances in fabrication methods have provided pathways to creating architected structural meta-materials similar to those found in natural organisms that are structurally robust and lightweight, such as diatoms. Structural meta-materials are materials with mechanical properties that are determined by material properties at various length scales, which range from the material microstructure (nm) to the macro-scale architecture (μm – mm). It is now possible to exploit material size effect, which emerge at the nanometer length scale, as well as structural effects to tune the material properties and failure mechanisms of small-scale cellular solids, such as nanolattices. This work demonstrates the fabrication and mechanical properties of 3-dimensional hollow nanolattices in both tension and compression. Hollow gold nanolattices loaded in uniaxial compression demonstrate that strength and stiffness vary as a function of geometry and tube wall thickness. Structural effects were explored by increasing the unit cell angle from 30° to 60° while keeping all other parameters constant; material size effects were probed by varying the tube wall thickness, t, from 200nm to 635nm, at a constant relative density and grain size. In-situ uniaxial compression experiments reveal an order-of-magnitude increase in yield stress and modulus in nanolattices with greater lattice angles, and a 150% increase in the yield strength without a concomitant change in modulus in thicker-walled nanolattices for fixed lattice angles. These results imply that independent control of structural and material size effects enables tunability of mechanical properties of 3-dimensional architected meta-materials and highlight the importance of material, geometric, and microstructural effects in small-scale mechanics. This work also explores the flaw tolerance of 3D hollow-tube alumina kagome nanolattices with and without pre-fabricated notches, both in experiment and simulation. Experiments demonstrate that the hollow kagome nanolattices in uniaxial tension always fail at the same load when the ratio of notch length (a) to sample width (w) is no greater than 1/3, with no correlation between failure occurring at or away from the notch. For notches with (a/w) > 1/3, the samples fail at lower peak loads and this is attributed to the increased compliance as fewer unit cells span the un-notched region. Finite element simulations of the kagome tension samples show that the failure is governed by tensile loading for (a/w) < 1/3 but as (a/w) increases, bending begins to play a significant role in the failure. This work explores the flaw sensitivity of hollow alumina kagome nanolattices in tension, using experiments and simulations, and demonstrates that the discrete-continuum duality of architected structural meta-materials gives rise to their flaw insensitivity even when made entirely of intrinsically brittle materials.

The reduced-alpha-width of the lowest 1¯ state of ^(16)O

Cross sections for the reaction ¹²C(α,γ)¹⁶O have been measured for a range of center-of-mass alpha particle energies extending from 1.72 MeV to 2.94 MeV. Two 8"x5" NaI (Tℓ) crystals were used to detect gamma rays; time-of-flight technique was employed to suppress cosmic ray background and background due to neutrons arising mainly from the ¹³C(α,n)¹⁶O reaction. Angular distributions were measured at center-of-mass alpha energies of 2.18, 2.42, 2.56 and 2.83 MeV. Upper limits were placed on the amount of radiation cascading through the 6.92 or 7.12-MeV states in ¹⁶O. By means of theoretical fits to the measured electric dipole component of the total cross section, in which interference between the 1¯ states in ¹⁶O at 7.12 MeV and at 9.60 MeV is taken into account, it is possible to extract the dimensionless, reduced-alpha-width of the 7.12-MeV state in ¹⁶O. A three-level R-matrix parameterization of the data yields the width Θ_α,F² = 0.14^+0.10_-0.08. A "hybrid" R-matrix-optical-model parameterization yields Θ_α,F² = 0.11^+0.11_-0.07. This quantity is of crucial importance in determining the abundances of ¹²C and ¹⁶O at the end of helium burning in stars.

Pele como tinta: o corpo entre gesto e vinco

Pele como tinta: o corpo entre gesto e vinco discute o gesto como meio sem finalidade, dentro da ideia de processo artístico, diante da relação envolvendo a prática artística do vídeo e da intervenção com experiências desenvolvidas durante o mestrado na linha de Processos Artísticos Contemporâneos, em trabalhos como Auto-retrato, Tarja, Peles institucionais e Onde fica o Galpão? Dentre os gestos trabalhados está o gesto desterritorializante, no qual a instituição de ensino é convocada como espaço onde suas fronteiras são tratadas como forma de se pensar o fazer artístico, assim como o conceito de instituição. Além desse, outro trabalho proposto é o que relaciona o vídeo e o frame em texturas temporais dinâmicas. O gesto de tinta registrado em vídeo é condicionado a uma volta da pintura fixa da tela. Em Peles a estrutura do vinco é requisitada para compor os afetos e as construções que norteiam a escrita do e no corpo

Deslocamentos da dança contemporânea: por uma condição conceitual

Esta dissertação focaliza o diálogo entre dança contemporânea e artes visuais a partir dos anos 1990 e as novas configurações e discussões presentes nos trabalhos de criadores que transitam entre esses dois campos. Procura pensar a dança como arte contemporânea, indagando a si mesma sobre sua condição: o que a constrói e define nesses termos. As relações entre dança contemporânea e o conceitualismo são traçadas observando obras que, abandonando o formalismo e o puro exercício da estética, propõem-se a acrescentar algo em termos de concepção da arte e questionar sua própria natureza. Repensar as convenções da própria dança, o modelo de espetáculo, os espaços e formas de visibilidade são as principais questões investigadas. Especificamente, são abordados os trabalhos de Tino Sehgal (Londres, 1976- ), Wagner Schwartz (Volta Redonda, 1972- ) e a própria produção artística da autora para pensar essas relações, reivindicando uma condição conceitual da dança contemporânea nas obras próprias e nas dos artistas estudados. As desestabiliza-ções e fissuras que essa condição provoca são as ferramentas para potencializar e ampliar a visão da dança como arte contemporânea

Ouvir na pele o terceiro som: ficções experimentadas e transformações sensoriais

A pesquisa surgiu a partir de investigações e experiências próprias com a escuta, a produção de sonoridades, a criação de ambientes e a realização de derivas intersensoriais. A articulação se dá segundo uma perspectiva transdisciplinar e em relação a alguns trabalhos artísticos e textuais especialmente significativos. A construção do sensorial e das subjetividades e suas possibilidades de transformação e emancipação, através de uma arte vinculada à vida, são questões centrais. Os conceitos de fabulação, linhas, cartografias e desterritorializações desenvolvidos por Deleuze, a ecosofia de Félix Guattari e a noção de corpos vibráteis em Suely Rolnik são fundamentais, assim como as observações de Lygia Clark e Hélio Oiticica a respeito de suas próprias experiências. Estudos históricos e culturais dos sentidos, como os de Constance Classen e David Howes, além de observações de teóricos distintos como Karl Marx, Walter Benjamin, Michel Serres e Jacques Ranciére auxiliam a traçar um panorama inicial do constructo sensorial no Ocidente moderno e contemporâneo. Questões relativas a som, silêncio e ruído levaram à utilização de conceitos como escuta e ressonância em um sentido ampliado, que não se restringe a fenômenos sonoros ou físicos. A articulação entre escuta, intersensorialidade, imaginação e memória contribuiu para o desenvolvimento inicial do conceito de terceiro som aqui presente. A percepção do texto como ativador de sensações e devaneios, as relações entre conceito e concreto e o relato não-realista de acontecimentos levaram às ficções experimentadas. O ato da deriva relaciona-se ao desregramento de todos sentidos e implica a vivência de margens, desvios e extremos, fronteiras em dissolução, diásporas nos interstícios. Poéticas e políticas da alteridade, da diferença e do estranhamento fazem-se presentes em experiências de um ambiente-vivo, paisagem-corpo-outro. Tais questões atravessam meus trabalhos, que são realizados de diferentes maneiras, em cartografias e rituais que podem incluir sons, textos, desenhos, objetos, fotografia, vídeos, vestimentas, ações, situações, etc. A abordagem das questões presentes se dá através de algumas passagens por escritores como Rimbaud, Borges e Italo Calvino; teóricos de diferentes áreas, como Guy Brett, Douglas Kahn, De Certeau, Michel Onfray, James J.Gibson e Donna Haraway; e trabalhos e textos de diversos artistas fundamentais, como Marcel Duchamp, John Cage, Allan Kaprow, George Maciunas e o Fluxus, Yoko Ono, Laurie Anderson, Gordon-Matta-Clark, Robert Smithson, Bill Viola, Cildo Meireles e Lygia Pape, entre outros

Alcohol-Related Brain Damage in Humans

Chronic excessive alcohol intoxications evoke cumulative damage to tissues and organs. We examined prefrontal cortex (Brodmann's area (BA) 9) from 20 human alcoholics and 20 age, gender, and postmortem delay matched control subjects. H & E staining and light microscopy of prefrontal cortex tissue revealed a reduction in the levels of cytoskeleton surrounding the nuclei of cortical and subcortical neurons, and a disruption of subcortical neuron patterning in alcoholic subjects. BA 9 tissue homogenisation and one dimensional polyacrylamide gel electrophoresis (PAGE) proteomics of cytosolic proteins identified dramatic reductions in the protein levels of spectrin beta II, and alpha- and beta-tubulins in alcoholics, and these were validated and quantitated by Western blotting. We detected a significant increase in a-tubulin acetylation in alcoholics, a non-significant increase in isoaspartate protein damage, but a significant increase in protein isoaspartyl methyltransferase protein levels, the enzyme that triggers isoaspartate damage repair in vivo. There was also a significant reduction in proteasome activity in alcoholics. One dimensional PAGE of membrane-enriched fractions detected a reduction in beta-spectrin protein levels, and a significant increase in transmembranous alpha 3 (catalytic) subunit of the Na+, K+-ATPase in alcoholic subjects. However, control subjects retained stable oligomeric forms of a-subunit that were diminished in alcoholics. In alcoholics, significant loss of cytosolic alpha-and beta-tubulins were also seen in caudate nucleus, hippocampus and cerebellum, but to different levels, indicative of brain regional susceptibility to alcohol-related damage. Collectively, these protein changes provide a molecular basis for some of the neuronal and behavioural abnormalities attributed to alcoholics

Genetic variation between outer-coastal and fjord populations of Pacific herring (Clupea pallasii) in the eastern Gulf of Alaska

Pacific herring (Clupea pallasii) from the Gulf of Alaska were screened for temporal and spatial genetic variation with 15 microsatellite loci. Thirteen collections were examined in this study: 11 from Southeast Alaska and 2 from Prince William Sound, Alaska. Although FST values were low, a neighbor-joining tree based on genetic distance, homogeneity, and FST values revealed that collectively, the Berners Bay and Lynn Canal (interior) collections were genetically distinct from Sitka Sound and Prince of Wales Island (outer-coastal) collections. Temporal genetic variation within regions (among three years of Berners Bay spawners and between the two Sitka Sound spawners) was zero, whereas 0.05% was attributable to genetic variation between Berners Bay and Sitka Sound. This divergence may be attributable to environmental differences between interior archipelago waters and outer-coast habitats, such as differences in temperature and salinity. Early spring collections of nonspawning Lynn Canal herring were nearly genetically identical to collections of spawning herring in Berners Bay two months later—an indication that Berners Bay spawners over-winter in Lynn Canal. Southeast Alaskan herring (collectively) were significantly different from those in Prince William Sound. This study illustrates that adequate sample size is needed to detect variation in pelagic fish species with a large effective population size, and microsatellite markers may be useful in detecting low-level genetic divergence in Pacific herring in the Gulf of Alaska.

BotCam: a baited camera system for nonextractive monitoring of bottomfish species

A stereo-video baited camera system (BotCam) has been developed as a fishery-independent tool to monitor and study deepwater fish species and their habitat. During testing, BotCam was deployed primarily in water depths between 100 and 300 m for an assessment of its use in monitoring and studying Hawaiian bottomfish species. Details of the video analyses and data from the pilot study with BotCam in Hawai`i are presented. Multibeam bathymetry and backscatter data were used to delineate bottomfish habitat strata, and a stratified random sampling design was used for BotCam deployment locations. Video data were analyzed to assess relative fish abundance and to measure f ish size composition. Results corroborate published depth ranges and zones of the target species, as well as their habitat preferences. The results indicate that BotCam is a promising tool for monitoring and studying demersal fish populations associated with deepwater habitats to a depth of 300 m, at mesohabitat scales. BotCam is a flexible, nonextractive, and economical means to better understand deepwater ecosystems and improve science-based ecosystem approaches to management.

Teen-age identity construction in Stephen King: A gendered view

280 p.

Corpo em festa: Juventude, sociabilidade e produção de sentidos nos bailes cariocas

A presente pesquisa consiste em um estudo da representação do corpo jovem a partir de dois bailes: o baile coletivo de debutantes promovido pela Unidade de Polícia Pacificadora (UPP) para as moradoras de algumas comunidades cariocas, e o baile do passinho, vertente do funk carioca, que atrai os meninos das comunidades e ressignifica seu papel social dentro das favelas onde vivem. O recorte para o estudo parte, inicialmente, de questões de gênero atribuídas a ambos os bailes. O fim dos bailes funk no processo de pacificação das favelas tem desdobramentos significativos na rotina dos jovens. De um lado, a reivindicação das jovens deu origem ao baile coletivo de debutantes como estratégia de aproximação da polícia com o público feminino; por outro, levou o passinho para as lan houses e fez dos cômodos das casas cenário para a gravação de vídeos e a sua divulgação e compartilhamento em rede. O objetivo do trabalho é observar nos jovens que participam dos bailes supracitados a maneira pela qual seus corpos são "adequados" para tais festas e quais os aspectos que influenciam e afetam a construção da identidade juvenil. A estratégia metodológica desenvolvida contemplou a pesquisa documental disponível em mídia impressa e digital sobre os bailes e suas danças, a realização de entrevistas abertas e semi-estruturadas, a observação dos jovens participantes nos bailes, e a pesquisa bibliográfica para embasamento teórico - sendo considerado o referencial sócio-antropológico de David Le Breton, Michel Maffesoli, Roberto DaMatta e Hermano Vianna, a sociologia de Émile Durkheim e Marcel Mauss, os estudos culturais de Raymond Williams, Peter Burke, Néstor Garcia Canclini e Stuart Hall, além das pesquisas em comunicação de Denise Siqueira e Christine Greiner. Para a presente pesquisa as projeções no corpo impelem um olhar crítico e o analisar das referências que circundam os jovens moradores das comunidades cariocas. Desta forma, questionar as representações do corpo em festa move este estudo.