Fragment-Based QSAR and Molecular Modeling Studies on a Series of Discodermolide Analogs as Microtubule-Stabilizing Anticancer Agents

Inhibition of microtubule function is an attractive rational approach to anticancer therapy. Although taxanes are the most prominent among the microtubule-stabilizers, their clinical toxicity, poor pharmacokinetic properties, and resistance have stimulated the search for new antitumor agents having the same mechanism of action. Discodermolide is an example of nontaxane natural product that has the same mechanism of action, demonstrating superior antitumor efficacy and therapeutic index. The extraordinary chemical and biological properties have qualified discodermolide as a lead structure for the design of novel anticancer agents with optimized therapeutic properties. In the present work, we have employed a specialized fragment-based method to develop robust quantitative structure - activity relationship models for a series of synthetic discodermolide analogs. The generated molecular recognition patterns were combined with three-dimensional molecular modeling studies as a fundamental step on the path to understanding the molecular basis of drug-receptor interactions within this important series of potent antitumoral agents.

Synthesis of the C11-C23 Fragment of the Potent Antitumor Agent Dictyostatin

We wish to report here our initial efforts toward the total synthesis of the potent antitumor agent dictyostatin, describing a short and efficient synthesis of the C11-C23 fragment. ( (C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

The Cochaperone BAG2 Sweeps Paired Helical Filament-Insoluble Tau from the Microtubule

Tau inclusions are a prominent feature of many neurodegenerative diseases including Alzheimer`s disease. Their accumulation in neurons as ubiquitinated filaments suggests a failure in the degradation limb of the Tau pathway. The components of a Tau protein triage system consisting of CHIP/Hsp70 and other chaperones have begun to emerge. However, the site of triage and the master regulatory elements are unknown. Here, we report an elegant mechanism of Tau degradation involving the cochaperone BAG2. The BAG2/Hsp70 complex is tethered to the microtubule and this complex can capture and deliver Tau to the proteasome for ubiquitin-independent degradation. This complex preferentially degrades Sarkosyl insoluble Tau and phosphorylated Tau. BAG2 levels in cells are under the physiological control of the microRNA miR-128a, which can tune paired helical filament Tau levels in neurons. Thus, we propose that ubiquitinated Tau inclusions arise due to shunting of Tau degradation toward a less efficient ubiquitin-dependent pathway.

Stabilizing Nonstationary Electrochemical Time Series

Electrochemical systems are ideal working-horses for studying oscillatory dynamics. Experimentally obtained time series, however, are usually associated with a spontaneous drift in some uncontrollable parameter that triggers transitions among different oscillatory patterns, despite the fact that all controllable parameters are kept constant. Herein we present an empirical method to stabilize experimental potential time series. The method consists of applying a negative galvanodynamic sweep to compensate the spontaneous drift and was tested for the oscillatory electro-oxidation of methanol on platinum. For a wide range of applied currents, the base system presents spontaneous transitions from quasi-harmonic to mixed mode oscillations. Temporal patterns were stabilized by galvanodynamic sweeps at different rates. The procedure resulted in a considerable increase in the number of oscillatory cycles from 5 to 20 times, depending on the specific temporal pattern. The spontaneous drift has been associated with uncompensated oscillations, in which the coverage of some adsorbed species are not reestablished after one cycle; i.e., there is a net accumulation and/or depletion of adsorbed species during oscillations. We interpreted the rate of the galvanodynamic sweep in terms of the time scales of the poisoning processes that underlies the uncompensated oscillations and thus the spontaneous slow drift.

Analysis of TMJ vibration sounds before and after use of two types of occlusal splints

Temporomandibular joint (TMJ) sounds are important and common physical signs of temporomandibular disorders (TMD). The aim of this study was to evaluate the influence of the effect of the use of occlusal bite splints (stabilizing and repositioning) on the sounds produced in the TMJ, by means of the electrovibratography (EVG). Thirty-one patients with TMD from the Dental School of Ribeirão Preto, University of São Paulo, Brazil were selected for this study. Group 1 (n=23) wore stabilizing bite splints and Group 2 (n=8) used anterior repositioning splints. Before and after treatment with occlusal splints both groups were analyzed using the SonoPAK Q/S recording system (BioResearch System, Inc.). The treatments with stabilizing bite splints were satisfactory, since they reduced the total amount of the sound energies (p<0.05), but the use of anterior repositioning splints for no more than 4 weeks produced significantly better results (p<0.01). The total amount of vibration energy involved in the vibrating movements of the TMJ showed significant improvement using anterior repositioning splints.

Structural and chemical basis for anticancer activity of a series of 'beta'-tubulin ligands: molecular modeling and 3D QSAR studies

An important approach to cancer therapy is the design of small molecule modulators that interfere with microtubule dynamics through their specific binding to the ²-subunit of tubulin. In the present work, comparative molecular field analysis (CoMFA) studies were conducted on a series of discodermolide analogs with antimitotic properties. Significant correlation coefficients were obtained (CoMFA(i), q² =0.68, r²=0.94; CoMFA(ii), q² = 0.63, r²= 0.91), indicating the good internal and external consistency of the models generated using two independent structural alignment strategies. The models were externally validated employing a test set, and the predicted values were in good agreement with the experimental results. The final QSAR models and the 3D contour maps provided important insights into the chemical and structural basis involved in the molecular recognition process of this family of discodermolide analogs, and should be useful for the design of new specific ²-tubulin modulators with potent anticancer activity.

Idade e uso de preservativo na iniciação sexual de adolescentes brasileiros

OBJETIVO: Analisar a idade e o uso do preservativo na iniciação sexual de adolescentes brasileiros em dois períodos: 1998 e 2005. MÉTODOS: Amostras representativas da população urbana brasileira foram entrevistadas em inquérito domiciliar por duas pesquisas, realizadas em 1998 e 2005. Dentre os entrevistados, 670 jovens (16 a 19 anos) sexualmente ativos foram selecionados para o estudo, 312 de 1998 e 358 de 2005. Para análise dos dados ponderados foram utilizados o teste qui-quadrado de Pearson e o teste exato de Fisher (±<5%). RESULTADOS: Em 2005, 61,6% dos jovens entrevistados tinham iniciado-se sexualmente, cuja idade média foi 14,9 anos, sem diferenças significativas para os jovens entrevistados em 1998. O uso de preservativo na primeira relação sexual aumentou significativamente em relações estáveis (48,5% em 1998 vs. 67,7% em 2005) e casuais (47,2% em 1998 vs. 62,6% em 2005) em quase todos os segmentos. Persistiram as diferenças relacionadas à iniciação sexual e ao uso de preservativos segundo gênero, cor da pele e escolaridade, tal como observado em 1998. A diminuição no uso de preservativo entre os jovens que se iniciaram sexualmente antes dos 14 anos, em todos os contextos de parceria, foi expressiva na região Sudeste e entre os mais escolarizados. CONCLUSÕES: Como em outros países, observou-se tendência à estabilização da idade da iniciação sexual entre jovens de 15 a 19 anos. O adiamento do início da vida sexual, mais freqüente entre os jovens mais escolarizados, deve ser tema discutido no planejamento da educação dos adolescentes para a sexualidade e prevenção das IST. Quanto à diminuição da vulnerabilidade ao HIV, é relevante e significativo o incremento no uso de preservativo na iniciação sexual.

Migração lateral da desembocadura do Rio Itapocú, SC, Brasil: evolução morfológica e condicionantes físicas

Desembocaduras são ambientes bastante dinâmicos e sujeitos à complexa interação entre fatores estabilizadores e desestabilizadores. Dependendo dessa interação, desembocaduras podem apresentar a tendência de migração ao longo de barreiras arenosas. Um dos mecanismos mais eficientes de transporte de sedimento paralelo à costa, e consequentemente migração de canais, são as correntes longitudinais geradas pelas ondas se aproximando obliquamente à costa. A motivação do presente trabalho é entender o comportamento morfodinâmico do sistema de desembocadura do rio Itapocú, localizado no centro-norte de Santa Catarina (SC), frente aos processos forçantes que atuam na sua migração ao longo da linha de costa. A morfologia dos pontais arenosos foi obtida a partir de levantamentos morfológicos com o uso de DGPS. Para analisar a refração de ondas foi utilizado o modelo numérico MIKE 21 SW, sendo considerados como condições de contorno os dados de ondas referentes ao ano de 2002 e os dados de ondas previstos referentes ao período de coleta. Os dados de saída do modelo foram utilizados para estimar a deriva litorânea potencial na região. Os resultados morfológicos obtidos demonstraram uma migração da desembocadura para o norte durante o período analisado, sendo mais intenso durante o inverno e o verão. Ondas incidentes do quadrante sul sofreram mais o fenômeno da refração e as ondas de leste apresentaram menor variação angular ao se aproximarem à costa. A deriva litorânea potencial anual para os dados de ondas de 2002 apresentou sentido norte-sul, com inversão de sentido durante o outono. Utilizando os dados de ondas previstas para o período dos levantamentos, a deriva litorânea potencial estimada apresentou sentido sul-norte, concordando com a migração observada. Na região próxima a desembocadura, nos pontais arenosos, a deriva potencial apresentou direção para o norte durante todas as estações. Os dados de descarga fluvial não apresentaram influência na migração do canal, porém apresentaram uma relação com a largura do mesmo sazonalmente.Os dados de morfologia juntamente com os dados de deriva litorânea referentes às ondas de 2004/2005 mostraram claramente a migração do canal para o norte sendo a deriva a principal contribuinte para a migração da desembocadura.

Hydrodynamics and suspended sediment transport in the Camboriú estuary - Brazil: pre jetty conditions

Estuarine hydrodynamics is a key factor in the definition of the filtering capacity of an estuary and results from the interaction of the processes that control the inlet morphodynamics and those that are acting in the mixing of the water in the estuary. The hydrodynamics and suspended sediment transport in the Camboriú estuary were assessed by two field campaigns conducted in 1998 that covered both neap and spring tide conditions. The period measured represents the estuarine hydrodynamics and sediment transport prior to the construction of the jetty in 2003 and provides important background information for the Camboriú estuary. Each field campaign covered two complete tidal cycles with hourly measurements of currents, salinity, suspended sediment concentration and water level. Results show that the Camboriú estuary is partially mixed with the vertical structure varying as a function of the tidal range and tidal phase. The dynamic estuarine structure can be balanced between the stabilizing effects generated by the vertical density gradient, which produces buoyancy and stratification flows, and the turbulent effects generated by the vertical velocity gradient that generates vertical mixing. The main sediment source for the water column are the bottom sediments, periodically resuspended by the tidal currents. The advective salt and suspended sediment transport was different between neap and spring tides, being more complex at spring tide. The river discharge term was important under both tidal conditions. The tidal correlation term was also important, being dominant in the suspended sediment transport during the spring tide. The gravitational circulation and Stokes drift played a secondary role in the estuarine transport processes.

Minimum alveolar concentrations and hemodynamic effects of two different preparations of sevoflurane in pigs

BACKGROUND: Original sevoflurane (Sevo A) is made with water, while a generic sevoflurane (Sevocris) is produced with propylene glycol as a stabilizing additive. We investigated whether the original and generic sevoflurane preparations differed in terms of their minimum alveolar concentration (MAC) values and hemodynamic effects. METHODS: Sixteen pigs weighing 31.6±1.8 kg were randomly assigned to the Sevo A or Sevocris groups. After anesthesia induction via mask with the appropriate sevoflurane preparation (6% in 100% oxygen), the MAC was determined for each animal. Hemodynamic and oxygenation parameters were measured at 0.5 MAC, 1 MAC and 1.5 MAC. Histopathological analyses of lung parenchyma were performed. RESULTS: The MAC in the Sevo A group was 4.4±0.5%, and the MAC in the Sevocris group was 4.1±0.7%. Hemodynamic and metabolic parameters presented significant differences in a dose-dependent pattern as expected, but they did not differ between groups. Cardiac indices and arterial pressures decreased in both groups when the sevoflurane concentration increased from 0.5 to 1 and 1.5 MAC. The oxygen delivery index (DO2I) decreased significantly at 1.5 MAC. CONCLUSION: Propylene glycol as an additive for sevoflurane seems to be as safe as a water additive, at least in terms of hemodynamic and pulmonary effects.

Survival and Neuronal Differentiation of Mesenchymal Stem Cells Transplanted into the Rodent Brain Are Dependent upon Microenvironment

Introduction: The successful integration of stem cells in adult brain has become a central issue in modern neuroscience. In this study we sought to test the hypothesis that survival and neurodifferentiation of mesenchymal stem cells (MSCs) may be dependent upon microenvironmental conditions according to the site of implant in the brain. Methods: MSCs were isolated from adult rats and labeled with enhanced-green fluorescent protein (eGFP) lentivirus. A cell suspension was implanted stereotactically into the brain of 50 young rats, into one neurogenic area (hippocampus), and into another nonneurogenic area (striatum). Animals were sacrificed 6 or 12 weeks after surgery, and brains were stained for mature neuronal markers. Cells coexpressing NeuN (neuronal specific nuclear protein) and GFP (green fluorescent protein) were counted stereologically at both targets. Results: The isolated cell population was able to generate neurons positive for microtubule-associated protein 2 (MAP2), neuronal-specific nuclear protein (NeuN), and neurofilament 200 (NF200) in vitro. Electrophysiology confirmed expression of voltage-gated ionic channels. Once implanted into the hippocampus, cells survived for up to 12 weeks, migrated away from the graft, and gave rise to mature neurons able to synthesize neurotransmitters. By contrast, massive cell degeneration was seen in the striatum, with no significant migration. Induction of neuronal differentiation with increased cyclic adenosine monophosphate in the culture medium before implantation favored differentiation in vivo. Conclusions: Our data demonstrated that survival and differentiation of MSCs is strongly dependent upon a permissive microenvironment. Identification of the pro-neurogenic factors present in the hippocampus could subsequently allow for the integration of stem cells into nonpermissive areas of the central nervous system.

Comparative Study of the Changes in Partial Pressure of Plasma Carbon Dioxide During Carbon Dioxide Insufflation into the Intraperitoneal and Preperitoneal Spaces

Background: We aimed to compare plasma concentrations of carbon dioxide (CO(2)) in dogs that underwent intra- and preperitoneal CO(2) insufflation. Materials and Methods: Thirty dogs were studied. Ten formed a control group, 10 underwent intraperitoneal CO(2) insufflation, and 10 underwent preperitoneal CO(2) insufflation. General anesthesia with controlled ventilation was standardized for all dogs. After stabilizing the anesthesia, blood samples were collected at predetermined times and were sent for immediate gasometric analysis. Analysis of variance was used for comparing variables. Results: The plasma CO(2) concentration in the intraperitoneal insufflation group increased significantly more than in the preperitoneal insufflation group and was significantly greater than in the control group (P < 0.05). The pH values in the intraperitoneal group were lower than in the preperitoneal group (P < 0.05). Conclusion: The data from this study suggest that a greater plasma concentration of CO(2) is achieved by insufflation at constant pressure into the intraperitoneal space than into the preperitoneal space.

Nonaxisymmetric magnetorotational instability in ideal and viscous plasmas

The excitation of magnetorotational instability (MRI) in rotating laboratory plasmas is investigated. In contrast to astrophysical plasmas, in which gravitation plays an important role, in laboratory plasmas it can be neglected and the plasma rotation is equilibrated by the pressure gradient. The analysis is restricted to the simple model of a magnetic confinement configuration with cylindrical symmetry, in which nonaxisymmetric perturbations are investigated using the local approximation. Starting from the simplest case of an ideal plasma, the corresponding dispersion relations are derived for more complicated models including the physical effects of parallel and perpendicular viscosities. The Friemann-Rotenberg approach used for ideal plasmas is generalized for the viscous model and an analytical expression for the instability boundary is obtained. It is shown that, in addition to the standard effect of radial derivative of the rotation frequency (the Velikhov effect), which can be destabilizing or stabilizing depending on the sign of this derivative in the ideal plasma, there is a destabilizing effect proportional to the fourth power of the rotation frequency, or, what is the same, to the square of the plasma pressure gradient, and to the square of the azimuthal mode number of the perturbations. It is shown that the instability boundary also depends on the product of the plasma pressure and density gradients, which has a destabilizing effect when it is negative. In the case of parallel viscosity, the MRI looks like an ideal instability independent of viscosity, while, in the case of strong perpendicular viscosity, it is a dissipative instability with the growth rate inversely proportional to the characteristic viscous decay rate. We point out, however, that the modes of the continuous range of the magnetohydrodynamics spectrum are not taken into account in this paper, and they can be more dangerous than those that are considered. (c) 2008 American Institute of Physics.

Matter-wave two-dimensional solitons in crossed linear and nonlinear optical lattices

The existence of multidimensional matter-wave solitons in a crossed optical lattice (OL) with a linear optical lattice (LOL) in the x direction and a nonlinear optical lattice (NOL) in the y direction, where the NOL can be generated by a periodic spatial modulation of the scattering length using an optically induced Feshbach resonance is demonstrated. In particular, we show that such crossed LOLs and NOLs allow for stabilizing two-dimensional solitons against decay or collapse for both attractive and repulsive interactions. The solutions for the soliton stability are investigated analytically, by using a multi-Gaussian variational approach, with the Vakhitov-Kolokolov necessary criterion for stability; and numerically, by using the relaxation method and direct numerical time integrations of the Gross-Pitaevskii equation. Very good agreement of the results corresponding to both treatments is observed.

Sodium piperidine-1-carbodithioate dihydrate

The asymmetric unit of the title compound, Na(+)center dot C(6)H(10)NS(2) center dot 2H(2)O, is composed of a sodium cation, a piperidinedithiocarbamate anion which exhibits positional disorder, and two lattice water molecules. The atoms of the piperidine ring are divided over two sites with occupancy factors of 0.554 (6) and 0.446 (6). In the crystal, the sodium cation (coordination number of 6) and the piperidinedithiocarbamate anion are linked, forming an infinite two-dimensional network extending parallel to (001). O-H center dot center dot center dot S hydrogen bonds, involving the lattice water molecules, also aid in stabilizing the crystal sructure.