Nitric oxide is the key mediator of death induced by fisetin in human acute monocytic leukemia cells

Nitric oxide ( NO) has been shown to be effective in cancer chemoprevention and therefore drugs that help generate NO would be preferable for combination chemotherapy or solo use. This study shows a new evidence of NO as a mediator of acute leukemia cell death induced by fisetin, a promising chemotherapeutic agent. Fisetin was able to kill THP-1 cells in vivo resulting in tumor shrinkage in the mouse xenograft model. Death induction in vitro was mediated by an increase in NO resulting in double strand DNA breaks and the activation of both the extrinsic and the intrinsic apoptotic pathways. Double strand DNA breaks could be reduced if NO inhibitor was present during fisetin treatment. Fisetin also inhibited the downstream components of the mTORC1 pathway through downregulation of levels of p70 S6 kinase and inducing hypo-phosphorylation of S6 Ri P kinase, eIF4B and eEF2K. NO inhibition restored phosphorylation of downstream effectors of mTORC1 and rescued cells from death. Fisetin induced Ca2+ entry through L-type Ca2+ channels and abrogation of Ca2+ influx reduced caspase activation and cell death. NO increase and increased Ca2+ were independent phenomenon. It was inferred that apoptotic death of acute monocytic leukemia cells was induced by fisetin through increased generation of NO and elevated Ca2+ entry activating the caspase dependent apoptotic pathways. Therefore, manipulation of NO production could be viewed as a potential strategy to increase efficacy of chemotherapy in acute monocytic leukemia.

Mycobacterium tuberculosis has diminished capacity to counteract redox stress induced by elevated levels of endogenous superoxide

Mycobacterium tuberculosis (Mtb) has evolved protective and detoxification mechanisms to maintain cytoplasmic redox balance in response to exogenous oxidative stress encountered inside host phagocytes. In contrast, little is known about the dynamic response of this pathogen to endogenous oxidative stress generated within Mtb. Using a noninvasive and specific biosensor of cytoplasmic redox state of Mtb, we for first time discovered a surprisingly high sensitivity of this pathogen to perturbation in redox homeostasis induced by elevated endogenous reactive oxygen species (ROS). We synthesized a series of hydroquinone-based small molecule ROS generators and found that ATD-3169 permeated mycobacteria to reliably enhance endogenous ROS including superoxide radicals. When Mtb strains including multidrug-resistant (MDR) and extensively drug-resistant (XDR) patient isolates were exposed to this compound, a dose-dependent, long-lasting, and irreversible oxidative shift in intramycobacterial redox potential was detected. Dynamic redox potential measurements revealed that Mtb had diminished capacity to restore cytoplasmic redox balance in comparison with Mycobacterium smegmatis (Msm), a fast growing nonpathogenic mycobacterial species. Accordingly, Mtb strains were extremely susceptible to inhibition by ATD-3169 but not Msm, suggesting a functional linkage between dynamic redox changes and survival. Microarray analysis showed major realignment of pathways involved in redox homeostasis, central metabolism, DNA repair, and cell wall lipid biosynthesis in response to ATD-3169, all consistent with enhanced endogenous ROS contributing to lethality induced by this compound. This work provides empirical evidence that the cytoplasmic redox poise of Mtb is uniquely sensitive to manipulation in steady-state endogenous ROS levels, thus revealing the importance of targeting intramycobacterial redox metabolism for controlling TB infection. (C) 2015 The Authors. Published by Elsevier Inc.

Phenomenology and control of buckling dynamics in multicomponent colloidal droplets

Self-assembly of nano sized particles during natural drying causes agglomeration and shell formation at the surface of micron sized droplets. The shell undergoes sol-gel transition leading to buckling at the weakest point on the surface and produces different types of structures. Manipulation of the buckling rate with inclusion of surfactant (sodium dodecyl sulphate, SDS) and salt (anilinium hydrochloride, AHC) to the nano-sized particle dispersion (nanosilica) is reported here in an acoustically levitated single droplet. Buckling in levitated droplets is a cumulative, complicated function of acoustic streaming, chemistry, agglomeration rate, porosity, radius of curvature, and elastic energy of shell. We put forward our hypothesis on how buckling occurs and can be suppressed during natural drying of the droplets. Global precipitation of aggregates due to slow drying of surfactant-added droplets (no added salts) enhances the rigidity of the shell formed and hence reduces the buckling probability of the shell. On the contrary, adsorption of SDS aggregates on salt ions facilitates the buckling phenomenon with an addition of minute concentration of the aniline salt to the dispersion. Variation in the concentration of the added particles (SDS/AHC) also leads to starkly different morphologies and transient behaviour of buckling (buckling modes like paraboloid, ellipsoid, and buckling rates). Tuning of the buckling rate causes a transition in the final morphology from ring and bowl shapes to cocoon type of structure. (C) 2015 AIP Publishing LLC.

Direct Measurement of Three-Dimensional Forces in Atomic Force Microscopy

Direct measurement of three-dimensional (3-D) forces between an atomic force microscope (AFM) probe and the sample benefits diverse applications of AFM, including force spectroscopy, nanometrology, and manipulation. This paper presents the design and evaluation of a measurement system, wherein the deflection of the AFM probe is obtained at two points to enable direct measurement of all the three components of 3-D tip-sample forces in real time. The optimal locations for measurement of deflection on the probe are derived for a conventional AFM probe. Further, a new optimal geometry is proposed for the probe that enables measurement of 3-D forces with identical sensitivity and nearly identical resolution along all three axes. Subsequently, the designed measurement system and the optimized AFM probe are both fabricated and evaluated. The evaluation demonstrates accurate measurement of tip-sample forces with minimal cross-sensitivities. Finally, the real-time measurement system is employed as part of a feedback control system to regulate the normal component of the interaction force, and to perform force-controlled scribing of a groove on the surface of polymethyl methacrylate.

La enseñanza de la bioética personalista promueve cambios en las actitudes de los alumnos adolescentes de la escuela pública

En este artículo se relata una experiencia de la enseñanza de la Bioética personalista aplicada a estudiantes de segundo año del nivel secundario de dos escuelas públicas ubicadas en una ciudad del interior de Río Grande do Sul, Brasil. Con el objetivo de evaluar la receptividad de la Bioética personalista se aplicó un cuestionario antes y después de dar charlas a un total de 194 alumnos de ambos sexos, entre 15 y 17 años. Se realizó un análisis estadístico comparativo de los resultados. Se evidenció la coincidencia de los alumnos en el pensar ontológico personalista, salvo en el área de la dignidad humana y la sexualidad. Los mejores resultados se obtuvieron en la escuela donde los profesores acompañaron el proceso. Se constató la necesidad de incentivar la capacidad crítica de los jóvenes para que aprendan a discernir los mecanismos de manipulación e imposición de determinadas ideologías. En este sentido, la formación de los educadores resultó ser muy necesaria y urgente para que los alumnos obtengan apoyo efectivo.

La cuestión del estatus de la bioética contemporánea

Resumen: Este artículo es una breve exposición sobre la consolidación de la bioética como práctica social que, a través de la atención acentuada en el actuar de la gente común y sus principios generales de resolución, describe conductas humanas capaces de resolver situaciones específicas con dilemas éticos. Además, muestra la disposición de la bioética para encarar amenazas de la biomedicina o consecuencias negativas del mercantilismo y pragmatismo en la manipulación de la vida, la medicina o la fármaco-industria; así también, su capacidad para facilitar el diálogo sobre la admisibilidad moral de nuevas bio-tecnologías, para desarrollar la cosmovisión profesional en la toma de posicionamiento moral, o como una institución social en formación.

Problemática ético morales vinculadas a las técnicas de fertilización asistida

Resumen: En los últimos 30 años han ocurrido grandes avances en el área de la medicina reproductiva, no solo respecto a los desarrollos científicotécnicos, sino que también han surgido una gran cantidad de cuestionamientos éticos, legales y sociales vinculados a la definición del concepto de dificultad en la concepción; del estatuto de embrión y la posibilidad de su manipulación; y la conformación de familias por la intervención de terceras personas, ya sea por la dación de gametas, embriones, o la subrogación de úteros. En este trabajo se presentará una revisión de los aspectos ético morales vinculados a las técnicas de fertilización asistida y su repercusión en la sociedad.

El embrión humano. Aspectos éticos y biológicos del Informe Warnock ante las nuevas evidencias científicas

La vida humana es un proceso que se inicia después de que un oocito humano es fecundado por un espermatozoide humano y que acaba en el instante en el cual se produce su fin natural. Pretender fijar límites arbitrarios puede llevar a contradecir verdades biológicas científicamente comprobables. Exponer los datos sobre embriología humana que ofrece el Informe Warnock y presentar las nuevas evidencias científicas surgidas durante estos últimos años, tiene como objeto destacar que cuando las ciencias biomédicas son entendidas como un servicio a la humanidad, la manipulación desproporcionada del hombre por el hombre no admite justificaciones ni excusas.

Sobre la filosofía del Informe Warnock

El Informe Warnock, basado en una filosofía utilitarista, presenta principios que muestran el ideal moral social en relación con la manipulación y destrucción de embriones humanos hasta el día 14 de fecundación (pre-embrión), donde la ley es independiente de las creencias. El Personalismo, basado en la ley moral natural, presenta una concepción filosófica basada en valores fundamentales: el derecho a la vida desde la concepción y la dignidad del ser humano.

Eredu narratiboen manipulazioa Harry Potter-en saileko liburuetan

[Es] Una vez dada por finalizada la serie de siete entregas de Harry Potter, de J. K. Rowling, este artículo analiza la hábil integración de diferentes modelos narrativos previos para obtener un producto más complejo que la literatura popular, que es capaz de apelar a públicos lectores diversos, desde los lectores jóvenes hasta lectores adultos altamente competentes. Para este trabajo se ha partido de los estudios polisistémicos de Itamar Even-Zohar y Zohar Shavit.

Evaluation of bioactive sphingolipids in 4-HPR-resistant leukemia cells

Background -- N-(4-hydroxyphenyl)retinamide (4-HPR, fenretinide) is a synthetic retinoid with potent pro-apoptotic activity against several types of cancer, but little is known regarding mechanisms leading to chemoresistance. Ceramide and, more recently, other sphingolipid species (e.g., dihydroceramide and dihydrosphingosine) have been implicated in 4-HPR-mediated tumor cell death. Because sphingolipid metabolism has been reported to be altered in drug-resistant tumor cells, we studied the implication of sphingolipids in acquired resistance to 4-HPR based on an acute lymphoblastic leukemia model. Methods -- CCRF-CEM cell lines resistant to 4-HPR were obtained by gradual selection. Endogenous sphingolipid profiles and in situ enzymatic activities were determined by LC/MS, and resistance to 4-HPR or to alternative treatments was measured using the XTT viability assay and annexin V-FITC/propidium iodide labeling. Results -- No major crossresistance was observed against other antitumoral compounds (i.e. paclitaxel, cisplatin, doxorubicin hydrochloride) or agents (i.e. ultra violet C, hydrogen peroxide) also described as sphingolipid modulators. CCRF-CEM cell lines resistant to 4-HPR exhibited a distinctive endogenous sphingolipid profile that correlated with inhibition of dihydroceramide desaturase. Cells maintained acquired resistance to 4-HPR after the removal of 4-HPR though the sphingolipid profile returned to control levels. On the other hand, combined treatment with sphingosine kinase inhibitors (unnatural (dihydro)sphingosines ((dh)Sph)) and glucosylceramide synthase inhibitor (PPMP) in the presence or absence of 4-HPR increased cellular (dh)Sph (but not ceramide) levels and were highly toxic for both parental and resistant cells. Conclusions -- In the leukemia model, acquired resistance to 4-HPR is selective and persists in the absence of sphingolipid profile alteration. Therapeutically, the data demonstrate that alternative sphingolipid-modulating antitumoral strategies are suitable for both 4-HPR-resistant and sensitive leukemia cells. Thus, whereas sphingolipids may not be critical for maintaining resistance to 4-HPR, manipulation of cytotoxic sphingolipids should be considered a viable approach for overcoming resistance.

Research on Q-Switched Nd : YAG laser engraving

IN this paper, the engraving process with Q-Switched Nd:YAG laser is investigated. High power density is the pre- requisition to vapor materials, and high repetition rate makes the engraving process highly efficient. An acousto- optic Q-Switch is applied in the cavity of CW 200 W Nd:YAG laser to achieve the high peak power density and the high pulse repetition rate. Different shape craters are formed in a patterned structure on the material surface when the laser beam irradiates on it by controlling power density, pulse repetition rate, pulse quantity and pulse interval. In addition, assisting oxygen gas is used for not only improving combustion to deepen the craters but also removing the plasma that generated on the top of craters. Off-focus length classified as negative and positive has a substantial effect on crater diameters. According to the message of rotating angle positions from material to be engraved and the information of graph pixels from computer, a special graph is imparted to the material by integrating the Q- Switched Nd:YAG laser with the computer graph manipulation and the numerically controlled worktable. The crater diameter depends on laser beam divergence and laser focal length. The crater diameter changes from 50 micrometers to 300 micrometers , and the maximum of crater depth reaches one millimeter.

Traducción y manipulación: el caso de Ezra Pound

Eguíluz, Federico; Merino, Raquel; Olsen, Vickie; Pajares, Eterio; Santamaría, José Miguel (eds.)

La responsabilidad de la traducción

Eguíluz, Federico; Merino, Raquel; Olsen, Vickie; Pajares, Eterio; Santamaría, José Miguel (eds.)

Sexual Reproduction and Early Development in the Estuarine Sea Anemone, Nematostella vectensis Stephenson, 1935

This dissertation: 1) determines the factor(s) responsible for spawning induction in NematosteJla vectensis; 2) isolates, describes, and documents the source of jelly from egg masses of N. vectensis; and 3) describes N. vectensis' early development. Namatostella vectensis were maintained on a 7-day mussel feeding/water change regime over 159 days. Within 36 hours of mussel feeding/water change. 69.1% of females and 78.5% of males spawned reliably. Through manipulation of feeding, water change, oxygen and nitrogenous waste concentrations, spawning induction was found to be triggered by the oxygen concentration associated with water change, and not by feeding. Ammonia, anemones' major waste product, inhibited this induction in a concentration-dependent manner. Female N. vectensis release eggs in a persistent jellied egg mass which is unique among the Actiniaria. The major component of this egg mass jelly was a positive periodic acid-Schiffs staining, 39.5-40.5 kD glycoprotein. Antibodies developed in rabbits against this glycoprotein bound to jelly of intact egg masses and to granules (~ 2.8 IJm in diameter) present in female anemone mesenteries and their associated filaments. Antibodies did not label male tissues. Nematostella vecfensis embryos underwent first karyokinesis -60 minutes following the addition of sperm to eggs. Second nuclear division took place, followed by first cleavage, 90-120 minutes later. Each of the 4 blastomeres that resulted from first cleavage contained a single nucleus. Arrangement of these blastomeres ranged from radial to pseudospiral. Embryonic development was both asynchronous and holoblastic. Following formation of the 4-cell stage, 71% of embryos proceeded to cleave again to form an 8-cell stage. In each of the remaining 29% of embryos, a fusion of from 2-4 blastomeres resulted in 4 possible patterns which had no affect on either cleavage interval timing or subsequent development. The fusion event was not due to ooplasmic segregation. Blastomeres isolated from 4-celled embryos were regulative and developed into normal planula larvae and juvenile anemones that were 1/4 the size of those that developed from intact 4-celled embryos. Embryos exhibiting the fusion phenomenon were examined at the fine structural level. The fusion phenomenon resulted in formation of a secondary syncytium and was not a mere compaction of blastomeres.