Targeting aquaporin function: potent inhibition of aquaglyceroporin-3 by a gold-based compound.

Aquaporins (AQPs) are membrane channels that conduct water and small solutes such as glycerol and are involved in many physiological functions. Aquaporin-based modulator drugs are predicted to be of broad potential utility in the treatment of several diseases. Until today few AQP inhibitors have been described as suitable candidates for clinical development. Here we report on the potent inhibition of AQP3 channels by gold(III) complexes screened on human red blood cells (hRBC) and AQP3-transfected PC12 cells by a stopped-flow method. Among the various metal compounds tested, Auphen is the most active on AQP3 (IC(50) = 0.8±0.08 µM in hRBC). Interestingly, the compound poorly affects the water permeability of AQP1. The mechanism of gold inhibition is related to the ability of Au(III) to interact with sulphydryls groups of proteins such as the thiolates of cysteine residues. Additional DFT and modeling studies on possible gold compound/AQP adducts provide a tentative description of the system at a molecular level. The mapping of the periplasmic surface of an homology model of human AQP3 evidenced the thiol group of Cys40 as a likely candidate for binding to gold(III) complexes. Moreover, the investigation of non-covalent binding of Au complexes by docking approaches revealed their preferential binding to AQP3 with respect to AQP1. The high selectivity and low concentration dependent inhibitory effect of Auphen (in the nanomolar range) together with its high water solubility makes the compound a suitable drug lead for future in vivo studies. These results may present novel metal-based scaffolds for AQP drug development.

Exploration of alpine orographic precipitation patterns with radar image processing and clustering techniques

A methodology of exploratory data analysis investigating the phenomenon of orographic precipitation enhancement is proposed. The precipitation observations obtained from three Swiss Doppler weather radars are analysed for the major precipitation event of August 2005 in the Alps. Image processing techniques are used to detect significant precipitation cells/pixels from radar images while filtering out spurious effects due to ground clutter. The contribution of topography to precipitation patterns is described by an extensive set of topographical descriptors computed from the digital elevation model at multiple spatial scales. Additionally, the motion vector field is derived from subsequent radar images and integrated into a set of topographic features to highlight the slopes exposed to main flows. Following the exploratory data analysis with a recent algorithm of spectral clustering, it is shown that orographic precipitation cells are generated under specific flow and topographic conditions. Repeatability of precipitation patterns in particular spatial locations is found to be linked to specific local terrain shapes, e.g. at the top of hills and on the upwind side of the mountains. This methodology and our empirical findings for the Alpine region provide a basis for building computational data-driven models of orographic enhancement and triggering of precipitation. Copyright (C) 2011 Royal Meteorological Society .

Targeting renal cell carcinoma with NVP-BEZ235, a dual PI3K/mTOR inhibitor, in combination with sorafenib.

Background: Targeted therapies for metastatic renal cell carcinoma (RCC), including mammalian target of rapamycin (mTOR) inhibitors and small-molecule multikinase inhibitors, have produced clinical effects. However, most patients acquire resistance over time. Thus, new therapeutic strategies need to be developed. Here, we evaluated the effect of the dual PI3K/mTOR inhibitor NVP-BEZ235, in combination with the multikinase inhibitor sorafenib on renal cancer cell proliferation and survival in vitro as well as on tumor growth in vivo.Methods: The renal carcinoma cell lines 786-0 and Caki-1 were treated with NVP-BEZ235 or sorafenib, either alone or in combination. Tumor cell proliferation and apoptosis were investigated in vitro. The anticancer efficacy of NVP-BEZ235 alone, or in combination with sorafenib, was also evaluated on RCC xenografts in nude mice.Results: Treatment of 786-0 and Caki-1 cells with NVP-BEZ235 or sorafenib resulted in reduced tumor cell proliferation and increased tumor cell apoptosis in vitro. The combination of NVP-BEZ235 and sorafenib was more effective than each compound alone. Similarly, in vivo, NVP-BEZ235 or sorafenib reduced the growth of xenografts generated from 786-0 or Caki-1 cells. The antitumor efficacy of NVP-BEZ235 in combination with sorafenib was superior to NVP-BEZ235 or sorafenib alone.Conclusions: Our findings indicate that the simultaneous use of NVP-BEZ235 and sorafenib has greater antitumor benefit compared to either drug alone and thus provides a treatment strategy in RCC.

Els marges del pensament polític contemporani

La crisi i esfondrament del pensament metafísic heretat de la modernitat deixa la filosofia contemporània davant d'un nou paradigma on el coneixement s’ha de construir prescindint de tota identitat i fonamentació. El meu projecte s’estableix com un recorregut descendent que parteix d’un àmbit concret, com és el del problema de la manca de fonamentació en la filosofia política contemporània, per arribar a la veritable arrel del problema general que no és altre que la mateixa naturalesa del llenguatge filosòfic. El punt de partida és la pregunta sobre la possibilitat d’una filosofia política en termes postmetafísics. La filosofia política, atrapada entre les forces de la tirania unitària del concepte metafísic i la dissolució pràctica en pro de la realitat instrumental, traça ponts cap a l’estètica i la deconstrucció, que tenen com a corol•lari final qüestionar-nos els propis límits del pensament polític. El concepte d’impolític és una sortida deconstructiva a aquest atzucac. Des d’Esposito, Rancière, Nancy, però sobretot Massimo Cacciari, he aprofundit en el paradigma postmetafísic que origina aquesta negació política de la pròpia política, política com els seus límits, relació com a distància i identitat com a silenci. És evident que la clau de volta és l’herència i recepció contemporània de Nietzsche i la seva crítica a la transcendentalitat moderna en el sí de l’elaboració d’un coneixement en un naufragi constant pel fracàs de la síntesi que anhela. És aquesta herència la que ha possibilitat aquest pensament negatiu contemporani, el del joc wittgensteinià, la deconstrucció del valor que queda convertit en el seu propi marge (Derrida). Definim així no només una comunitat política basada en la incommensurabilitat dels seus membres alhora buits de contingut (Musil), sinó un model de llenguatge que és el seu propi silenci, un llenguatge en contínua lluita contra sí mateix. El meu projecte és una relectura d’aquesta veritat no identitària on el concepte de diàleg pren una importància cabdal. La filosofia de la música aquí es presenta com un terreny fèrtil d’eines conceptuals a l’hora de desenvolupar-ho. La música és el llenguatge negatiu que només troba possibilitat en la seva pròpia impossibilitat de contingut sintètic. Més enllà de les referències obligatòries a chönberg i Adorno entre altres, el camí iniciat per Bergson amb la introducció de la temporalitat a la discussió obra la porta al paper de l’esdveniment en aquest discurs sobre la impossibilitat. Tornant a la filosofia, on el propi llenguatge filosòfic es defineix ja com a impossible, l’esdeveniment reobre l’antiga tensió entre l’escriptura i la paraula viva, veritable fonament del problema, i vèrtex de la possibilitat d’aquesta filosofia impossible.

Holografia de microones en banda X

Aquest projecte es basa, en el disseny i construcció d’una aplicació directa de l’holografia de microones. Està compost per el disseny d’un sistema el qual és capaç de mesurar la potència que arriba a un sistema d’antenes receptores al travessar un obstacle i posteriorment, mitjançant una sèrie de passos que caracteritzen l’holografia, el que permet és, recuperar una imatge virtual de l’obstacle en qüestió el qual s’ha volgut holografiar. Aquest sistema s’ha elaborat mitjançant un motor rotatori i posteriorment lineal per fer l’escaneig de potència. Primerament el que s’ha dut a terme és una simulació de com el sistema es comportaria en un entorn ideal i posteriorment, s’ha dut a la realitat amb un sistema el qual ens ha permès fer una comparació amb els resultats obtinguts en la simulació. Finalment es mostren els resultats sobre la seva viabilitat.

Multimodal evaluation for medical image segmentation

This paper is a joint effort between five institutionsthat introduces several novel similarity measures andcombines them to carry out a multimodal segmentationevaluation. The new similarity measures proposed arebased on the location and the intensity values of themisclassified voxels as well as on the connectivity andthe boundaries of the segmented data. We showexperimentally that the combination of these measuresimprove the quality of the evaluation. The study that weshow here has been carried out using four differentsegmentation methods from four different labs applied toa MRI simulated dataset of the brain. We claim that ournew measures improve the robustness of the evaluation andprovides better understanding about the differencebetween segmentation methods.

An empirical study of machine learning techniques applied to image watermarking

A study of how the machine learning technique, known as gentleboost, could improve different digital watermarking methods such as LSB, DWT, DCT2 and Histogram shifting.

Aplicación de gestión de ficheros de configuración de Asterisk : Conexión de Asterisk con Google App corportativo

El objetivo de este trabajo es desarrollar una aplicación web que sirva de gestión de los aparatos conectados a la centralita Asterisk y generar los ficheros de configuración, tanto para los terminales como para el correcto funcionamiento de la centralita. Además, se instalará un servidor que conecte centralita y Google Apps para que los usuarios puedan usar el videochat de Gmail como softphone, permitiéndoles enviar y recibir llamadas a través de la centralita de la universidad en cualquier parte del mundo.

Targeting essential pathways in trypanosomatids gives insights into protozoan mechanisms of cell death.

Apoptosis is a normal component of the development and health of multicellular organisms. However, apoptosis is now considered a prerogative of unicellular organisms, including the trypanosomatids of the genera Trypanosoma spp. and Leishmania spp., causative agents of some of the most important neglected human diseases. Trypanosomatids show typical hallmarks of apoptosis, although they lack some of the key molecules contributing to this process in metazoans, like caspase genes, Bcl-2 family genes and the TNF-related family of receptors. Despite the lack of these molecules, trypanosomatids appear to have the basic machinery to commit suicide. The components of the apoptotic execution machinery of these parasites are slowly coming into light, by targeting essential processes and pathways with different apoptogenic agents and inhibitors. This review will be confined to the events known to drive trypanosomatid parasites to apoptosis.

Effect of mouse antisera targeting the Phlebotomus papatasi midgut chitinase PpChit1 on sandfly physiology and fitness

In sandflies, the absence of the peritrophic matrix (PM) affects the rate of blood digestion. Also, the kinetics of PM secretion varies according to species. We previously characterised PpChit1, a midgut-specific chitinase secreted in Phlebotomus papatasi (PPIS) that is involved in the maturation of the PM and showed that antibodies against PpChit1 reduce the chitinolytic activity in the midgut of several sandfly species. Here, sandflies were fed on red blood cells reconstituted with naïve or anti-PpChit1 sera and assessed for fitness parameters that included blood digestion, oviposition onset, number of eggs laid, egg bouts, average number of eggs per bout and survival. In PPIS, anti-PpChit1 led to a one-day delay in the onset of egg laying, with flies surviving three days longer compared to the control group. Anti-PpChit1 also had a negative effect on overall ability of flies to lay eggs, as several gravid females from all three species were unable to lay any eggs despite having lived longer than control flies. Whereas the longer survival might be associated with improved haeme scavenging ability by the PM, the inability of females to lay eggs is possibly linked to changes in PM permeability affecting nutrient absorption.

Living with digestive stomas: strategies to cope with the new bodily reality.

OBJECTIVE the objective in this study was to describe the strategies developed by digestive stoma patients to cope with their situation. METHOD a qualitative and descriptive study was undertaken, involving 21 stoma patients living in the provinces of Málaga and Granada (Spain). The informants were selected in accordance with criteria of appropriateness and diversity, through intentional sampling. The data were collected by means of semistructured interviews. RESULTS the content analysis revealed three categories around which the distinct strategies were developed: Self-care, Adaptation to the bodily change and Self-help. CONCLUSION the strategies developed are focusing on achieving the effective management of the stoma and are closely linked with the achievement of autonomy. Discovering the strategies applied is fundamental for the nursing professionals to offer high-quality care, centered on people and their process.

Sustained activation and tumor targeting of NKT cells using a CD1d-anti-HER2-scFv fusion protein induce antitumor effects in mice

Invariant NKT (iNKT) cells are potent activators of DCs, NK cells, and T cells, and their antitumor activity has been well demonstrated. A single injection of the high-affinity CD1d ligand alpha-galactosylceramide (alphaGalCer) leads to short-lived iNKT cell activation followed, however, by long-term anergy, limiting its therapeutic use. In contrast, we demonstrated here that when alphaGalCer was loaded on a recombinant soluble CD1d molecule (alphaGalCer/sCD1d), repeated injections led to sustained iNKT and NK cell activation associated with IFN-gamma secretion as well as DC maturation in mice. Most importantly, when alphaGalCer/sCD1d was fused to a HER2-specific scFv antibody fragment, potent inhibition of experimental lung metastasis and established s.c. tumors was obtained when systemic treatment was started 2-7 days after the injection of HER2-expressing B16 melanoma cells. In contrast, administration of free alphaGalCer at this time had no effect. The antitumor activity of the CD1d-anti-HER2 fusion protein was associated with HER2-specific tumor localization and accumulation of iNKT, NK, and T cells at the tumor site. Targeting iNKT cells to the tumor site thus may activate a combined innate and adaptive immune response that may prove to be effective in cancer immunotherapy