Isthmin exerts pro-survival and death-promoting effect on endothelial cells through alphavbeta5 integrin depending on its physical state

10.1038/cddis.2011.37Cell Death and Disease25

«La relation de limitation et d’exception dans le français d’aujourd’hui : excepté, sauf et hormis comme pivots d’une relation algébrique »

L’analyse des emplois prépositionnels et des emplois conjonctifs d’ “excepté”, de “sauf” et d’ “hormis” permet d’envisager les trois prépositions/conjonctions comme le pivot d’un binôme, comme la plaque tournante d’une structure bipolaire. Placées au milieu du binôme, ces prépositions sont forcées par leur sémantisme originaire dûment métaphorisé de jouer le rôle de marqueurs d’inconséquence systématique entre l’élément se trouvant à leur gauche et celui qui se trouve à leur droite. L’opposition qui surgit entre les deux éléments n’est donc pas une incompatibilité naturelle, intrinsèque, mais extrinsèque, induite. Dans la plupart des cas (emplois limitatifs), cette opposition prend la forme d’un rapport entre une « classe » et le « membre (soustrait) de la classe », ou bien entre un « tout » et une « partie » ; dans d’autres (emplois exceptifs), cette opposition se manifeste au contraire comme une attaque de front portée par un « tout » à un autre « tout ». De plus, l’inconséquence induite mise en place par la préposition/conjonction paraît, en principe, tout à fait insurmontable. Dans l’assertion « les écureuils vivent partout, sauf en Australie » (que l’on peut expliciter par « Les écureuils vivent partout, sauf [qu’ils ne vivent pas] en Australie »), la préposition semble en effet capable d’impliquer le prédicat principal avec signe inverti, et de bâtir sur une telle implication une sorte de sous énoncé qui, à la rigueur, est totalement inconséquent avec celui qui le précède (si « les écureuils ne vivent pas en Australie », le fait qu’ils « vivent partout » est faux). Néanmoins, l’analyse montre qu’alors que certaines de ces oppositions peuvent enfin être dépassées, d’autres ne le peuvent pas. C’est, respectivement, le cas des relations limitatives et des relations exceptives. La relation limitative, impliquant le rapport « tout » - « partie », permet de résoudre le conflit dans les termes d’une somme algébrique entre deux sous énoncés pourvus de différent poids informatif et de signe contraire. Les valeurs numériques des termes de la somme étant déséquilibrées, le résultat est toujours autre que zéro. La relation exceptive, au contraire, qui n’implique pas le rapport « tout » - « partie », n’est pas capable de résoudre le conflit entre deux sous énoncés pourvus du même poids informatif et en même temps de signe contraire : les valeurs numériques des termes de la somme étant symétriques et égales, le résultat sera toujours équivalent à zéro

Investigaciones arqueológicas en el centro de la provincia de Corrientes: primeros resultados de las prospecciones en el sistema Iberá

Las investigaciones arqueológicas en el centro de la provincia de Corrientes han sido escasas y discontinuas. Con el objetivo de revertir este panorama se iniciaron trabajos de campo en el sector sur y sursureste del macrosistema Iberá (Reserva Provincial Iberá y Parque Nacional Iberá). En este trabajo se presentan los resultados de las actividades de prospección y excavación desarrolladas. Como resultado de las mismas, se identificaron 11 áreas en las que los materiales arqueológicos se presentan en densidades variables y asociados a una matriz sedimentaria con alta proporción de conchillas. En líneas generales, estas se caracterizan por la presencia de material cerámico, lítico, restos óseos humanos y faunísticos, ornamentos, entre otros. A esta información, se integran y discuten los antecedentes para el sector, confirmando el alto potencial arqueológico del área. La evaluación de la red de permeabilidad del sector permitió identificar tres formas posibles de desplazamiento práctico entre la totalidad de los sitios hasta ahora identificados (n= 33)

Anti-Angiogenic Therapy Induces Integrin-Linked Kinase 1 Up-Regulation in a Mouse Model of Glioblastoma

BACKGROUND: In order to improve our understanding of the molecular pathways that mediate tumor proliferation and angiogenesis, and to evaluate the biological response to anti-angiogenic therapy, we analyzed the changes in the protein profile of glioblastoma in response to treatment with recombinant human Platelet Factor 4-DLR mutated protein (PF4-DLR), an inhibitor of angiogenesis. METHODOLOGY/PRINCIPAL FINDINGS: U87-derived experimental glioblastomas were grown in the brain of xenografted nude mice, treated with PF4-DLR, and processed for proteomic analysis. More than fifty proteins were differentially expressed in response to PF4-DLR treatment. Among them, integrin-linked kinase 1 (ILK1) signaling pathway was first down-regulated but then up-regulated after treatment for prolonged period. The activity of PF4-DLR can be increased by simultaneously treating mice orthotopically implanted with glioblastomas, with ILK1-specific siRNA. As ILK1 is related to malignant progression and a poor prognosis in various types of tumors, we measured ILK1 expression in human glioblastomas, astrocytomas and oligodendrogliomas, and found that it varied widely; however, a high level of ILK1 expression was correlated to a poor prognosis. CONCLUSIONS/SIGNIFICANCE: Our results suggest that identifying the molecular pathways induced by anti-angiogenic therapies may help the development of combinatorial treatment strategies that increase the therapeutic efficacy of angiogenesis inhibitors by association with specific agents that disrupt signaling in tumor cells

Targeting ανβ3 and ανβ5 inhibits photon-induced hypermigration of malignant glioma cells

Sublethal photon irradiation was recently suspected to increase tumor cell motility and promote locoregional recurrence of disease. This study was set up to describe mechanisms underlying increased glioma cell migration through photon irradiation and to analyse the modifiability of photon-altered glioma cell motility by integrin inhibition

Regulation of DNA Repair Mechanism in Human Glioma Xenograft Cells both In Vitro and In Vivo in Nude Mice

Glioblastoma Multiforme (GBM) is the most lethal form of brain tumor. Efficient DNA repair and anti-apoptotic mechanisms are making glioma treatment difficult. Proteases such as MMP9, cathepsin B and urokinase plasminogen activator receptor (uPAR) are over expressed in gliomas and contribute to enhanced cancer cell proliferation. Non-homologous end joining (NHEJ) repair mechanism plays a major role in double strand break (DSB) repair in mammalian cells.Here we show that silencing MMP9 in combination with uPAR/cathepsin B effects NHEJ repair machinery. Expression of DNA PKcs and Ku70/80 at both mRNA and protein levels in MMP9-uPAR (pMU) and MMP9-cathepsin B (pMC) shRNA-treated glioma xenograft cells were reduced. FACS analysis showed an increase in apoptotic peak and proliferation assays revealed a significant reduction in the cell population in pMU- and pMC-treated cells compared to untreated cells. We hypothesized that reduced NHEJ repair led to DSBs accumulation in pMU- and pMC-treated cells, thereby initiating cell death. This hypothesis was confirmed by reduced Ku70/Ku80 protein binding to DSB, increased comet tail length and elevated γH2AX expression in treated cells compared to control. Immunoprecipitation analysis showed that EGFR-mediated lowered DNA PK activity in treated cells compared to controls. Treatment with pMU and pMC shRNA reduced the expression of DNA PKcs and ATM, and elevated γH2AX levels in xenograft implanted nude mice. Glioma cells exposed to hypoxia and irradiation showed DSB accumulation and apoptosis after pMU and pMC treatments compared to respective controls.Our results suggest that pMU and pMC shRNA reduce glioma proliferation by DSB accumulation and increase apoptosis under normoxia, hypoxia and in combination with irradiation. Considering the radio- and chemo-resistant cancers favored by hypoxia, our study provides important therapeutic potential of MMP9, uPAR and cathepsin B shRNA in the treatment of glioma from clinical stand point

The Effect of a DNA Repair Gene on Cellular Invasiveness: Xrcc3 Over-Expression in Breast Cancer Cells

Over-expression of DNA repair genes has been associated with resistance to radiation and DNA-damage induced by chemotherapeutic agents such as cisplatin. More recently, based on the analysis of genome expression profiling, it was proposed that over-expression of DNA repair genes enhances the invasive behaviour of tumour cells. In this study we present experimental evidence utilizing functional assays to test this hypothesis. We assessed the effect of the DNA repair proteins known as X-ray complementing protein 3 (XRCC3) and RAD51, to the invasive behavior of the MCF-7 luminal epithelial-like and BT20 basal-like triple negative human breast cancer cell lines. We report that stable or transient over-expression of XRCC3 but not RAD51 increased invasiveness in both cell lines in vitro. Moreover, XRCC3 over-expressing MCF-7 cells also showed a higher tumorigenesis in vivo and this phenotype was associated with increased activity of the metalloproteinase MMP-9 and the expression of known modulators of cell-cell adhesion and metastasis such as CD44, ID-1, DDR1 and TFF1. Our results suggest that in addition to its' role in facilitating repair of DNA damage, XRCC3 affects invasiveness of breast cancer cell lines and the expression of genes associated with cell adhesion and invasion

Identifying the Big Questions in paleontology: a community-driven project

Paleontology provides insights into the history of the planet, from the origins of life billions of years ago to the biotic changes of the Recent. The scope of paleontological research is as vast as it is varied, and the field is constantly evolving. In an effort to identify “Big Questions” in paleontology, experts from around the world came together to build a list of priority questions the field can address in the years ahead. The 89 questions presented herein (grouped within 11 themes) represent contributions from nearly 200 international scientists. These questions touch on common themes including biodiversity drivers and patterns, integrating data types across spatiotemporal scales, applying paleontological data to contemporary biodiversity and climate issues, and effectively utilizing innovative methods and technology for new paleontological insights. In addition to these theoretical questions, discussions touch upon structural concerns within the field, advocating for an increased valuation of specimen-based research, protection of natural heritage sites, and the importance of collections infrastructure, along with a stronger emphasis on human diversity, equity, and inclusion. These questions offer a starting point—an initial nucleus of consensus that paleontologists can expand on—for engaging in discussions, securing funding, advocating for museums, and fostering continued growth in shared research directions. La paleontología permite conocer la historia del planeta, desde los orígenes de la vida hace miles de millones de años hasta los cambios bióticos de épocas recientes. El ámbito de la investigación paleontológica es tan vasto como variado y está en constante evolución. En un esfuerzo por identificar las “grandes preguntas” de la paleontología, expertos de todo el mundo se reunieron para elaborar una lista de cuestiones prioritarias que el campo puede abordar en los próximos años. Las 89 preguntas aquí presentadas (agrupadas en 11 temas) representan las contribuciones de casi 200 científicos internacionales. Estas preguntas se refieren a temas comunes, entre los que se incluyen los motores y patrones de la biodiversidad, la integración de diferentes tipos de datos a lo largo de escalas espacio-temporales, la aplicación de datos paleontológicos para resolver cuestiones contemporáneas de biodiversidad y clima, y la utilización eficaz de métodos y tecnologías innovadoras para obtener nuevos conocimientos paleontológicos. Además de estos interrogantes teóricos, los debates abordan inquietudes estructurales dentro del campo, y abogan por una mayor valoración de la investigación basada en especímenes, la protección de los sitios del patrimonio natural y la importancia de la infraestructura de las colecciones; junto con un mayor énfasis en la diversidad humana, la equidad y la inclusión. Estas preguntas representan un punto de partida—un núcleo inicial de consenso que los paleontólogos pueden ampliar—para fomentar debates, obtener financiación, abogar por el apoyo a los museos y estimular el crecimiento continuo en direcciones de investigación compartidas. La paleontologia offre spunti fondamentali per comprendere la storia del pianeta, dalle origini della vita miliardi di anni fa fino ai cambiamenti biotici più recenti. L’ambito della ricerca paleontologica è tanto vasto quanto diversificato e rappresenta un campo in continua evoluzione. In questo studio, esperti provenienti da tutto il mondo si sono riuniti per redigere un elenco di “Grandi Domande” prioritarie che la paleontologia potrà affrontare nei prossimi anni. Le 89 domande qui presentate, raggruppate in 11 temi, rappresentano il contributo di circa 200 scienziati internazionali. Queste domande riguardano tematiche come i meccanismi e i pattern di biodiversità, l’integrazione di varie tipologie di dati su scale spazio-temporali multiple, l’applicazione delle conoscenze paleontologiche ai problemi attuali della crisi climatica e della biodiversità, e l’uso efficace di metodi e tecnologie innovative per ottenere nuove intuizioni paleontologiche. Oltre a questi temi teorici, la discussione si focalizza su problematiche strutturali del campo, promuovendo una maggiore valorizzazione della ricerca basata sugli esemplari, la protezione dei siti di interesse culturale e paleontologico, e l’importanza delle infrastrutture per preservare le collezioni, insieme a una crescente enfasi su un apporto multiculturale, equo e inclusivo. Queste domande costituiscono un punto di partenza—un nucleo di consenso iniziale che i paleontologi possono espandere—per avviare discussioni, ottenere finanziamenti, promuovere i musei e favorire una crescita continua verso direzioni condivise di ricerca

Identifying the Big Questions in paleontology: a community-driven project

Paleontology provides insights into the history of the planet, from the origins of life billions of years ago to the biotic changes of the Recent. The scope of paleontological research is as vast as it is varied, and the field is constantly evolving. In an effort to identify “Big Questions” in paleontology, experts from around the world came together to build a list of priority questions the field can address in the years ahead. The 89 questions presented herein (grouped within 11 themes) represent contributions from nearly 200 international scientists. These questions touch on common themes including biodiversity drivers and patterns, integrating data types across spatiotemporal scales, applying paleontological data to contemporary biodiversity and climate issues, and effectively utilizing innovative methods and technology for new paleontological insights. In addition to these theoretical questions, discussions touch upon structural concerns within the field, advocating for an increased valuation of specimen-based research, protection of natural heritage sites, and the importance of collections infrastructure, along with a stronger emphasis on human diversity, equity, and inclusion. These questions offer a starting point—an initial nucleus of consensus that paleontologists can expand on—for engaging in discussions, securing funding, advocating for museums, and fostering continued growth in shared research directions