1,070 research outputs found
Exploring downstream pathways of aberrantly activated kinases for targeted leukemia therapy
Full text linkGenetic alterations resulting in uncontrolled protein tyrosine kinases (PTKs) activity are frequently found in leukemia and in human solid cancers. Although the development of small molecule kinase inhibitors has revolutionized therapy for PTKinduced chronic myeloid leukemia, their effect is limited in cancers with several genetic alterations and increased multi-factorial drug resistance is hampering therapies. To overcome these limitations, it is indispensable to identify essential targets acting downstream of an oncogenic PTK. FLT3-ITD mediated leukemogenesis is associated with increased expression of oncogenic PIM serine/threonine kinases. To dissect their role in FLT3-ITDmediated transformation, we performed bone marrow reconstitution assays. Unexpectedly, FLT3-ITD cells deficient for PIM1 failed to reconstitute lethally irradiated recipients whereas lack of PIM2 induction did not interfere with FLT3-ITDinduced disease. PIM1-deficient bone marrow showed defects in homing and migration and displayed decreased surface CXCR4 expression and impaired CXCL12/CXCR4 signaling. Through siRNA-mediated knockdown, chemical inhibition, expression of a dominant negative mutant or and re-expression in knockout cells we found PIM1 activity to be essential for proper CXCR4 surface expression and migration of cells towards a CXCL12 gradient. PIM1 directly phosphorylated Serine 339, a residue in the CXCR4 intracellular domain essential for normal receptor recycling. In primary leukemic blasts high levels of surface CXCR4 were associated with increased PIM1 expression, and could be significantly reduced by a small molecule PIM inhibitor in some patients. Our data suggest that PIM1 activity is essential for homing and migration of hematopoietic cells through direct modification of CXCR4. Since CXCR4 is also important for homing and maintenance of cancer stem cells, PIM1 inhibitors may exert their anti-tumor effects in part by interfering with interactions with the microenvironment. We extensively tested different classes of PIM inhibitors and could show that some of these compounds could impair survival and growth of different hematopoietic cellular systems, including blasts from AML patients. The second goal of my thesis was to create a mouse model for a PTK-fusion gene, NUP214/ABL1, associated with human T-cell acute leukemia. We generated two transgenic lines expressing the NUP214/ABL1 fusion from a T-cell linked (lck) promoter. However, no phenotype was observed after more than one year. Further experiments are ongoing to analyze whether co-expression of putative collaborating oncogenes, associated in human T-cell leukemia, such as HOX11/HX11L2 is able toinduce or respectively accelerate leukemogenesis
Expression of the MAST family of serine/threonine kinases
No full textThe Microtubule-Associated Serine/Threonine Kinase family (MAST1-4, and MAST-like) is characterised by the presence of a serine/threonine kinase domain and a postsynaptic density protein-95/discs large/zona occludens-1 domain (PDZ). This latter domain gives the MAST family the capacity to scaffold its own kinase activity. In the present study we have profiled the mRNA for each member of the MAST family transcripts across various tissues, with particular focus on rodent brain. Reverse-transcriptase polymerase chain reaction (RT-PCR) has shown equivalent patterns of expression for MAST1 and 2 in multiple tissues. Both MAST3 and 4 show more distinct expression in several tissues, and MAST-like appears to be predominantly expressed in heart and testis. In situ hybridisation reveals overlapping expression of MAST1 and 2 in specific brain regions. In contrast, MAST3 shows selective expression in the striatum and cerebral cortex. MAST4 also exhibits distinct expression in oligodendrocytes of white matter containing brain regions. In keeping with previous results, this family member also shows increased expression in the hippocampus following seizure-like activity. Our analysis of MAST family expression provides support for the role of these kinases in a broad range of neural functions
Model Transformation with ATL into MDA from CIM to PIM Structured through MVC
No full textAbstractModels transformation is the most important key in Model Driven Architecture (MDA). The first transformation in MDA is Computing Independent Model (CIM) to Platform Independent Model (PIM) transformation, the second is PIM to Platform Specific Model (PSM) transformation. This latter transformation deals the two less abstract levels, PIM and PSM, for that most researchers focused on this kind of transformation. Nevertheless, the top level of abstraction, CIM, and its transformation to PIM is rarely discussed in research topics. Our goal in this paper is to represent an approach that allows mastering transformation from CIM to PIM in accordance with MDA. Our method based on creating a good CIM level, using construction rules, to facilitate the transformation to PIM level. Next, our transformation rules, implemented with Atlas Transformation Language (ATL), ensure a semi-automatic transformation from CIM to PIM. Our approach conforms to MDA, because it allows considering the business dimension in the CIM level, and it allows modelling this latter level by using Business Process Model and Notation (BPMN), this latter is the OMG standard for modelling the business process. However, we founded on UML to model PIM level, because UML is advocated by MDA in PIM. Our proposal results a set of classes, organized according to the Model View Controller (MVC)
ES-PIM applied to buckling of variable angle tow laminates
No full textThe increasing need for automatic mesh generation has led to the development of efficient triangulation algorithms that are able to discretize any 2D or 3D domain. Modern finite element formulations based on strain smoothing techniques (SFEM) provide enhanced convergence properties, preventing yet the stiffening behavior of triangular meshes. Recent research has shown that meshless methods based on triangular mapping of the integration domain can be used to produce even better convergence properties than SFEM. The present study explores the Edge-based Smoothed Point Interpolation Method (ES-PIM) as a meshless solution to investigate linear buckling on variable angle tow (VAT) laminates. Such advanced composite structures show a heterogeneous distribution of constitutive properties and thickness, presenting additional challenges to the numerical solution. Important aspects related to the transverse shear correction herein adopted are investigated, leading to interesting conclusions regarding the possibility to use the ES-PIM for conservative estimates of the critical buckling load of VAT laminates.Aerospace Structures & Computational Mechanic
«Paisible sauvagerie» : Les enfants et la mort dans la littérature et le film français modernes
No full textI examine the intersection of childhood and death in four works of modern French literature and film: La Maison de Claudine (Colette),\ud
W… (Perec), Les Mots ( Sartre), and Jeux interdits (Clément). Drawing on the French tradition of psychoanalysis and Freud’s theory of the “death instinct,” I examine these young characters and argue that their concretization of death is far more courageous and cathartic\ud
than society’s tendency to deny it. I also apply the image of the child exploring death as a metaphor for the modern French author, whose creative power stems from his appraisal and acceptance of personal loss
ASO Author Reflections: Vascular Resection in Perihilar Cholangiocarcinoma Surgery
No full textvascular resection in hilar cholangiocarcinom
Processing of complex near-net-shaped tungsten parts by PIM
No full textIn the framework of the EUROfusion materials development project, promising fabrication methods in view of large-scale production of complex parts such as Powder Injection Molding (PIM) are intensively investigated at Karlsruhe Institute of Technology (KIT). With its near-net-shape precision the method offers particularly the advantage of cost-saving. Isotropic materials, equiaxed grain orientation, good thermal shock resistance, shape complexity and high final density are several typical properties of powder injection molded tungsten. Therefore, this technique is an ideal tool for scientific investigations and for developing industrial products. This contribution describes the characterization and analyses of prototype materials produced via PIM. The investigation of pure tungsten and oxide or carbide doped tungsten materials comprises the microstructure examination, element allocation, texture analyses, and mechanical testing. In addition, fabricated near-net-shape Langmuir probes for diagnostics for the French tokamak WEST will be presented
Rapid material development and processing of complex near-net-shaped parts by PIM
Full text linkA promising fabrication method in view of large-scale production of complex parts is Powder Injection Molding (PIM) which has been intensively investigated at Karlsruhe Institute of Technology (KIT). With its near-net-shape precision the method offers particularly the advantage of cost-saving. PIM as special process allows the mass production of components, the creation of composite and prototype materials. Furthermore it is an ideal tool for scientific investigations for R&D in general, and for developing industrial products for a wide range of applications.
This contribution describes the characterization and analyses of prototype materials produced via PIM. The investigation of pure tungsten and oxide or carbide doped tungsten materials comprises the microstructure examination, element allocation, texture analyses, and mechanical testing.
In addition, fabricated near-net-shape Langmuir probes for diagnostics for the French tokamak WEST will be presented
Siete años de investigación sobre la seguridad de la tenencia: Principales conclusiones y lecciones aprendidas del Informe de referencia 5 del PIM
No full textEn los países menos desarrollados, un total de 3140 millones de personas dependen de los bosques y la agricultura para su subsistencia (Tseng et al., 2020). Desde la década de 1990, las investigaciones han puesto de relieve la importancia de los derechos de tenencia para este sector de la población, tanto para la gestión sostenible de los recursos naturales como para la mitigación de la pobreza y la mejora de la nutrición y la seguridad alimentaria. Los derechos específicos, o la combinación de derechos, de un individuo, un hogar o una comunidad afectan al acceso a la tierra y a los recursos, así como al modo en que se pueden utilizar esa tierra y esos recursos y durante cuánto tiempo (Larson y Springer, 2016). Igualmente importante es el grado en que los propietarios de tierras perciben que su tenencia es segura. Es más probable que los propietarios se comprometan con la conservación de la tierra y los recursos si perciben que hay pocas probabilidades de perder sus derechos sobre la tierra o los recursos (Robinson et al., 2018). Entre 2013 y 2021, los investigadores apoyados por el Programa de Investigación del GCIAR sobre Políticas, Instituciones y Mercados (PIM) exploraron los factores que impulsan la inseguridad de la tenencia y sus consecuencias, así como los mecanismos para mejorar la seguridad de la tenencia. Su trabajo se centró en los derechos de las personas y los hogares, y en los derechos colectivos. Este informe sobre políticas describe los principales resultados de la investigación sobre la seguridad de la tenencia y las reformas normativas destinadas a reforzar los derechos de los pequeños agricultores y las comunidades.Non-PRIFPRI1; CRP2; 1 Fostering Climate-Resilient and Sustainable Food Supply; 5 Strengthening Institutions and GovernancePIMCGIAR Research Program on Policies, Institutions, and Markets (PIM
Librarians alert : how can we exploit what is happening with personal information management (PIM), reference management and related issues?
No full textThis column aims to explore the potential of personal information management (PIM) and reference management. It seeks to focus on how librarians can stay alert on new developments regarding PIM and related issues such as plagiarism, reference techniques, information literacy and information behaviour. It also tries to stimulate interest in looking for hidden gems that can be of value in their careers as well as those of library users by considering the innovative and creative use of PIM, e.g. by also monitoring the potential of mind maps and concept maps. The column is written against the background of research from information behaviour, PIM, information curation, alerts on software development and related issues, and also social bookmarking. There are many ways in which librarians can stay abreast of what is happening with PIM, reference management and related issues. There are also many things to note such as improvement of the software, uses of PIM and reference management, teaching skills in PIM and reference management, ways of sharing information, linking to innovation and creativity, and linking to information literacy and information behaviour. Although much has been published on developments in PIM and reference management, the author is not aware of other attempts to link alerting services on PIM and reference management to go beyond developments in software.http://www.emeraldinsight.com/0737-8831.htmdm201
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