SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism

Spleen tyrosine kinase (SYK) is an important oncogene and signaling mediator activated by cell surface receptors crucial for acute myeloid leukemia (AML) maintenance and progression. Genetic or pharmacologic inhibition of SYK in AML cells leads to increased differentiation, reduced proliferation, and cellular apoptosis. Herein, we addressed the consequences of SYK inhibition to leukemia stem-cell (LSC) function and assessed SYK-associated pathways in AML cell biology. Using gain-of-function MEK kinase mutant and constitutively active STAT5A, we demonstrate that R406, the active metabolite of a small-molecule SYK inhibitor fostamatinib, induces differentiation and blocks clonogenic potential of AML cells through the MEK/ERK1/2 pathway and STAT5A transcription factor, respectively. Pharmacological inhibition of SYK with R406 reduced LSC compartment defined as CD34+CD38-CD123+ and CD34+CD38-CD25+ in vitro, and decreased viability of LSCs identified by a low abundance of reactive oxygen species. Primary leukemic blasts treated ex vivo with R406 exhibited lower engraftment potential when xenotransplanted to immunodeficient NSG/J mice. Mechanistically, these effects are mediated by disturbed mitochondrial biogenesis and suppression of oxidative metabolism (OXPHOS) in LSCs. These mechanisms appear to be partially dependent on inhibition of STAT5 and its target gene MYC, a well-defined inducer of mitochondrial biogenesis. In addition, inhibition of SYK increases the sensitivity of LSCs to cytarabine (AraC), a standard of AML induction therapy. Taken together, our findings indicate that SYK fosters OXPHOS and participates in metabolic reprogramming of AML LSCs in a mechanism that at least partially involves STAT5, and that SYK inhibition targets LSCs in AML. Since active SYK is expressed in a majority of AML patients and confers inferior prognosis, the combination of SYK inhibitors with standard chemotherapeutics such as AraC constitutes a new therapeutic modality that should be evaluated in future clinical trials

Influence by the number of measured parcel boundary points on the accuracy of land parcel area calculation

The question undertaken in the research was: how does the number of measurement points influence the error of the land parcel's area calculation? The field measurements relied on continuous land parcel's GPS measurement with various intervals of the record. Simulated area accuracy calculated from Gauss's formula increases with the increase number of points. The experiment of continuously GPS measurement did not confirm simulated accuracy in all points¿ number range. The largest difference was observed for few number of measuring points, for which the prognosis error was much bigger (almost 2 times) than the error obtained during measurements. A relationship between amount of the points and area accuracy was also compared with the literature (Bogaert i et. al. 2005). The results of our research also only partly confirmed results published in the literature. Main discrepancy was observed for small point¿s amount. In our research, area error increases with decreasing number of points, in the literature on the contrary area error decreases. Explanation of this phenomenon requires further research especially because that our field measurements not correspond full to the simulation from the literature.JRC.DDG.H.4-Monitoring agricultural resource

La théorie évolutive de la connaissance. La relation phylogénétique de la représentation à l'objet

I examine the hypothesis that there exist synthetic a priori (innate), not available for the agent's control, Phylogenetically Acquired Representations (PAR), that have their origin in the causal, selective relations between the organism and some factors from its phylogenetic environment; the adaptative genesis of PAR would provide them the status of knowledge. The validity of this hypothesis is analysed in confrontation with the major tenets of the Modern Synthesis, such as the concept of the gene and of the genetic causation; the concept of the unit of selection; the concept of the species; the concepts of information and of innateness. I examine the metaphysical suppositions underlying taxonomical practice. I introduce the Relativist Theory of Evolution, inspired by the theory of evolutionary constructivism (by R. Lewontin) and by the Theory of Niche Construction (by J.Odling-Smee), breaking with externalist models of the relation environment/organism of the Modern Synthesis.Dans ma thèse j'examine l'hypothèse affirmant qu'il existe des représentations synthétiques a priori (innées), non accessibles au contrôle du sujet (Représentations Acquises Phylogénétiquement, RAP), et que ces représentations proviennent de relations causales sélectives entre l'organisme et certains facteurs de l'environnement phylogénétique; la genèse adaptative des RAP leur procurerait le statut de connaissance. La validité de cette hypothèse est analysée à travers l'étude critique des concepts principaux de la Théorie Synthétique de l'Evolution, tels que le concept du gène, de la causalité génétique, de l'unité de sélection, de l'espèce ; le concept de l'information ; le concept de l'inné. J'examine des suppositions métaphysiques sous-tendant la pratique taxinomique. Enfin, j'introduis la Théorie Relativiste de l'Evolution, inspirée par la théorie du constructivisme évolutif (R. Lewontin) et par la théorie de la construction de niche (Niche Construction de J.Odling-Smee), rompant avec la modélisation externaliste de la relation environnement/organisme propre à la Théorie Synthétique de l'Evolution.LYON3-Bibliothèques (693872102) / SudocLYON-BIU-LSH (693872101) / SudocSudocFranceF

Influence of an Electronic Structure of N-TiO2 on Its Photocatalytic Activity towards Decomposition of Acetaldehyde under UV and Fluorescent Lamps Irradiation

The electronic structure of N-TiO2 samples prepared by a sol-gel method was investigated by EPR (Electronic Paramagnetic Resonance) measurements and the energy-resolved distribution of electron traps. In EPR spectra, some of the resonance lines assigned to paramagnetic species of nitrogen and Ti3+ were detected. Sample prepared at 300 degrees C revealed the highest intensity line of the nitrogen paramagnetic centers, whereas that prepared at 400 degrees C showed a paramagnetic line for Ti3+. Measurements of the electron trap distribution showed higher density of electron traps for sample prepared at 400 degrees C than that at 300 degrees C. Sample prepared at 300 degrees C, which revealed the highest amount of nitrogen built in the titania in the interstitial position was the most active under visible light. It was evidenced that photocatalytic decomposition of acetaldehyde was dependent strongly on the BET surface area and electrokinetic potential of the photocatalyst surface. The UV content in the fluorescent lamp affected the yield of acetaldehyde decomposition

Lipid profile changes in erythrocyte membranes of women with diagnosed GDM.

Gestational diabetes mellitus (GDM) is a glucose intolerance that begins or is first recognized during pregnancy. It is currently a growing health problem worldwide affecting from 1% to 14% of all pregnant women depending on racial and ethnic group as well as the diagnostic and screening criteria. Our preliminary study aimed at investigating the erythrocyte membrane fatty acid profiles of pregnant women, in particular with diagnosed with gestational diabetes mellitus (GDM), and with normal glucose tolerant (NGT) pregnant women as a control group. The study group comprised 43 pregnant women, 32 of whom were diagnosed with GDM according to the WHO criteria, and 11 with normal glucose tolerance. The erythrocyte membrane phospholipids were obtained according to the Folch extraction procedure. Fatty acids (FA) were analyzed by gas chromatography (GC) as the corresponding fatty acid methyl esters (FAME). A cluster of 14 fatty acids identified contained >98% of the recognized peaks in the GC analysis. The analysis of fatty acids from erythrocytes revealed important differences between GDM and NGT women in the third trimester, and the results were correlated with biochemical data. Among the 14 measured FA representing the membrane lipidomic profile, the levels of three saturated FA (myristic, palmitic, stearic acids) tended to decrease in GDM patients, with the percentage content of stearic acid significantly changed. The relative content of monounsaturated fatty acids (MUFA) tended to increase, in particular the oleic acid and vaccenic acid contents were significantly increased in erythrocyte membranes of the GDM group in comparison with the NGT group. The GDM group demonstrated higher sapienic acid levels (+29%) but this change was not statistically significant. This study revealed association between an impaired cis-vaccenic acid concentration in erythrocytes membrane and GDM development. No significant changes of polyunsaturated fatty acids (PUFA) were observed in GDM and NGT erythrocytes. We postulate, basing on the differences between the GDM and NGT lipidomic profiles, that stearic and cis-vaccenic acids can be considered as dual biomarkers of specific SFA-MUFA conversion pathway, involving the coupling of delta-9 desaturase and elongase enzymes. Our results indicate that the SFA-MUFA families may be involved in the pathophysiology of metabolic diseases such as GDM, but the further studies are needed to confirm our hypothesis. In conclusion, the erythrocyte membranes of GDM women undergo remodeling resulting in abnormal fatty acid profiles, which are reflection of the long-term status of organism and can have great impact on both the mother and her offspring