Etude du potentiel des nanotubes de carbone dans la microélectronique de puissance

The work presented in this thesis was a scientific cooperation between the society ST Microelectronics in Tours, the laboratories of LMR and CEMHTI within the framework of the project Région Centre “ConnectiC”. The main issue of that project concerns the interconnections for the future generation of integrated circuits. In comparison with the current interconnection technologies on metallic alloys as connectors; the integration of carbon nanotubes (CNT) as connector in power microelectronics would limit effects of overheating in the chip-structure due to their interesting transport properties. CNT can provide at the same time good electrical, thermal conduction characteristics and can be a mechanical support of chip packages. The aims of this work were: firstly, obtain a reproducible growth process of vertically aligned CNT on different kinds of substrate; secondly: to elaborate a test vehicle with CNT interconnects allowing the electrical, thermal and mechanical characterization. The experimental method used herein for synthesis of CNT interconnects combines the catalyst deposition (Ni, Fe), the structuration by both means of hydrogen plasma treatment and thermal annealing, and a RF PECVD method using ethylene and hydrogen for the CNT growth. Optimal reproducible conditions were found using a novel in situ Raman spectroscopy diagnostic developed in collaboration with the CEMHTI. The carpet of CNT (height of 10 µm) produced presents the electrical (⍴ = 10⁻⁵ Ω.m), thermal (λth = 40-60 W.m⁻¹.K⁻¹), and mechanical (E = 480 GPa) performances comparable with the metallic. Finally, by means of thermocompression, we assembled CNT on substrates from the microelectronics.Le travail présenté dans ce manuscrit de thèse s’inscrit dans le cadre d’une coopération scientifique notamment à travers le projet Région Centre « Connectic » en partenariat avec la société STMicroelectronics de Tours, les laboratoires LMR et CEMHTI. Il concerne les interconnexions des générations futures de circuits intégrés. Par rapport aux technologies d’interconnexion à base d’alliage métallique l’intégration de nanotubes de carbone (NTC) comme connecteur en microélectronique de puissance limiterait les effets d’échauffement dans les empilements de puces grâce à leurs propriétés de transport intéressantes. Les NTC peuvent assurer simultanément une bonne conduction électrique et un maintien mécanique des assemblages de puces. Les objectifs de ce travail étaient d’établir dans un premier temps un procédé reproductible d’élaboration de NTC verticalement alignés sur des substrats de nature multiple, et de réaliser dans un deuxième temps un véhicule test qui permet de caractériser leurs propriétés électrique, thermique et mécanique. Le dispositif expérimental d’élaboration présenté dans cette étude utilise le dépôt de catalyseur (Ni, Fe), la structuration par plasma d’hydrogène simultanément à un recuit thermique, ainsi que la méthode de CVD assistée par plasma radiofréquence d’éthylène et d’hydrogène pour la croissance des NTC. Des conditions optimales reproductibles d’obtention des NTC ont été établies à la suite d’une étude paramétrée utilisant notamment un diagnostic original de suivi in situ par spectroscopie Raman développé en collaboration avec le CEMHTI. Dans le cas d’un tapis de NTC de 10 µm de haut, des performances électrique (⍴ = 10⁻⁵ Ω.m), thermique (λth = 40-60 W.m⁻¹.K⁻¹), et mécanique (E = 480 GPa) comparables aux alliages métalliques ont été établies. Enfin, nous avons été capables d’assembler les substrats de la microélectronique et les NTC par un procédé de thermocompression

miR-146a controls CXCR4 expression in a pathway that involves PLZF and can be used to inhibit HIV-1 infection of CD4+ T lymphocytes

Abstract MicroRNA miR-146a and PLZF are reported as major players in the control of hematopoiesis, immune function and cancer. PLZF is described as a miR-146a repressor, whereas CXCR4 and TRAF6 were identified as miR-146a direct targets in different cell types. CXCR4 is a co-receptor of CD4 molecule that facilitates HIV-1 entry into T lymphocytes and myeloid cells, whereas TRAF6 is involved in immune response. Thus, the role of miR-146a in HIV-1 infection is currently being thoroughly investigated. In this study, we found that PLZF mediates suppression of miR-146a to control increases of CXCR4 and TRAF6 protein levels in human primary CD4 + T lymphocytes. We show that miR-146a upregulation by AMD3100 treatment or PLZF silencing, decreases CXCR4 protein expression and prevents HIV-1 infection of leukemic monocytic cell line and CD4 + T lymphocytes. Our findings improve the prospects of developing new therapeutic strategies to prevent HIV-1 entry via CXCR4 by using the PLZF/miR-146a axis

Effects of Sphingosine-1-Phosphate on Neural Differentiation and Neurite Outgrowth in Neuroblastoma Cells

Sphingosine-1-phosphate (S1P) is emerging as a new class of second messenger involved in cellular proliferation, differentiation, and apoptosis and is implicated in diverse physiological functions. Despite many studies on the biological functions of S1P, however, little is known about its role in neuronal differentiation. By use of reverse transcription-polymerase chain reaction and immunostaining, this study aimed to explore whether S1P can differentiate neuroblastoma cells into neural cells. After incubation with 1 uM or 10 uM S1P, the number of neurite-bearing cells increased. Furthermore, the neuroblastoma cells revealed immunoreactivity for neural-specific markers such as GAP43, NFH, and SYP by immunostaining. The expression of NFH, MAP2, SYP, NeuroD1, and SYT mRNA, which is specific for neurons, was increased as shown by RT-PCR studies. The results of this study suggest that that S1P can induce neuronal differentiation and may be a good candidate for the treatment of neurodegenerative diseases

Twist-1 regulates the miR-199a/214 cluster during development

MicroRNAs are known to regulate developmental processes but their mechanism of regulation remains largely uncharacterized. We show the transcription factor Twist-1 drives the expression of a 7.9-kb noncoding RNA transcript (from the Dynamin-3 gene intron) that encodes a miR-199a and miR-214 cluster. We also show that knocking down Twist-1 with shRNAs decreased miR-199a/214 levels and that Twist-1 bound an E-Box promoter motif to developmentally regulate the expression of these miRNAs. The expression of HIF-1 (known to mediate Twist-1 transcription), miR-199a and miR-214 was maximal at E12.5 and the miRNAs were expressed specifically in mouse cerebellum, midbrain, nasal process and fore- and hindlimb buds. This study shows the expression of the miR199a/214 cluster is controlled by Twist-1 via an E-Box promoter element and supports a role for these miRNAs as novel intermediates in the pathways controlling the development of specific neural cell populations

The emerging role of MIR-146A in the control of hematopoiesis, immune function and cancer

MicroRNA (miRs) represent a class of small non-coding regulatory RNAs playing a major role in the control of gene expression by repressing protein synthesis at the post-transcriptional level. Studies carried out during the last years have shown that some miRNAs plays a key role in the control of normal and malignant hgematopoiesis. In this review we focus on recent progress in analyzing the functional role of miR-146a in the control of normal and malignant hematopoiesis. On the other hand, this miRNA has shown to impact in the control of innate immune responses. Finally, many recent studies indicate a deregulation of miR-146 in many solid tumors and gene knockout studies indicate a role for this miRNA as a tumor suppressor

Abnormal regulation of soluble and anchored IL-6 receptor in monocytes from patients with essential thrombocythemia

Objective: In a previous study, we found increased plasma soluble receptor for interleukin-6 (sIL-6R) levels in patients with essential thrombocythemia (ET) that could promote megakaryopoiesis through IL-6 binding and further interaction with the signal transducer gp130. Here we have searched for the cell source of sIL-6R within mononuclear cells in these patients and the underlying abnormalities involved in its overproduction. Materials and Methods: Thirty patients with the diagnosis of ET were studied. sIL-6R levels were measured by enzyme-linked immunosorbent assay technique in the supernatants of peripheral monocyte and lymphocyte cultures. Expression of membrane-anchored IL-6R was determined by flow cytometry. In order to study the mechanism of sIL-6R production, tumor necrosis factor−α protease inhibitor was added to specifically block IL-6R shedding. Gene expression of sIL-6R levels were evaluated by reverse transcription polymerase chain reaction. Results: Monocytes were the main source of sIL-6R. Besides, in ET patients, monocyte sIL-6R release was higher than that of controls (p = 0.0014). Lymphocytes enhanced monocyte sIL-6R production by cell-mediated contact in normal controls, but this cooperation could not be seen in patients. Membrane expression of IL-6R was increased after monocyte adhesion in ET. sIL-6R synthesis was upregulated in most patients, while messenger RNA was normal. Conclusions: Our results indicate that ET monocytes are responsible for sIL-6R overproduction within mononuclear cells through synthesis upregulation. In addition, the lack of cooperation of lymphocytes in monocyte sIL-6R production in ET could be due to a monocyte abnormality. The agonistic effect of sIL-6R on IL-6 action could contribute to the exacerbated megakaryocytic growth in ET.Fil: Goette, Nora Paula. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; ArgentinaFil: Lev, Paola Roxana. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; ArgentinaFil: Heller, Paula Graciela. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; ArgentinaFil: Glembotsky, Ana Claudia. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; ArgentinaFil: Chazarreta, Carlos Daniel. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; ArgentinaFil: Salim, Juan Pablo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; ArgentinaFil: Molinas, Felisa Concepcion. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; ArgentinaFil: Marta, Rosana Fernanda. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; Argentin

MicroRNA-146a and AMD3100, two ways to control CXCR4 expression in acute myeloid leukemias

CXCR4 is a negative prognostic marker in acute myeloid leukemias (AMLs). Therefore, it is necessary to develop novel ways to inhibit CXCR4 expression in leukemia. AMD3100 is an inhibitor of CXCR4 currently used to mobilize cancer cells. CXCR4 is a target of microRNA (miR)-146a that may represent a new tool to inhibit CXCR4 expression. We then investigated CXCR4 regulation by miR-146a in primary AMLs and found an inverse correlation between miR-146a and CXCR4 protein expression levels in all AML subtypes. As the lowest miR-146a expression levels were observed in M5 AML, we analyzed the control of CXCR4 expression by miR-146a in normal and leukemic monocytic cells and showed that the regulatory miR-146a/CXCR4 pathway operates during monocytopoiesis, but is deregulated in AMLs. AMD3100 treatment and miR-146a overexpression were used to inhibit CXCR4 in leukemic cells. AMD3100 treatment induces the decrease of CXCR4 protein expression, associated with miR-146a increase, and increases sensitivity of leukemic blast cells to cytotoxic drugs, this effect being further enhanced by miR-146a overexpression. Altogether our data indicate that miR-146a and AMD3100, acting through different mechanism, downmodulate CXCR4 protein levels, impair leukemic cell proliferation and then may be used in combination with anti-leukemia drugs, for development of new therapeutic strategies

Combined Characterization of microRNA and mRNA Profiles Delineates Early Differentiation Pathways of CD133+ and CD34+ Hematopoietic Stem and Progenitor Cells

MicroRNAs (miRNAs) have been shown to play an important role in hematopoiesis. To elucidate the role of miRNAs in the early steps of hematopoiesis, we directly compared donor-matched CD133+ cells with the more differentiated CD34+CD133− and CD34−CD133− cells from bone marrow on the miRNA and mRNA level. Using quantitative whole genome miRNA microarray and sequencing-based profiling, we found that between 109 (CD133+) and 216 (CD34−CD133−) miRNAs were expressed. Quantification revealed that the 25 highest expressed miRNAs accounted for 73% of the total miRNA pool. miR-142-3p was the highest expressed miRNA with up to 2,000 copies per cell in CD34+CD133− cells. Eighteen miRNAs were significantly differentially expressed between CD133+ and CD34+CD133− cells. We analyzed their biological role by examining the coexpression of miRNAs and its bioinformatically predicted mRNA targets and luciferase-based reporter assays. We provide the first evidence for a direct regulation of CD133 by miR-142-3p as well as tropomyosin 1 and frizzled homolog 5 by miR-29a. Overexpression of miRNAs in CD133+ cells demonstrated that miR-142-3p has a negative influence on the overall colony-forming ability. In conclusion, the miRNAs expressed differentially between the CD133+ and CD34+CD133− cells are involved in inhibition of differentiation, prevention of apoptosis, and cytoskeletal remodeling. These results are highly relevant for stem cell-based therapies with CD133+ cells and delineate for the first time how the stem cell character of CD133+ cells is defined by the expression of specific miRNAs. Stem Cells 2011;29:847–85