Molecular features of hepatosplenic T-cell lymphoma unravels potential novel therapeutic targets.

The pathogenesis of hepatosplenic T-cell lymphoma (HSTL), a rare entity mostly derived from γδ T cells and usually with a fatal outcome, remains largely unknown. In this study, HSTL samples (7γδ and 2αβ) and the DERL2 HSTL cell line were subjected to combined gene-expression profiling and array-based comparative genomic hybridization. Compared with other T-cell lymphomas, HSTL had a distinct molecular signature irrespective of TCR cell lineage. Compared with peripheral T-cell lymphoma, not otherwise specified and normal γδ T cells, HSTL overexpressed genes encoding NK-cell-associated molecules, oncogenes (FOS and VAV3), the sphingosine-1-phosphatase receptor 5 involved in cell trafficking, and the tyrosine kinase SYK, whereas the tumor-suppressor gene AIM1 (absent in melanoma 1) was among the most down-expressed. We found highly methylated CpG islands of AIM1 in DERL2 cells, and decitabine treatment induced a significant increase in AIM1 transcripts. Syk was present in HSTL cells and DERL2 cells contained phosphorylated Syk and were sensitive to a Syk inhibitor in vitro. Genomic profiles confirmed recurrent isochromosome 7q (n = 6/9) without alterations at the SYK and AIM1 loci. Our results identify a distinct molecular signature for HSTL and highlight oncogenic pathways that offer rationale for exploring new therapeutic options such as Syk inhibitors and demethylating agents.

Uncovering Financial Markets Beliefs About Inflation Targets

This paper exploits the term structure of interest rates to develop testable economic restrictions on the joint process of long-term interest rates and inflation when the latter is subject to a targeting policy by the Central Bank. Two competing models that econometrically describe agents’ inferences about inflation targets are developed and shown to generate distinct predictions on the behavior of interest rates. In an empirical application to the Canadian inflation target zone, results indicate that agents perceive the band to be substantially narrower than officially announced and asymmetric around the stated mid-point. The latter result (i) suggests that the monetary authority attaches different weights to positive and negative deviations from the central target, and (ii) challenges on empirical grounds the assumption, frequently made in the literature, that the policy maker’s loss function is symmetric (usually a quadratic function) around a desired inflation value.

The Inflation Bias When the Central Bank Targets, the Natural Rate of Unemployment

This paper studies the proposition that an inflation bias can arise in a setup where a central banker with asymmetric preferences targets the natural unemployment rate. Preferences are asymmetric in the sense that positive unemployment deviations from the natural rate are weighted more (or less) severely than negative deviations in the central banker's loss function. The bias is proportional to the conditional variance of unemployment. The time-series predictions of the model are evaluated using data from G7 countries. Econometric estimates support the prediction that the conditional variance of unemployment and the rate of inflation are positively related.

Identification and characterization of the transcriptional targets of the WNT/β-catenin signaling pathway in granulosa cells

Les Wnts représentent une famille de glycoprotéines de signalisation qui sont connues pour les nombreux rôles qu'ils jouent durant le développement embryonnaire et dans la cancerogénèse. Plusieurs Wnts, leurs récepteurs (Fzd) et d'autres composants des voies de signalisation des Wnt sont exprimés dans l’ovaire postnatal, et il a été démontré que l’expression de certains de ces gènes est régulée pendant le développement et l'ovulation/luteinization folliculaires. Toutefois, leurs rôles physiologiques dans l’ovaire demeurent mal définis. Pour étudier le rôle de WNT4 dans le développement folliculaire, nous avons entrepris d’identifier ses cibles transcriptionnels dans les cellules de la granulosa. Pour ce faire, nous avons employé la souris Catnbflox(ex3)/flox(ex3), chez laquelle une activation constitutive de la voie de Wnt/β-catenin a lieu suite à l’action de la recombinare Cre. Des cellules de la granulosa de ces souris ont été mises en culture et infectées avec un adenovirus pour causer la surexpression de WNT4 ou l’expression de Cre. L’ARN a alors été extrait de ces cellules et analysé par micro-puce. Les résultats ont démontré qu’une forte proportion des gènes induits par WNT4 étaient des gènes impliqués dans la réponse cellulaire au stress. Presque tous gènes induits par WNT4 ont également été induits par Cre, indiquant que WNT4 signale via la voie Wnt/β-catenin dans ces cellules. Nos résultats suggèrent donc que WNT4 favorise la survie des follicules par l’induction de gènes de réponse au stress dans les cellules de la granulosa, augmentant ainsi la résistance cellulaire à l'apoptose.

Uranium à Sept-Îles : ethnographie d'un refus. Essai de résistance populaire.

Ce mémoire de maîtrise traite d’un phénomène social critique qui a gagné en importance au Québec : la montée des groupes de résistance populaire contre des projets d’exploitation des ressources naturelles. À partir d’une étude de cas, l’auteur tâche ici d’approfondir les questions relatives à ces luttes collectives tout en mettant en lumière les diverses modalités d’engagement qui, par leurs registres et leurs compositions en « systèmes-experts », se répercutent dans l’espace public tout en transformant, d’une certaine manière, l’arène politique. Ces dynamiques des mouvements de résistance tendent également à s’infléchir en amont des projets de développement, pour se matérialiser en aval, soit dès les premières phases d’appropriation territoriale, c’est-à-dire les premiers travaux exploratoires comme tels. Cette enquête de terrain se focalise sur ces enjeux. En prenant comme observatoire le projet de Terra Ventures à Sept-Îles, en région nord-côtière, concernant un projet d’exploration uranifère, l’auteur insiste sur les multiples références collectives qui sont autant de perspectives pour comprendre ce phénomène. À travers l’étude de cette résistance populaire qui s’est profilée contre ce projet d’exploration, c’est l’industrie minière au Québec, son histoire, ses mythes, et sa mémoire qui est, enfin, en trame de fond.

Spectrum simulation of rough and nanostructured targets from their 2D and 3D image by Monte Carlo methods

Corteo is a program that implements Monte Carlo (MC) method to simulate ion beam analysis (IBA) spectra of several techniques by following the ions trajectory until a sufficiently large fraction of them reach the detector to generate a spectrum. Hence, it fully accounts for effects such as multiple scattering (MS). Here, a version of Corteo is presented where the target can be a 2D or 3D image. This image can be derived from micrographs where the different compounds are identified, therefore bringing extra information into the solution of an IBA spectrum, and potentially significantly constraining the solution. The image intrinsically includes many details such as the actual surface or interfacial roughness, or actual nanostructures shape and distribution. This can for example lead to the unambiguous identification of structures stoichiometry in a layer, or at least to better constraints on their composition. Because MC computes in details the trajectory of the ions, it simulates accurately many of its aspects such as ions coming back into the target after leaving it (re-entry), as well as going through a variety of nanostructures shapes and orientations. We show how, for example, as the ions angle of incidence becomes shallower than the inclination distribution of a rough surface, this process tends to make the effective roughness smaller in a comparable 1D simulation (i.e. narrower thickness distribution in a comparable slab simulation). Also, in ordered nanostructures, target re-entry can lead to replications of a peak in a spectrum. In addition, bitmap description of the target can be used to simulate depth profiles such as those resulting from ion implantation, diffusion, and intermixing. Other improvements to Corteo include the possibility to interpolate the cross-section in angle-energy tables, and the generation of energy-depth maps.

The Role of Diffusion in ISOL Targets for the Production of Radioactive Ion Beams

On line isotope separation techniques (ISOL) for production of ion beams of short-lived radionuclides require fast separation of nuclear reaction products from irradiated target materials followed by a transfer into an ion source. As a first step in this transport chain the release of nuclear reaction products from refractory metals has been studied systematically and will be reviewed. High-energy protons (500 - 1000 MeV) produce a large number of radionuclides in irradiated materials via the nuclear reactions spallation, fission and fragmentation. Foils and powders of Re, W, Ta, Hf, Mo, Nb, Zr, Y, Ti and C were irradiated with protons (600 - 1000 MeV) at the Dubna synchrocyclotron, the CERN synchrocyclotron and at the CERN PS-booster to produce different nuclear reaction products. The main topic of the paper is the determination of diffusion coefficients of the nuclear reaction products in the target matrix, data evaluation and a systematic interpretation of the data. The influence of the ionic radius of the diffusing species and the lattice type of the host material used as matrix or target on the diffusion will be evaluated from these systematics. Special attention was directed to the release of group I, II and III-elements. Arrhenius plots lead to activation energies of the diffusion process.

Synergistic solvent extraction of Thorium(IV) and Uranium(VI) with β-diketones in presence of oxo-donors

The thesis entitled “Synergistic solvent extraction of Thorium(IV) and Uranium(VI) with β-diketones in presence of oxo-donors” embodies the results of the investigations carried out on the extraction of thorium(IV) an uranium(VI) with heterocyclic β-diketones in the presence and absence of various macrocyclic ligands and neutral organophosphorus extractants. The objective of this work is to generate the knowledge base to achieve better selectivity between thorium(IV) and uranium(VI) by understanding the interactions of crown ethers or neutral organophosphorus extractants with metal-heterocyclic β-diketonate complexes. Para-substituted 1-phenyl-3-methyl-4-aroyl-5-pyrazolones, namely,1-phenyl-3-methyl-4-(4-fluorobenzoyl)-5-pyrazolone (HPMFBP) and 1-phenyl-3-methyl-4-(4-toluoyl)-5-pyrazolone (HPMTP) were synthesized and characterized by elemental analysis, IR and H NMR spectral data. The synthesized ligands have been utilized for the extraction of thorium(IV) and uranium(VI) from nitric acid solutions in the presence and absence of various crown ethers. Thorium(IV) and uranium(VI) complexes with HPMPP(1-Phenyl-3-methyl-4-pivaloyl-5-pyrazolone) and neutral organophosphorus extractants were synthesized and characterized by IR and P NMR spectral data to further understand the interactions of neutral organophosphorus extractants with metal-chelates. Solid complexes of thorium(IV) and uranium(VI) with para-substituted 4-aroyl-5-isoxazolones and crown ethers were isolated and characterized by various spectroscopic techniques to further clarify the nature of the extracted complexes.

Characterization and Imaging Diagnostics of Laser Induced Plasma from Solid Targets

Laser induced plasma (LIP) emissions from some metal oxide targets were studied with corresponding metal targets of pure quality as a reference. Atomic emissions in the visible region were used in the spectroscopic procedures of LIP characterization. The studies were meant to throw light into LIP dynamics and they provided many experimental results which improved the general awareness of plasma state.When target materials were photo-ablated with an energetically suitable laser pulse, they developed electric charges in them.An electrical signal which was delivered from the target served as an alternative probe signal for the diagnostics of LIP and to track different charged states in the plasma. The signal showed a double peak distribution with positive polarity and a modified time of flight with various voltage levels of a given polarity.The expansion dynamics of LIP in magnetic field were also investigated by monitoring the voltage transients generated at the target.

Application of Imaging to Study the Evolution and Dynamics of Laser Produced Plasma from Solid and Thin Film Li Targets

The present thesis report the results obtained from the studies carried out on the laser blow off plasma (LBO) from LiF-C (Lithium Fluoride with Carbon) thin film target, which is of particular importance in Tokamak plasma diagnostics. Keeping in view of its significance, plasma generated by the irradiation of thin film target by nanosecond laser pulses from an Nd:YAG laser over the thin film target has been characterized by fast photography using intensified CCD. In comparison to other diagnostic techniques, imaging studies provide better understanding of plasma geometry (size, shape, divergence etc) and structural formations inside the plume during different stages of expansion.

Reduction of radar cross section of targets using periodic strip grating technique

The- classic: experiment of Heinrich Hertz verified the theoretical predict him of Maxwell that kxnfli radio and light waves are physical phenomena governed by the same physical laws. This has started a.rnnJ era of interest in interaction of electromagnetic energy with matter. The scattering of electromagnetic waves from a target is cleverly utilized im1 RADAR. This electronic system used tx> detect and locate objects under unfavourable conditions or obscuration that would render the unaided eye useless. It also provides a means for measuring precisely the range, or distance of an object and the speed of a moving object. when an obstacle is illuminated by electromagnetic waves, energy is dispersed in all directions. The dispersed energy depends on the size, shape and composition of the obstacle and frequency and nature of the incident wave. This distribution of energy’ is known as ‘scattering’ and the obstacle as ‘scatterer’ or 'target'.

Investigation on key molecular targets responsible for antidiabetic properties of Symplocos cochinchinensis (Lour.) S. Moore

Diabetes mellitus is a heterogeneous metabolic disorder characterized by hyperglycemia with disturbances in carbohydrate, protein and lipid metabolism resulting from defects in insulin secretion, insulin action or both. Currently there are 387 million people with diabetes worldwide and is expected to affect 592 million people by 2035. Insulin resistance in peripheral tissues and pancreatic beta cell dysfunction are the major challenges in the pathophysiology of diabetes. Diabetic secondary complications (like liver cirrhosis, retinopathy, microvascular and macrovascular complications) arise from persistent hyperglycemia and dyslipidemia can be disabling or even life threatening. Current medications are effective for control and management of hyperglycemia but undesirable effects, inefficiency against secondary complications and high cost are still serious issues in the present prognosis of this disorder. Hence the search for more effective and safer therapeutic agents of natural origin has been found to be highly demanding and attract attention in the present drug discovery research. The data available from Ayurveda on various medicinal plants for treatment of diabetes can efficiently yield potential new lead as antidiabetic agents. For wider acceptability and popularity of herbal remedies available in Ayurveda scientific validation by the elucidation of mechanism of action is very much essential. Modern biological techniques are available now to elucidate the biochemical basis of the effectiveness of these medicinal plants. Keeping this idea the research programme under this thesis has been planned to evaluate the molecular mechanism responsible for the antidiabetic property of Symplocos cochinchinensis, the main ingredient of Nishakathakadi Kashayam, a wellknown Ayurvedic antidiabetic preparation. A general introduction of diabetes, its pathophysiology, secondary complications and current treatment options, innovative solutions based on phytomedicine etc has been described in Chapter 1. The effect of Symplocos cochinchinensis (SC), on various in vitro biochemical targets relevant to diabetes is depicted in Chapter 2 including the preparation of plant extract. Since diabetes is a multifactorial disease, ethanolic extract of the bark of SC (SCE) and its fractions (hexane, dichloromethane, ethyl acetate and 90 % ethanol) were evaluated by in vitro methods against multiple targets such as control of postprandial hyperglycemia, insulin resistance, oxidative stress, pancreatic beta cell proliferation, inhibition of protein glycation, protein tyrosine phosphatase-1B (PTP-1B) and dipeptidyl peptidase-IV (DPPxxi IV). Among the extracts, SCE exhibited comparatively better activity like alpha glucosidase inhibition, insulin dependent glucose uptake (3 fold increase) in L6 myotubes, pancreatic beta cell regeneration in RIN-m5F and reduced triglyceride accumulation in 3T3-L1 cells, protection from hyperglycemia induced generation of reactive oxygen species in HepG2 cells with moderate antiglycation and PTP-1B inhibition. Chemical characterization by HPLC revealed the superiority of SCE over other extracts due to presence of bioactives (beta-sitosterol, phloretin 2’glucoside, oleanolic acid) in addition to minerals like magnesium, calcium, potassium, sodium, zinc and manganese. So SCE has been subjected to oral sucrose tolerance test (OGTT) to evaluate its antihyperglycemic property in mild diabetic and diabetic animal models. SCE showed significant antihyperglycemic activity in in vivo diabetic models. Chapter 3 highlights the beneficial effects of hydroethanol extract of Symplocos cochinchinensis (SCE) against hyperglycemia associated secondary complications in streptozotocin (60 mg/kg body weight) induced diabetic rat model. Proper sanction had been obtained for all the animal experiments from CSIR-CDRI institutional animal ethics committee. The experimental groups consist of normal control (NC), N + SCE 500 mg/kg bwd, diabetic control (DC), D + metformin 100 mg/kg bwd, D + SCE 250 and D + SCE 500. SCEs and metformin were administered daily for 21 days and sacrificed on day 22. Oral glucose tolerance test, plasma insulin, % HbA1c, urea, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, total protein etc. were analysed. Aldose reductase (AR) activity in the eye lens was also checked. On day 21, DC rats showed significantly abnormal glucose response, HOMA-IR, % HbA1c, decreased activity of antioxidant enzymes and GSH, elevated AR activity, hepatic and renal oxidative stress markers compared to NC. DC rats also exhibited increased level of plasma urea and creatinine. Treatment with SCE protected from the deleterious alterations of biochemical parameters in a dose dependent manner including histopathological alterations in pancreas. SCE 500 exhibited significant glucose lowering effect and decreased HOMA-IR, % HbA1c, lens AR activity, and hepatic, renal oxidative stress and function markers compared to DC group. Considerable amount of liver and muscle glycogen was replenished by SCE treatment in diabetic animals. Although metformin showed better effect, the activity of SCE was very much comparable with this drug. xxii The possible molecular mechanism behind the protective property of S. cochinchinensis against the insulin resistance in peripheral tissue as well as dyslipidemia in in vivo high fructose saturated fat diet model is described in Chapter 4. Initially animal were fed a high fructose saturated fat (HFS) diet for a period of 8 weeks to develop insulin resistance and dyslipidemia. The normal diet control (ND), ND + SCE 500 mg/kg bwd, high fructose saturated fat diet control (HFS), HFS + metformin 100 mg/kg bwd, HFS + SCE 250 and HFS + SCE 500 were the experimental groups. SCEs and metformin were administered daily for the next 3 weeks and sacrificed at the end of 11th week. At the end of week 11, HFS rats showed significantly abnormal glucose and insulin tolerance, HOMA-IR, % HbA1c, adiponectin, lipid profile, liver glycolytic and gluconeogenic enzyme activities, liver and muscle triglyceride accumulation compared to ND. HFS rats also exhibited increased level of plasma inflammatory cytokines, upregulated mRNA level of gluconeogenic and lipogenic genes in liver. HFS exhibited the increased expression of GLUT-2 in liver and decreased expression of GLUT-4 in muscle and adipose. SCE treatment also preserved the architecture of pancreas, liver, and kidney tissues. Treatment with SCE reversed the alterations of biochemical parameters, improved insulin sensitivity by modifying gene expression in liver, muscle and adipose tissues. Overall results suggest that SC mediates the antidiabetic activity mainly via alpha glucosidase inhibition, improved insulin sensitivity, with antiglycation and antioxidant activities.