X-linked inhibitor of apoptosis protein mediates tumor cell resistance to antibody-dependent cellular cytotoxicity.

Inflammatory breast cancer (IBC) is the deadliest, distinct subtype of breast cancer. High expression of epidermal growth factor receptors [EGFR or human epidermal growth factor receptor 2 (HER2)] in IBC tumors has prompted trials of anti-EGFR/HER2 monoclonal antibodies to inhibit oncogenic signaling; however, de novo and acquired therapeutic resistance is common. Another critical function of these antibodies is to mediate antibody-dependent cellular cytotoxicity (ADCC), which enables immune effector cells to engage tumors and deliver granzymes, activating executioner caspases. We hypothesized that high expression of anti-apoptotic molecules in tumors would render them resistant to ADCC. Herein, we demonstrate that the most potent caspase inhibitor, X-linked inhibitor of apoptosis protein (XIAP), overexpressed in IBC, drives resistance to ADCC mediated by cetuximab (anti-EGFR) and trastuzumab (anti-HER2). Overexpression of XIAP in parental IBC cell lines enhances resistance to ADCC; conversely, targeted downregulation of XIAP in ADCC-resistant IBC cells renders them sensitive. As hypothesized, this ADCC resistance is in part a result of the ability of XIAP to inhibit caspase activity; however, we also unexpectedly found that resistance was dependent on XIAP-mediated, caspase-independent suppression of reactive oxygen species (ROS) accumulation, which otherwise occurs during ADCC. Transcriptome analysis supported these observations by revealing modulation of genes involved in immunosuppression and oxidative stress response in XIAP-overexpressing, ADCC-resistant cells. We conclude that XIAP is a critical modulator of ADCC responsiveness, operating through both caspase-dependent and -independent mechanisms. These results suggest that strategies targeting the effects of XIAP on caspase activation and ROS suppression have the potential to enhance the activity of monoclonal antibody-based immunotherapy.

Exploring a new transmission window for telecommunications in the 2 μm waveband

In this paper, we will demonstrate the possibility of opening a new telecommunications transmission window around the 2 μm wavelength, in order to exploit the potential low loss of hollow-core photonic bandgap fibers, with the benefits of significantly lower non-linearity and latency. We will show recent efforts developing a dense wavelength division multiplexing testbed at this waveband, with 100 GHz spacing wavelength channels and 105 Gbit/s total capacity achieved.

Amélioration des propriétés pharmacocinétiques de peptides par différentes alkylations N-terminales

Modélisations moléculaires réalisés avec le logiciel HyperChem 8.

Planktic foraminifera isotopes, temperature and d18O of seawater at the central Walvis Ridge for Termination II (MIS 6 to 5), sediment core 64PE-174P13

Salty and warm Indian Ocean waters enter the South Atlantic via the Agulhas leakage, south of Africa. Model simulations and proxy evidence of Agulhas leakage strengthening during glacial terminations led to the hypothesis that it was an important modulator of the Atlantic Ocean circulation. Yet, the fate of the leakage salinity and temperature anomalies remains undocumented beyond the southern tip of Africa. Downstream of the leakage, new paleoceanographic evidence from the central Walvis Ridge (southeast Atlantic) shows that salinity increased at the thermocline, and less so at the surface, during glacial termination II. Thermocline salinity change coincided with higher frequency of Agulhas rings passage at the core location and with salinity maxima in the Agulhas leakage area, suggesting that leakage waters were incorporated in the Atlantic circulation through the thermocline. Hydrographic changes at the Walvis Ridge and in the leakage area display a distinct two-step structure, with a reversal at ca. 134 ka. This matched a wet interlude within the East Asia weak monsoon interval of termination II, and a short-lived North Atlantic warming. Such concurrence points to a Bølling-Allerød-like recovery of the Atlantic circulation amidst termination II, with a northward shift of the Intertropical Convergence Zone and Southern Hemisphere westerlies, and attendant curtailment of the interocean connection south of Africa.

Joint Compensation of I/Q Impairments and PA Nonlinearity for Concurrent Dual-Band Transmitters using Two-Box Model

A novel two-box model for joint compensation of nonlinear distortion introduced from both in-phase/quadrature modulator and power amplifier is proposed for concurrent dual-band wireless transmitters. Compensation of nonlinear distortion is accomplished in two phases, where phases are identified separately. It is shown that complexity of the digital predistortion is reduced. The performance of the proposed model is evaluated in terms of ACPR, EVM and NMSE improvements using 1.4 MHz LTE and WCDMA signals.

Design, analysis and evaluation of sigma-delta based beamformers for medical ultrasound imaging applications

The inherent analogue nature of medical ultrasound signals in conjunction with the abundant merits provided by digital image acquisition, together with the increasing use of relatively simple front-end circuitries, have created considerable demand for single-bit  beamformers in digital ultrasound imaging systems. Furthermore, the increasing need to design lightweight ultrasound systems with low power consumption and low noise, provide ample justification for development and innovation in the use of single-bit  beamformers in ultrasound imaging systems. The overall aim of this research program is to investigate, establish, develop and confirm through a combination of theoretical analysis and detailed simulations, that utilize raw phantom data sets, suitable techniques for the design of simple-to-implement hardware efficient  digital ultrasound beamformers to address the requirements for 3D scanners with large channel counts, as well as portable and lightweight ultrasound scanners for point-of-care applications and intravascular imaging systems. In addition, the stability boundaries of higher-order High-Pass (HP) and Band-Pass (BP) Σ−Δ modulators for single- and dual- sinusoidal inputs are determined using quasi-linear modeling together with the describing-function method, to more accurately model the  modulator quantizer. The theoretical results are shown to be in good agreement with the simulation results for a variety of input amplitudes, bandwidths, and modulator orders. The proposed mathematical models of the quantizer will immensely help speed up the design of higher order HP and BP Σ−Δ modulators to be applicable for digital ultrasound beamformers. Finally, a user friendly design and performance evaluation tool for LP, BP and HP  modulators is developed. This toolbox, which uses various design methodologies and covers an assortment of  modulators topologies, is intended to accelerate the design process and evaluation of  modulators. This design tool is further developed to enable the design, analysis and evaluation of  beamformer structures including the noise analyses of the final B-scan images. Thus, this tool will allow researchers and practitioners to design and verify different reconstruction filters and analyze the results directly on the B-scan ultrasound images thereby saving considerable time and effort.

Design and implementation of generalized topologies of time-interleaved variable bandpass Σ−Δ modulators

In this thesis, novel analog-to-digital and digital-to-analog generalized time-interleaved variable bandpass sigma-delta modulators are designed, analysed, evaluated and implemented that are suitable for high performance data conversion for a broad-spectrum of applications. These generalized time-interleaved variable bandpass sigma-delta modulators can perform noise-shaping for any centre frequency from DC to Nyquist. The proposed topologies are well-suited for Butterworth, Chebyshev, inverse-Chebyshev and elliptical filters, where designers have the flexibility of specifying the centre frequency, bandwidth as well as the passband and stopband attenuation parameters. The application of the time-interleaving approach, in combination with these bandpass loop-filters, not only overcomes the limitations that are associated with conventional and mid-band resonator-based bandpass sigma-delta modulators, but also offers an elegant means to increase the conversion bandwidth, thereby relaxing the need to use faster or higher-order sigma-delta modulators. A step-by-step design technique has been developed for the design of time-interleaved variable bandpass sigma-delta modulators. Using this technique, an assortment of lower- and higher-order single- and multi-path generalized A/D variable bandpass sigma-delta modulators were designed, evaluated and compared in terms of their signal-to-noise ratios, hardware complexity, stability, tonality and sensitivity for ideal and non-ideal topologies. Extensive behavioural-level simulations verified that one of the proposed topologies not only used fewer coefficients but also exhibited greater robustness to non-idealties. Furthermore, second-, fourth- and sixth-order single- and multi-path digital variable bandpass digital sigma-delta modulators are designed using this technique. The mathematical modelling and evaluation of tones caused by the finite wordlengths of these digital multi-path sigmadelta modulators, when excited by sinusoidal input signals, are also derived from first principles and verified using simulation and experimental results. The fourth-order digital variable-band sigma-delta modulator topologies are implemented in VHDL and synthesized on Xilinx® SpartanTM-3 Development Kit using fixed-point arithmetic. Circuit outputs were taken via RS232 connection provided on the FPGA board and evaluated using MATLAB routines developed by the author. These routines included the decimation process as well. The experiments undertaken by the author further validated the design methodology presented in the work. In addition, a novel tunable and reconfigurable second-order variable bandpass sigma-delta modulator has been designed and evaluated at the behavioural-level. This topology offers a flexible set of choices for designers and can operate either in single- or dual-mode enabling multi-band implementations on a single digital variable bandpass sigma-delta modulator. This work is also supported by a novel user-friendly design and evaluation tool that has been developed in MATLAB/Simulink that can speed-up the design, evaluation and comparison of analog and digital single-stage and time-interleaved variable bandpass sigma-delta modulators. This tool enables the user to specify the conversion type, topology, loop-filter type, path number and oversampling ratio.

Two-Path All-pass Based Half-Band Infinite Impulse Response Decimation Filters and the Effects of Their Non-Linear Phase Response on ECG Signal Acquisition

This paper is based on the novel use of a very high fidelity decimation filter chain for Electrocardiogram (ECG) signal acquisition and data conversion. The multiplier-free and multi-stage structure of the proposed filters lower the power dissipation while minimizing the circuit area which are crucial design constraints to the wireless noninvasive wearable health monitoring products due to the scarce operational resources in their electronic implementation. The decimation ratio of the presented filter is 128, working in tandem with a 1-bit 3rd order Sigma Delta (ΣΔ) modulator which achieves 0.04 dB passband ripples and -74 dB stopband attenuation. The work reported here investigates the non-linear phase effects of the proposed decimation filters on the ECG signal by carrying out a comparative study after phase correction. It concludes that the enhanced phase linearity is not crucial for ECG acquisition and data conversion applications since the signal distortion of the acquired signal, due to phase non-linearity, is insignificant for both original and phase compensated filters. To the best of the authors’ knowledge, being free of signal distortion is essential as this might lead to misdiagnosis as stated in the state of the art. This article demonstrates that with their minimal power consumption and minimal signal distortion features, the proposed decimation filters can effectively be employed in biosignal data processing units.

Late-career international migration and reproductive work. A comparison between Peruvian and Ukrainian women in the Southern Europe

Research on the relationship between reproductive work and women´s life trajectories including the experience of labour migration has mainly focused on the case of relatively young mothers who leave behind, or later re-join, their children. While it is true that most women migrate at a younger age, there are a significant number of cases of men and women who move abroad for labour purposes at a more advanced stage, undertaking a late-career migration. This is still an under-estimated and under-researched sub-field that uncovers a varied range of issues, including the global organization of reproductive work and the employment of migrant women as domestic workers late in their lives. By pooling the findings of two qualitative studies, this article focuses on Peruvian and Ukrainian women who seek employment in Spain and Italy when they are well into their forties, or older. A commonality the two groups of women share is that, independently of their level of education and professional experience, more often than not they end up as domestic and care workers. The article initially discusses the reasons for late-career female migration, taking into consideration the structural and personal determinants that have affected Peruvian and Ukrainian women’s careers in their countries of origin and settlement. After this, the focus is set on the characteristics of domestic employment at later life, on the impact on their current lives, including the transnational family organization, and on future labour and retirement prospects. Apart from an evaluation of objective working and living conditions, we discuss women’s personal impressions of being domestic workers in the context of their occupational experiences and family commitments. In this regard, women report varying levels of personal and professional satisfaction, as well as different patterns of continuity-discontinuity in their work and family lives, and of optimism towards the future. Divergences could be, to some extent, explained by the effect of migrants´ transnational social practices and policies of states.

Migrant women’s employment in paid reproductive work through the crisis: the case of Italy (2007-2012)

Paid reproductive work, especially in the case of cleaning and home-care for elderly people, is an important sector for foreign women in Italy. For this reason, since the beginning of the current economic crisis, scholars have wondered about the impact of the recession on migrant domestic workers. They have looked particularly at possible competition with Italian women entering the sector for lack of better alternatives. Our paper takes this discussion a step further by assessing the overall changes affecting migrant women in the Italian labour market, 2007-2012. We will look at how their position has been transformed, by taking both an ethnic perspective, in relation to Italian women, and a gender perspective, in relation to migrant men. By way of a conclusion, the argument will be made that there is a substantial lack of competition between Italian and foreign women in the care and domestic sector due to differences in their earnings, hours of work and activities.

Raloxifene therapy does not affect uterine blood flow in postmenopausal women: a transvaginal Doppler study

AZEVEDO, George Dantas de et al. Raloxifene therapy does not affect uterine blood flow in postmenopausal women: a transvaginal Doppler study. Maturitas, Amsterdam, v.47, n.3, p.195-200, 2004

Isolation and Validation of Anti-B7-H4 scFvs from an Ovarian Cancer scFv Yeast-Display Library.

B7-H4 (VTCN1, B7x, B7s) is an inhibitory modulator of T-cell response implicated in antigen tolerization. As such, B7-H4 is an immune checkpoint of potential therapeutic interest. To generate anti-B7-H4 targeting reagents, we isolated antibodies by differential cell screening of a yeast-display library of recombinant antibodies (scFvs) derived from ovarian cancer patients and we screened for functional scFvs capable to interfere with B7-H4-mediated inhibition of antitumor responses. We found one antibody binding to B7-H4 that could restore antitumor T cell responses. This chapter gives an overview of the methods we developed to isolate a functional anti-B7-H4 antibody fragment.

Analisi e ottimizzazione del flusso di approvvigionamento in una produzione su commessa: il caso CT Pack S.r.l.

La tesi ha l'obiettivo di analizzare e ottimizzare i flussi di approvvigionamento in un'azienda che produce su commessa: CT Pack S.r.L, specializzata nella realizzazione di macchine automatiche per il packaging di biscotti, gelato e cioccolato. Per raggiungere l'obiettivo si è preso come riferimento il modello proposto dal BPR (Business Process Reengineering): sono stati analizzati i principali attori coinvolti, in particolare fornitori e magazzino, mediante l'uso di KPI definiti ad hoc. Sulla base di questi sono stati individuati due processi critici: il primo riguarda la gestione del magazzino, che presenta un'elevata quantità di codici non movimentati anche a causa del processo di gestione del materiale avanzato al termine di ciascuna commessa; il secondo riguarda il materiale a consumo, che impiega i magazzinieri per un tempo eccessivo, è caratterizzato da giacenze per il 30% non movimentate e da supermarket collocati in officina ridondanti e caratterizzati da bassi tassi di utilizzo (anche sotto il 50%). Per risolvere questi problemi ed effettuare una riprogettazione si fa affidamento agli strumenti proposti dal project management: si imposta quindi un progetto che ha l'obiettivo di ridurre nel breve periodo il valore di magazzino mediante lo smaltimento attraverso diverse vie di codici non utilizzati e agisce nel lungo periodo per evitare che le criticità si ripropongano. Mediante la riprogettazione della gestione dei resi di produzione si prevede un maggior controllo, grazie al lavoro congiunto di ufficio tecnico e ufficio acquisti. La nuova gestione del materiale a consumo ha in se alcune delle tecniche proposte dalla lean production (il kanban, per esempio) e integra il fornitore nella catena di approvvigionamento, garantendo un maggior controllo sulle quantità, un risparmio di circa 7 h/mese di lavoro per i magazzinieri e una riduzione delle giacenze del 46%.

Caracterização da fosfatase String/Cdc25 como um regulador da neurotoxicidade de Tau em Drosophila

As tauopatias, grupo onde se inclui a doença de Alzheimer (AD), são caracterizadas pela deposição intracelular de emaranhados neurofibrilares (NFTs), compostos principalmente por formas hiperfosforiladas da proteína Tau, uma proteína que se associa aos microtúbulos. Os mecanismos moleculares subjacentes à neurotoxicidade induzida por Tau não são ainda claros. Drosophila melanogaster tem sido usada para modelar diversas doenças neurodegenerativas humanas, incluindo as tauopatias. Neste trabalho foi usado o sistema visual de Drosophila como modelo para identificar os passos que podem levar à acumulação de Tau em Tauopatias. Durante o desenvolvimento do olho de Drosophila, a expressão ectópica de hTau induz um olho rugoso, em consequência da neurotoxicidade, e que pode ser utilizado para identificar modificadores do fenótipo. A fosfatase codificada por string /cdc25 (stg), um regulador universal da transição G2/M, foi previamente identificada como um supressor da neurotoxicidade associada à expressão da proteina Tau. No entanto, os mecanismos moleculares que estão na base desta interação genética nunca foram estudados, desconhecendo-se também se a atividade fosfatase de Stg/Cdc25 é essencial para modular os níveis de fosforilação de Tau. O objetivo deste projeto consistiu em elucidar os mecanismos que se encontram na base da interação Stg-Tau. Para alcançar este objectivo, usou-se uma abordagem genética e bioquímica. Os resultados obtidos sugerem que Stg é um possível modulador da neurotoxicidade de Tau.

Modulateurs intégrés sur silicium pour la transmission de signaux à modulation d'amplitude multi-niveau

Au cours des dernières années, la photonique intégrée sur silicium a progressé rapidement. Les modulateurs issus de cette technologie présentent des caractéristiques potentiellement intéressantes pour les systèmes de communication à courte portée. En effet, il est prévu que ces modulateurs pourront être opérés à des vitesses de transmission élevées, tout en limitant le coût de fabrication et la consommation de puissance. Parallèlement, la modulation d’amplitude multi-niveau (PAM) est prometteuse pour ce type de systèmes. Ainsi, ce travail porte sur le développement de modulateurs de silicium pour la transmission de signaux PAM. Dans le premier chapitre, les concepts théoriques nécessaires à la conception de modulateurs de silicium sont présentés. Les modulateurs Mach-Zehnder et les modulateurs à base de réseau de Bragg sont principalement abordés. De plus, les effets électro-optiques dans le silicium, la modulation PAM, les différents types d’électrodes intégrées et la compensation des distorsions par traitement du signal sont détaillés.Dans le deuxième chapitre, un modulateur Mach-Zehnder aux électrodes segmentées est présenté. La segmentation des électrodes permet la génération de signaux optiques PAM à partir de séquences binaires. Cette approche permet d’éliminer l’utilisation de convertisseur numérique-analogique en intégrant cette fonction dans le domaine optique, ce qui vise à réduire le coût du système de communication. Ce chapitre contient la description détaillée du modulateur, les résultats de caractérisation optique et de la caractérisation électrique, ainsi que les tests systèmes. De plus, les tests systèmes incluent l’utilisation de pré-compensation ou de post-compensation du signal sous la forme d’égalisation de la réponse en fréquence pour les formats de modulation PAM-4 et PAM-8 à différents taux binaires. Une vitesse de transmission de 30 Gb/s est démontrée dans les deux cas et ce malgré une limitation importante de la réponse en fréquence suite à l’ajout d’un assemblage des circuits radiofréquences (largeur de bande 3 dB de 8 GHz). Il s’agit de la première démonstration de modulation PAM-8 à l’aide d’un modulateur Mach-Zehnder aux électrodes segmentées. Finalement, les conclusions tirées de ce travail ont mené à la conception d’un deuxième modulateur Mach-Zehnder aux électrodes segmentées présentement en phase de test, dont les performances montrent un très grand potentiel. Dans le troisième chapitre, un modulateur à réseau de Bragg à deux sauts de phase est présenté. L’utilisation de réseaux de Bragg est une approche encore peu développée pour la modulation. En effet, la réponse spectrale de ces structures peut être contrôlée précisément, une caractéristique intéressante pour la conception de modulateurs. Dans ces travaux, nous proposons l’ajout de deux sauts de phase à un réseau de Bragg uniforme pour obtenir un pic de transmission dans la bande de réflexion de celui-ci. Ainsi, il est possible d’altérer l’amplitude du pic de transmission à l’aide d’une jonction pn. Comme pour le deuxième chapitre, ce chapitre inclut la description détaillée du modulateur, les résultats des caractérisations optique et électrique, ainsi que les tests systèmes. De plus, la caractérisation de jonctions pn à l’aide du modulateur à réseau de Bragg est expliquée. Des vitesses de transmission PAM-4 de 60 Gb/s et OOK de 55 Gb/s sont démontrées après la compensation des distorsions des signaux. À notre connaissance, il s’agit du modulateur à réseau de Bragg le plus rapide à ce jour. De plus, pour la première fois, les performances d’un tel modulateur s’approchent de celles des modulateurs de silicium les plus rapides utilisant des microrésonateurs en anneau ou des interféromètres Mach-Zehnder.