A citocinese bacteriana é controlada por diversas proteínas que se agrupam em um complexo chamado divisomo. O cerne do divisomo é constituído por FtsZ, uma proteína homóloga à tubulina eucariótica, que se auto-associa formando uma estrutura chamada anel Z. O anel Z serve como arcabouço e recruta diversas outras proteínas componentes do divisomo para o sítio onde o septo será sintetizado na célula. A formação do anel Z é modulada por proteínas que se ligam diretamente a FtsZ e regulam a sua auto-associação, tanto induzindo como inibindo a sua polimerização. Apesar de muitos destes moduladores de FtsZ já serem conhecidos, muito pouco se sabe sobre o mecanismo pelo qual eles controlam a estruturação do anel Z in vivo. O objetivo do presente trabalho foi estudar a interação entre FtsZ e um modulador de divisão, a proteína ZapA, da bactéria gram-positiva Bacillus subtilis. Para isso construímos uma biblioteca de mutantes de ftsZ por \"Error Prone PCR\", com aproximadamente 1 substituição por cópia de ftsZ e contendo um total de 1x105 clones. A partir dessa biblioteca, utilizamos duas triagens genéticas para identificar mutantes incapazes de interagir com ZapA. Na primeira estratégia, selecionamos 12 mutantes de FtsZ resistentes à superexpressão de uma forma tóxica de ZapA, que bloqueia a divisão, causando filamentação e morte das células. Surpreendentemente, apesar destes mutantes serem insensíveis ao efeito de ZapA, ensaios citológicos mostraram que nenhum deles perdeu a interação com ZapA. Como as mutações foram mapeadas nas vizinhanças do sítio catalítico e de polimerização de FtsZ, e como a maioria delas confere resistência cruzada aos efeitos de outros moduladores de FtsZ, suspeitamos que elas afetassem a estabilidade do polímero de FtsZ e, consequentemente, o comportamento do anel Z. Essas suspeitas foram confirmadas em ensaios de FRAP e cálculos de proporção de FtsZ no anel Z, indicando que os mutantes formam um anel Z mais estável que o normal. Como não obtivemos mutantes que perderam a interação com ZapA na primeira triagem, aplicamos a biblioteca em uma segunda estratégia de triagem genética, procurando um mutante de FtsZ que voltasse a interagir com um mutante de ZapA que não se liga mais a FtsZ (ZapAN62A). Esta estratégia de ganho de função identificou um candidato, FtsZE91V , que, tanto por critérios genéticos como citológicos, voltou a interagir com ZapAN62A. Apesar do mutante FtsZE91V mostrar-se capaz de restaurar a interação com ZapAN62A, ele não afetou a interação com ZapA selvagem, segundo nossos ensaios de microscopia de fluorescência e viabilidade. O mutante FtsZE91V, mapeia na hélice H3 de FtsZ. Esta hélice está exposta na superfície de FtsZ (compõe um dos lados da molécula de FtsZ) de uma maneira compatível com a idéia de que ela seria importante para interações laterais entre polímeros de FtsZ. Nossos resultados apontam, portanto, que a hélice H3 deve ser o sítio de interação para ZapA em FtsZ. / The bacterial cytokinesis is ruled by a number of proteins that constitute the divisome complex. FtsZ, a homologue of eukaryotic tubulin, is the main component of the divisome and self-associates in a structure named Z ring. The Z ring works as a scaffold and recruits the other components of divisome, establishing itself where the septum will be synthesized in the cell. Some of these proteins interact directly with FtsZ and control self-association, promoting polymerization or preventing it. Although there have been discovered many of FtsZ modulators, little is known about the mechanisms that control the formation of the Z ring in vivo. The aim of this work was study de interaction between FtsZ e one of its division modulators, ZapA protein, on Bacillus subtilis grampositive bacteria. We created a mutagenized ftsZ plasmid library by error prone PCR, which contained 1,0x105 transformants and exhibited a mutation rate of one substitution per ftsZ copy. The library was transformed into a modified Bacillus subtilis strain and we performed two genetic screenings to select cells with FtsZ mutants incapable of interacting with ZapA. In first strategy, we selected 12 resistant ftsZ mutants for a toxic ZapA overexpression, that blocked division and caused filamentation and cell death. Surprisingly, although these mutants were insensitive to ZapA effect, cytological assays showed that none of them lost interaction with ZapA. As the substitutions were mapped around the catalytic and interaction site of FtsZ structure and showed resistance to other modulators, we suspected that the mutations were affecting the polymer stability of FtsZ and, consequently, the behavior of Z ring. This hypothesis was confirmed by FRAP experiments and by calculations of FtsZ proportions in Z ring, pointing out that the mutants form more stable Z rings. As we didnt\' find mutants that lost their ZapA´s interaction, we applied our library in a second genetic screen, looking for mutants that return to interact with a ZapA mutant (ZapAN62A) that doesn´t bind to FtsZ anymore. This gain of function strategy identified one candidate, FtsZE91V, which returns to interact with ZapAN62A in our genetic and cytological assays. Although the mutant FtsZE91V showed itself capable to interact with ZapAN62A, that didn´t affect the interaction with wild type ZapA by our fluorescent microscopy and viability assays. The substitution E91V was mapped on H3 helix of FtsZ structure. This helix is exposed on FtsZ surfaces (on FtsZ´s lateral side), being compatible with the idea that lateral interaction is important in FtsZ polymers. So, we concluded that helix H3 is the binding site of ZapA in FtsZ.

Este trabalho descreve o projeto de um modulador Analógico-Digital (A/D) Sigma-Delta de 16 bits (98 dB de SNR) de baixo consumo em tecnologia CMOS para a aquisição de sinais de áudio. Para projetar o modulador foi utilizada a metodologia top down, a qual consiste em projetar desde o nível de sistema até os blocos básicos em nível de transistores. O sistema foi analizado e projetado utilizando equacões e modelos comportamentais para obter as especificações de cada bloco do modulador. Considerando um baixo consumo de potência foi escolhida a topologia CIFF (do inglês Chain of Integrator with FeedForward) de terceira ordem e quatro bits implementado com capacitores chaveados. O modulador projetado é composto por três integradores chaveados, um somador analógico, um weigthed DAC e um quantizador de quatro bits. A técnica de Chopper é incluida no modulador para diminuir o ruído Flicker na entrada do modulador. Os blocos de maior consumo dentro do modulador são as OTAs. Por esta razão eles são projetados utilizando a metodologia gm/ID reduzindo assim o consumo de potência. O projeto foi realizado na tecnologia IBM 0,18 \'mü\'m sendo utilizado o simulador spectre do Cadence. O modulador Sigma-Delta atinge um SNR de 98 dB para uma banda de 20 kHz e um consumo de potência de 2,4 mW para uma fonte de alimentação de 1,8 V. / This work describes the design of a 16 bits low power Sigma-Delta modulator (98 dB SNR) in a CMOS technology for the acquisition of audio signals. To design the modulator it was used the top-down methodology, which consists on the design from system level to the transistor-level basic blocks. The system was analyzed and designed using behavioral models and equations to obtain the specifications of each block of the modulator. Considering a low power consumption it was chosen a third-order four bits CIFF topology (Chain Integrator with feedforward) implemented with switched capacitors. The modulator is composed by three integrators, one analog adder, one weigthed DAC and one four bit quantizer. The Chopper technique is included in the modulator to reduce the Flicker noise at the input of the modulator. The blocks of higher consumption within the modulator are the OTAs. Hence, they was designed using the methodology gm/ID to reduce power consumption. It was designed on the 0.18 \'mü\'m IBM technology and using the Cadence Spectre simulator. The Sigma-Delta modulator achieves a SNR of 98 dB for a bandwidth of 20 kHz and a power consumption of 2.4 mW with a 1.8 V power supply.

Continuous-time (CT) Delta-Sigma Modulators (DSMs) have re-gained popularity recently for oversampling analog-to-digital conversion, because they are more suitable for low supply voltage implementation than their discrete-time (DT) counterparts, among other reasons. To the state of art at the low voltage front, a CT O.5-V audio-band DSM with a return-to-open feedback digital-to-analog converter has been reported. However, the O.5-V CT DSM has a limited performance of 74-dB SNDR due to clock jitters and other factors caused by the ultralow supply. / Finally, a O.5-V 2-1 cascaded CT DSM with SCR feedback is proposed. A new synthesis method is presented. Transistor-level simulations show that a 98dB SNDR is achieved over a 25-kHz signal bandwidth with a 6.4MHz sampling frequency and 350muW power consumption under a 0.5-V supply. / In this thesis, three novel ULV audio-band CT DSMs with high signal-to-noise-plus-distortion ratio (SNDR) are reported for a nominal supply of O.5V. The first one firstly realizes a switched-capacitor-resistor (SCR) feedback at O.5V, enabled by a fast amplifier at O.5V, for reduced clock jitter-sensitivity. Fabricated in a O.13mum CMOS process using only standard VT devices, the 3rd order modulator with distributed feedback occupies an active area of O.8mm2 . It achieves a measured SNDR of 81.2dB over a 25-kHz signal bandwidth while consuming 625muW at O.5-V. The measured modulator performance is consistent across a supply voltage range from O.5V to O.8V and a temperature range from -20°C to 90°C. Measurement results and thermal-noise calculation show that the peak SNDR is limited by thermal noise. / The scaling of the feature sizes of CMOS technologies results in a continuous reduction of supply voltage (VDD) to maintain reliability and to reduce the power dissipation per unit area for increasingly denser digital integrated circuits. The VDD for low-power digital circuits is predicted to drop to O.5V in about ten years. Ultra-low voltage (ULV) operation will also be required for the analog-to-digital converter, a universal functional block in mixed-signal integrated circuits, in situations where the benefits of using a single VDD out-weigh the overhead associated with multi-V DD solutions. / The second ULV CT DSM employs a feed-forward loop topology with SCR feedback. Designed in O.13mum CMOS process, the modulator achieves a post-layout simulation (thermal noise included) result of 89dB SNDR over a 25-kHz signal bandwidth. The 0.13mum CMOS chip consumes an active area of O.85mm2 and 682.5muW at O.5-V supply. It achieves an excellent measured performance of 87.8dB SNDR over a 25-kHz signal bandwidth and al02dB spurious-free dynamic range. To the best of our knowledge, this performance is the highest for DSMs in this supply voltage range. Thanks to the proposed adaptive biasing technique, the measured modulator performance is consistent across a supply voltage range from O.4V to O.75V and a temperature range from -20°C to 90°C. / Chen, Yan. / Adviser: Kong Pang Pun. / Source: Dissertation Abstracts International, Volume: 73-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 127-135). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

O trabalho de doutorado teve como objetivo desenvolver um modulador óptico baseado em filme magnetostrictivo para aplicação como magnetômetro. A modelagem e simulação do dispositivo foi realizada utilizando software com cálculo por método dos elementos finitos (MEF) e teve como finalidade auxiliar iterativamente os processos de projeto e fabricação do modulador. A originalidade da proposta baseia-se na construção de um guia de onda em óptica integrada recoberto por um filme magnetostrictivo para permitir a modulação , via efeito elasto-óptico, da onda guiada pela aplicação de campos magnéticos externos. O campo magnético aplicado provoca a deformação o material magnetostrictivo que induz uma modificação no perfil de esforço aplicado ao substrato. O substrato tem suas propriedades ópticas alteradas devido ao efeito elasto-óptico, o que provoca mudanças nas propriedades da luz transmitida. O trabalho tem seu início com o estudo e a caracterização de filmes magnetostrictivos de Tb25F275 e Tb23Co77 depositados por sputtering sobre substratos de silício. Uma técnica para preparação das amostras e medição da magnetostricção foi estabelecida e os coeficientes de magnetostrição dos filmes foram determinados a partir das medições diretas dos deslocamentos das amostras, em função dos campos magnéticos aplicados, utilizando a técnica de Atomic Force Microscopy (AFM). Os resultados experimentais obtidos permitiram a realização de simulações por MEF para verificação dos modos de guiamento da luz gerados pelo perfil de esforços induzidos termicamente no processo de deposição do filme magnetostrictivo sobre substrato de B12GeO4 (BGO). Foi modelado e simulado também o efeito da aplicação do campo magnético sobre o guia óptico obtido inicialmente pelo efeito de esforço térmico. No resultado das simulações foi possível verificar as alterações do índice de refração efetivo e da intensidade óptica do modo guiado em função de campos magnéticos aplicados ao modulador. Ao final do trabalho realizaram-se a fabricação de alguns protótipos. Os resultados das caracterizações dos moduladores construídos permitirão, no futuro, ajustar os modelos de simulação elaborados. / The doctoral work aims are the development and simulation of an optical modulator based on the effect of magnetostriction for application as magnetometer. The multiphysics simulations were performed using the Finite Elements Method (FEM). In the manufacturing process of optical modulator integrated optics techniques were applied. The originality of the proposal is based on the construction of an integrated optical waveguide covered by a magnetostrictive film to allow the modulation of the guided wave, through the elasto-optical effect, by the application of external magnetic fields. The applied magnetic field causes deformation of the magnetostrictive material that induces a modification of the stress profile produced in substrate. The substrate has its optical properties altered due to the elasto-optical effect, which causes changes in the properties of transmitted light. The work begins with the study and characterization of TbFe and TbCo2 magnetostrictive films deposited by sputtering on silicon substrates. A method for sample preparation and measurement of magnetostriction was established. The magnetostrictive coefficient of the films was determined from the direct measurement of displacements of samples by AFM technique for magnetic fields applied. The experimental results obtained allowed to perform MEF simulations to verify the light guided modes generated by the profile of thermally induced stress created by deposition process of magnetostrictive film on B12GeO4 (BGO) substrate. It was also modeled and simulated the effect of the application of magnetic field on the optical guide obtained initially by the effect of thermal stress. In simulation results, it was possible to verify the changes of effective refractive index and optical intensity of guided modes as functions of magnetic fields applied to the modulator. At the end of the work, some prototypes were fabricated. The results of characterizations of the built modulators will allow, in the future, adjustments in simulation models.

abstract: This dissertation proposes and presents two different passive sigma-delta modulator zoom Analog to Digital Converter (ADC) architectures. The first ADC is fullydifferential, synthesizable zoom-ADC architecture with a passive loop filter for lowfrequency Built in Self-Test (BIST) applications. The detailed ADC architecture and a step by step process designing the zoom-ADC along with a synthesis tool that can target various design specifications are presented. The design flow does not rely on extensive knowledge of an experienced ADC designer. Two example set of BIST ADCs have been synthesized with different performance requirements in 65nm CMOS process. The first ADC achieves 90.4dB Signal to Noise Ratio (SNR) in 512µs measurement time and consumes 17µW power. Another example achieves 78.2dB SNR in 31.25µs measurement time and consumes 63µW power. The second ADC architecture is a multi-mode, dynamically zooming passive sigma-delta modulator. The architecture is based on a 5b interpolating flash ADC as the zooming unit, and a passive discrete time sigma delta modulator as the fine conversion unit. The proposed ADC provides an Oversampling Ratio (OSR)- independent, dynamic zooming technique, employing an interpolating zooming front-end. The modulator covers between 0.1 MHz and 10 MHz signal bandwidth which makes it suitable for cellular applications including 4G radio systems. By reconfiguring the OSR, bias current, and component parameters, optimal power consumption can be achieved for every mode. The ADC is implemented in 0.13 µm CMOS technology and it achieves an SNDR of 82.2/77.1/74.2/68 dB for 0.1/1.92/5/10MHz bandwidth with 1.3/5.7/9.6/11.9mW power consumption from a 1.2 V supply. / Dissertation/Thesis / Doctoral Dissertation Electrical Engineering 2018

La maladie de Parkinson (MP) est une maladie neurodégénérative chronique qui apparait en moyenne à partir 55 ans. Sa cause reste inconnue mais son apparition et son développement sont corrélés avec la perte progressive des neurones dopaminergique de la substance noire qui innervent les ganglions de la base (GB). Jusqu'à ce jour le traitement le plus efficace est basé sur la compensation du déficit en dopamine (DA) par l'administration de son précurseur, la L-DOPA, qui est métabolisé en DA. Ce traitement améliore les symptômes moteurs de la maladie et donc la qualité de vie des patients. Néanmoins, après une certaine période des effets secondaires invalidants apparaissent, en particulier des fluctuations motrices et des mouvements anormaux involontaires appelés dyskinésies. De plus, ce traitement n'apporte pas de réponse à la progression de la dégénérescence et donc de la maladie. C'est pour ces raisons que la communauté scientifique est à la recherche d'une thérapie pharmacologique alternative à la L-DOPA, ou du moins visant à minimiser ses effets indésirables. Dans ce contexte, les récepteurs métabotropiques du glutamate, en particulier mGluR4, semblent constituer une cible privilégiée. En effet, mGluR4 est situé à des synapses des GB supposées hyperactives dans la MP, et son activation par des moyens pharmacologiques pourrait donc rétablir une activité normale grâce à son action inhibitrice sur la libération de neurotransmetteur. Nos résultats démontrent le bien-fondé de cette hypothèse sur le plan fonctionnel, en utilisant un nouvel agoniste allostérique spécifique de mGluR4, Lu AF21934. / Parkinson's disease (PD) is a progressive neurodegenerative disorder that appears around 55 years of age. The causes of PD remain unknown but its appearance and progression are correlated with the progressive loss of dopaminergic neurons of substantia nigra pars compacta innervating the basal ganglia (BG). Up to date, the most efficient treatment is based on restoring a normal level of dopamine (DA) in the brain by the administration of L-DOPA, a DA precursor that is metabolized to DA. However, at long term, L-DOPA treatment induces some side-effects, in particular the highly disabling L-DOPA-induced dyskinesia (LID). For this reason, the scientific community is searching for a pharmacological treatment alternative to L-DOPA and/or minimizing LID. In this context, metabotropic glutamate receptors, in particular mGluR4, are targets of interest. mGlu4 are localized at presynaptic terminals within BG circuitry that become hyperactive in PD. For this reason, mGluR4 has been considered a key strategic target for non-dopaminergic pharmacological treatments aimed at modulating these synapses, due to its ability to reduce neurotransmitter release. Herein we provide physiological and functional support to this hypothesis using Lu AF21934, a novel selective and brain-penetrant mGluR4 positive allosteric modulator (PAM). By in vitro electrophysiological recordings we demonstrate that Lu AF21934 inhibits corticostriatal synaptic transmission. In rats rendered parkinsonian, Lu AF21934 combined with sub-threshold doses of L-DOPA acted synergistically in alleviating akinesia in a dose-dependent manner and, notably, also reduced the incidence of LID.

Graduation date: 1996

Advances in electronic systems have lead to the demand for high resolution, high bandwidth Analog-to-Digital Converters (ADCs). Oversampled ADCs are well- known for high accuracy applications since they benefit from noise shaping and they usually do not need highly accurate components. However, as a consequence of oversampling, they have limited signal bandwidth. The signal bandwidth (BW) of oversampled ADCs can be increased either by increasing the sampling rate or reducing the oversampling ratio (OSR). Reducing OSR is a more promising method for increasing the BW, since the sampling speed is usually limited by the technology. The advantageous properties (e.g. low in-band quantization, relaxed accuracy requirements of components) of oversampled ADCs are usually diminished at lower OSRs and preserving these properties requires complicated and power hungry architectures. In this thesis, different combinations of delta-sigma and pipelined ADCs are explored and new techniques for designing oversampled ADCs are proposed. A Hybrid Delta-Sigma/Pipelined (HDSP) ADC is presented. This ADC uses a pipelined ADC as the quantizer of a single-loop delta-sigma modulator and benefits from the aggressive quantization of the pipelined quantizer at low OSRs. A Noise-Shaped Pipelined ADC is proposed which exploits a delta-sigma modulator as the sub-ADC of a pipeline stage to reduce the sensitivity to the analog imperfection. Three prototype ADCs were fabricated in 0.18μm CMOS technology to verify the effectiveness of the proposed techniques. The performance of these architectures is among the best reported for high bandwidth oversampled ADCs. / Graduation date: 2011

The quest for multi-standard and software-defined radio (SDR) receivers calls for high flexibility in the receiver building-blocks so that to accommodate several wireless services using a single receiver chain in mobile handsets. A potential approach to achieve flexibility in the receiver is to move the analog-to-digital converter (ADC) closer to the antenna so that to exploit the enormous advances in digital signal processing, in terms of technology scaling, speed, and programmability. In this context, continuous-time (CT) delta-sigma (ΔƩ) ADCs show up as an attractive option. CT ΔƩ ADCs have gained significant attention in wideband receivers, owing to their amenability to operate at a higher-speed with lower power consumption compared to discrete-time (DT) implementations, inherent anti-aliasing, and robustness to sampling errors in the loop quantizer. However, as the ADC moves closer to the antenna, several blockers and interferers are present at the ADC input. Thus, it is important to investigate the sensitivities of CT ΔƩ ADCs to out-of-band (OOB) blockers and find the design considerations and solutions needed to maintain the performance of CT ΔƩ modulators in presence of OOB blockers. Also, CT ΔƩ modulators suffer from a critical limitation due to their high sensitivity to the clock-jitter in the feedback digital-to-analog converter (DAC) sampling-clock. In this context, the research work presented in this thesis is divided into two main parts. First, the effects of OOB blockers on the performance of CT ΔƩ modulators are investigated and analyzed through a detailed study. A potential solution is proposed to alleviate the effect of noise folding caused by intermodulation between OOB blockers and shaped quantization noise at the modulator input stage through current-mode integration. Second, a novel DAC solution that achieves tolerance to pulse-width jitter by spectrally shaping the jitter induced errors is presented. This jitter-tolerant DAC doesn’t add extra requirements on the slew-rate or the gain-bandwidth product of the loop filter amplifiers. The proposed DAC was implemented in a 90nm CMOS prototype chip and provided a measured attenuation for in-band jitter induced noise by 26.7dB and in-band DAC noise by 5dB, compared to conventional current-steering DAC, and consumes 719µwatts from 1.3V supply.

The research investigates several critical design issues of continuous-time (CT) [Sigma Delta] modulators. The first is to investigate the sensitivity of CT [Sigma Delta] modulators to high-frequency clock spurs. These spurs down-convert the high-frequency quantization noise, degrading the dynamic range of the modulator. The second is to study the robustness of continuous-time loop filters under large RC product variations. Large RC variations in the CMOS process strongly degrade the performance of continuous-time [Sigma Delta] modulators, and reduce the production yield. The third is to model the harmonic distortion of one-bit continuous-time [Sigma Delta] modulators due to the interaction between the first integrator and the feedback digital-to-analog converter (DAC). A closed-form expression of the 3'rd-order harmonic distortion is derived and verified. Conventional CT [Sigma Delta] modulators employ all active integrators: each integrator needs an active amplifier. The research proposes a 5th-order continuous-time [Sigma Delta] modulator with a hybrid active-passive loop filter consisting of only three amplifiers. The passive integrators save power, and introduce no distortion. The active integrators provide gain and minimize internal noise contributions. A single-bit switched-capacitor DAC is employed as the main feedback DAC for high clock jitter immunity. An additional current steering DAC stabilizes the loop with the advantage of simplicity. To verify the proposed techniques, a prototype continuous-time [Sigma Delta] modulator with 2-MHz signal bandwidth is designed in a 0.25-¹m CMOS technology targeting for GPS or WCDMA applications. The experimental results show that the prototype modulator achieves 68-dB dynamic range over 2-MHz bandwidth with a 150-MHz clock, consuming 1.8 mA from a 1.5-V supply.