Ion channels are fundamental to the functioning of life, regulating processes as diverse as neural signaling, homeostasis, and environmental sensing, across the complexities of life from bacteria to the most advanced organisms. Among this vast diversity of ion channels, cyclic-nucleotide gated (CNG) channels hold particular significance and play a pivotal role in the sensory transduction across a variety of species. They transduce chemical signals into electrical signals, linking the external environment and our sensory perceptions. CNG channels were discovered almost 40 years ago and much knowledge has been gained on their physiological roles, biophysical properties, molecular characteristics, and channelopathies. However, the structural details of these channels remained elusive for a long time, mainly due to the lack of a full-length channel structure. It was only recently that atomic-resolution structures of full-length CNG channels became available, and structures of native mammalian CNG channels were only determined within the last two years. In my thesis, I use single particle cryogenic electron microscopy (cryo-EM) to determine the structures of native human cone CNGA3/CNGB3 channel in different biochemical environments and in different states, spanning the full spectrum of channel activation by its natural ligand cGMP. In addition, I use cryo-EM, electrophysiology, calcium imaging, and other biochemical techniques to characterize both wild-type and disease-associated mutant (DAM) CNG channels. Collectively, my thesis work contributes to a deeper understanding of the structural determinants of CNG channel properties, provides a detailed dissection of the CNG channel gating mechanism, demonstrates a potential CNG channel pathogenic mechanism, and calls for an interdisciplinary reevaluation of CNG channel DAMs.

Ion channels are fundamental and essential molecular machineries located in the membranes of diverse organelles, crucial for maintaining normal cellular function in response to various stimuli. The TRP channel family, discovered in the late 1980s, has been extensively studied for its structures and functions. TRP channels are involved in a broad spectrum of sensory processes such as temperature sensation, touch, pain, and osmolarity regulation. Given their role in sensing diverse stimuli, TRP channels play numerous physiological and pathological roles and have emerged as valuable therapeutic targets for various diseases. As a subfamily of the TRP channel superfamily, TRPML channels also fulfill various physiological functions. Among the TRPML channel subfamilies, TRPML1 and TRPML3 have been identified due to their association with human and mouse disease phenotypes, highlighting their crucial roles in maintaining cellular function and contributing to disease progression when dysfunctional. TRPML1 is extensively studied, likely due to its direct link to human diseases. In contrast, TRPML2 has not been extensively studied because it is not implicated in any disease phenotype. While they are expected to share specific biophysical properties and functions, recent research has increasingly focused on uncovering the unique and essential physiological roles of TRPML2. Studies have revealed its involvement as an osmo/mechanosensitive channel in the immune system and its structure in its apo state. However, further research is needed to fully understand the molecular mechanisms and broader physiological functions of TRPML2. In my thesis, I employ single-particle cryogenic electron microscopy (cryo-EM) to elucidate the structures of human and mouse TRPML2 in the presence of natural and synthetic agonists. These structures highlight distinctive structural characteristics of TRPML2 compared to other TRPML channels and suggest a cooperative and non-canonical activation mechanism involving multiple agonists under experimental conditions. Additionally, electrophysiology experiments were conducted to explore the relationship between the structure and function of human TRPML2. Overall, my thesis work contributes to uncovering unique structural elements and presents the first open-state structure of TRPML2. Furthermore, it offers insights into how TRPML2 interacts with ligands and is activated through a novel activation mechanism.

The objective of the proposed work is to study the behavior of SiGe HBTs at cryogenic temperatures and its relation to device scaling and optimization. Not only is cryogenic operation of these devices required by space missions, but characterizing their cryogenic behavior also helps to investigate the performance limits of SiGe HBTs and provides essential information for further device scaling. Technology computer aided design (TCAD) and sophisticated on-wafer DC and RF measurements are essential in this research. Drift-diffusion (DD) theory is used to investigate a novel negative differential resistance (NDR) effect and a collector current kink effect in first-generation SiGe HBTs at deep cryogenic temperatures. A theory of positive feedback due to the enhanced heterojunction barrier effect at deep cryogenic temperatures is proposed to explain such effects. Intricate design of the germanium and base doping profiles can greatly suppress both carrier freezeout and the heterojunction barrier effect, leading to a significant improvement in the DC and RF performance for NASA lunar missions. Furthermore, cooling is used as a tuning knob to better understand the performance limits of SiGe HBTs. The consequences of cooling SiGe HBTs are in many ways similar to those of combined vertical and lateral device scaling. A case study of low-temperature DC and RF performance of prototype fourth-generation SiGe HBTs is presented. This study summarizes the performance of all three prototypes of these fourth-generation SiGe HBTs within the temperature range of 4.5 to 300 K. Temperature dependence of a fourth-generation SiGe CML gate delay is also examined, leading to record performance of Si-based IC. This work helps to analyze the key optimization issues associated with device scaling to terahertz speeds at room temperature. As an alternative method, an fT -doubler technique is presented as an attempt to reach half-terahertz speeds. In addition, a roadmap for terahertz device scaling is given, and the potential relevant physics associated with future device scaling are examined. Subsequently, a novel superjunction collector design is proposed for higher breakdown voltages. Hydrodynamic models are used for the TCAD studies that complete this part of the work. Finally, Monte Carlo simulations are explored in the analysis of aggressively-scaled SiGe HBTs.

As Si-manufacturing compatible SiGe HBTs are making rapid in-roads into RF through mm-wave circuit applications, with performance levels steadily marching upward, the use of these devices under extreme environment conditions are being studied extensively. In this work, test structures of SiGe HBTs were designed and put into extremely low temperatures, and a new negative differential resistance effect and a novel collector current kink effect are investigated in the cryogenically-operated SiGe HBTs. Theory based on an enhanced positive feedback mechanism associated with heterojunction barrier effect at deep cryogenic temperatures is proposed. The accumulated charge induced by the barrier effect acts at low temperatures to enhance the total collector current, indirectly producing both phenomena. This theory is confirmed using calibrated 2-D DESSIS simulations over temperature. These unique cryogenic effects also have significant impact on the ac performance of SiGe HBTs operating at high-injection. Technology evolution plays an important role in determining the magnitude of the observed phenomena, and the scaling implications are addressed. Circuit implication is discussed.

This work investigates the challenges associated with designing silicon-germanium (SiGe) analog and mixed-signal circuits capable of operating reliably in extreme environment conditions. Three extreme environment operational conditions, namely, operation over an extremely wide temperature range, operation at extremely low temperatures, and operation under radiation exposure, are considered. As a representative for critical analog building blocks, bandgap voltage reference (BGR) circuit is chosen. Several architectures of the BGRs are implemented in two SiGe BiCMOS technology platforms. The effects of wide-temperature operation, deep cryogenic operation, and proton and x-ray irradiation on the performance of BGRs are investigated. The impact of Ge profile shape on BGR's wide-temperature performance is also addressed. Single-event transient response of the BGR circuit is studied through microbeam experiments. In addition, proton radiation response of high-voltage transistors, implemented in a low-voltage SiGe platform, is investigated. A platform consisting of a high-speed comparator, digital-to-analog (DAC) converter, and a high-speed flash analog-to-digital (ADC) converter is designed to facilitate the evaluation of the extreme environment capabilities of SiGe data converters. Room temperature measurement results are presented and predictions on how temperature and radiation will impact their key electrical properties are provided.

This work represents several years' research into the field of radiation hardening by design. The unique characteristics of a SiGe HBT, described in Chapter 1, make it ideally suitable for use in extreme environment applications. Chapter 2 describes the total ionizing dose effects experienced by a SiGe HBT, particularly those experienced on an Earth-orbital or lunar-surface mission. In addition, the effects of total dose are evaluated on passive devices. As opposed to the TID-hardness of SiGe transistors, a clear vulnerability to single-event effects does exist. This field is divided into three chapters. First, the very nature of single-event transients present in SiGe HBTs is explored in Chapter 3 using a heavy-ion microbeam with both bulk and SOI platforms [31]. Then, in Chapter 4, a new device-level SEU-hardening technique is presented along with circuit-design techniques necessarily for its implementation. In Chapter 5, the circuit-level radiation-hardening techniques necessarily to mitigate the effects shown in Chapter 3 are developed and tested [32]. Finally, in Chapter 6, the performance of the SiGe HBT in a cryogenic testing environment is characterized to understand how the widely-varying temperatures of outer space may affect device performance. Ultimately, the built-in performance, TID-tolerance, and now-developing SEU-hardness of the SiGe HBT make a compelling case for extreme environment electronics. The low-cost, high-yield, and maturity of Si manufacturing combine with modern bandgap engineering and modern CMOS to produce a high-quality, high-performance BiCMOS platform suitable for space-borne systems.

Les transistors ayant un faible niveau de bruit à basse fréquence, une faible puissance de dissipation et fonctionnant à basse température (≤ 4.2 K) sont actuellement inexistants alors qu’ils sont très demandés pour la réalisation de préamplificateurs à installer au plus près des détecteurs ou des dispositifs à la température de quelques dizaines de mK, dans le domaine de l’astrophysique, de la physique mésoscopique et de l’électronique spatiale. Une recherche menée depuis de nombreuses années au LPN vise à réaliser une nouvelle génération de HEMTs (High Electron Mobility Transistors) cryogéniques à haute performance pour répondre à ces demandes. Cette thèse, dans le cadre d’une collaboration entre le CNRS/LPN et le CEA/IRFU, a pour but la réalisation de préamplificateurs cryogéniques pour des microcalorimètres à 50 mK.Les travaux de cette thèse consistent en des caractérisations systématiques des paramètres électriques et des bruits des HEMTs (fabriqués au LPN) à basse température. En se basant sur les résultats expérimentaux, l’une des sources de bruit à basse fréquence dans les HEMTs a pu être identifiée, c’est-à-dire la part du courant tunnel séquentiel dans le courant de fuite de grille. Grâce à ce résultat, les hétérostructures ont été optimisées pour minimiser le courant de fuite de grille ainsi que le niveau de bruit à basse fréquence. Au cours de cette thèse, différentes méthodes spécifiques ont été développées pour mesurer de très faibles valeurs de courant de fuite de grille, les capacités du transistor et le bruit 1/f du transistor avec une très haute impédance d’entrée. Deux relations expérimentales ont été observées, l’une sur le bruit 1/f et l’autre sur le bruit blanc dans ces HEMTs à 4.2 K. Des avancées notables ont été réalisées, à titre d’indication, les HEMTs avec une capacité de grille de 92 pF et une consommation de 100 µW peuvent atteindre un niveau de bruit en tension de 6.3 nV/√Hz à 1 Hz, un niveau de bruit blanc de 0.2 nV/√Hz et un niveau de bruit en courant de 50 aA/√Hz à 10 Hz. Enfin, une série de 400 HEMTs, qui répondent pleinement aux spécifications demandées pour la réalisation de préamplificateurs au CEA/IRFU, a été réalisée. Les résultats de cette thèse constitueront une base solide pour une meilleure compréhension du bruit 1/f et du bruit blanc dans les HEMTs cryogéniques afin de les améliorer pour les diverses applications envisagées. / Transistors with low noise level at low frequency, low-power dissipation and operating at low temperature (≤ 4.2 K) are currently non-existent, however, they are widely required for realizing cryogenic preamplifiers which can be installed close to sensors or devices at a temperature of few tens of mK, in astrophysics, mesoscopic physics and space electronics. Research conducted over many years at LPN aims to a new generation of high-performance cryogenic HEMTs (High Electron Mobility Transistors) to meet these needs. This thesis, through the collaboration between the CNRS/LPN and the CEA/IRFU, aims for the realization of cryogenic preamplifiers for microcalorimeters at 50 mK.The work of this thesis consists of systematic characterizations of electrical and noise parameters of the HEMTs (fabricated at LPN) at low temperatures. Based on the experimental results, one of the low-frequency-noise sources in the HEMTs has been identified, i.e., the sequential tunneling part in the gate leakage current. Thanks to this result, heterostructures have been optimized to minimize the gate leakage current and the low frequency noise. During this thesis, specific methods have been developed to measure very low-gate-leakage-current values, transistor’s capacitances and the 1/f noise with a very high input impedance. Two experimental relationships have been observed, one for the 1/f noise and other for the white noise in these HEMTs at 4.2 K. Significant advances have been made, for information, the HEMTs with a gate capacitance of 92 pF and a consumption of 100 µW can reach a noise voltage of 6.3 nV/√ Hz at 1 Hz, a white noise voltage of 0.2 nV/√ Hz, and a noise current of 50 aA/√Hz at 10 Hz. Finally, a series of 400 HEMTs has been realized which fully meet the specifications required for realizing preamplifiers at CEA/IRFU. The results of this thesis will provide a solid base for a better understanding of 1/f noise and white noise in cryogenic HEMTs with the objective to improve them for various considered applications.