This study utilized paired tones at 1000 Hz with a 500 ms interpair interval and a 10 s interstimulus interval to assess sensory gating. Forty-two participants, ranging from 3-72 years of age were used to observe maturational changes in amplitude, latency, and suppression ratios of the P50 waveform. Previous research has shown that in normal adults the amplitude in response to the second of the paired tones is significantly suppressed compared to the amplitude in response to the first tone. The current study showed amplitude decreased with age to middle adulthood, where it increased slightly to later adulthood. Latencies decreased with age. Suppression ratios decreased from childhood to adolescence, with an increase from early adulthood to later adulthood. Sensory gating would appear to be a later developing aspect of human sensory physiology. Also similar to many other brain functions, sensory gating decreases in later adulthood.

Individuals diagnosed with autism spectrum disorder often experience difficulty during speech-in-noise (SIN) processing tasks. However, it remains unclear how behavioral and cortical mechanisms of auditory processing explain variability in SIN performance in adults with ASD and their neurotypical counterparts. The proposed research explored variability in SIN as it relates to behavioral, perceptual, and objective measures of auditory processing. Results showed significant differences between groups in SIN thresholds. In addition, neurotypicals outperformed the ASD group on measures of sustained auditory attention characterized by reduced impulsivity, increased inhibition, and increased selective auditory attention. Individuals with ASD showed decreased acceptance of noise as compared to neurotypical peers. Overall, results highlighted auditory processing deficits in individuals with ASD that contribute to SIN performance.

The unabated continuation of the Moore's law has allowed the doubling of the number of transistors per unit area of a silicon die every 2 years or so. At the same time, an increasing demand on consumer electronics and computing equipments to run sophisticated applications has led to an unprecedented complexity of hardware designs. These factors have necessitated the abstraction level of design-entry of hardware systems to be raised beyond the Register-Transfer-Level (RTL) to Electronic System Level (ESL). However, power envelope on the designs due to packaging and other thermal limitations, and the energy envelope due to battery life-time considerations have also created a need for power/energy efficient design. The confluence of these two technological issues has created an urgent need for solving two problems: (i) How do we enable a power-aware design flow with a design entry point at the Electronic System Level? (ii) How do we enable power aware High Level Synthesis to automatically synthesize RTL implementation from ESL? This dissertation distinguishes itself by addressing the following two issues: (i) Since power/energy consumption of electronic systems largely depends on implementation details, and high-level models abstract away from such details, power/energy estimation at such levels has not been addressed thoroughly. (ii) A lot of work has been done in applying various techniques on control-data-flow graphs (CDFG) to find power/area/latency pareto points during behavioral synthesis. However, high level C-based functional models of various compute-intensive components, which could be easily synthesized as co-processors, have many opportunities to reduce power. Some of these savings opportunities are traditional such as clock-gating, operand-isolation etc. The exploration of alternate granularities of these techniques with target applications in mind, opens the door for traditional power reduction opportunities at the high-level. This work therefore concentrates on the aforementioned two areas of inadequacy of hardware design methodologies. Our proposed solutions include utilizing ESL simulation traces and mapping those to lower abstraction levels for power estimation, derivation of statistical power models using regression based learning for power estimation at early design stages, etc. On the HLS front, techniques that insert the power saving features during the synthesis process using exploration of granularity and scope of clock-gating, sequential clock-gating are proposed. Finally, this work shows how to marry two domains, that is estimation and reduction. In this regard, a power model is proposed, which helps in predicting power savings obtained using clock-gating and further guiding HLS to selectively insert clock-gating. / Ph. D.

This thesis covers the individual work of Michael Chin as part of the sponsored research project funded by the U.S. State Department in support of a computational design of a "Mobile Pit Verification System" (MPVS), a mobile “drive by” passive radiation detection system to be applied in special nuclear materials (SNM) storage facilities for validation and compliance purposes. The MPVS system is intended to enable a comprehensive, rapid verification and validation of stored nuclear weapon core physics packages containing SNM, or so-called “weapon pits,” in weapon materials and stockpile storage facilities. The MPVS platform is designed to move at a constant speed and accumulate a signal for each stored weapon pit container. The gamma detector was selected to be a 4 × 4 × 8 cubic inch CsI detector while the neutron detector array designed for the “Transport Simulation and Validation of a Synthetic Aperture SNM Detection System (“T-SADS”) project was used in conjunction with this work; T-SADS was a 3 year project funded by DOE-NNSA which was completed on May 2013. The computational design effort for this project was completed in April 2013, and leveraged novel computational radiation transport methods, algorithms, and SNM identification methods, including a synthetic aperture collection approach, and a new gamma ratio methodology for distinguishing between naturally occurring radiation materials and weapon class SNM materials. Both forward and adjoint transport methods were utilized to characterize the adjoint reaction rate as a function of inter-source spacing, collimation thickness, linear and angular field of view, source age, source type, source geometry, and mobile platform speed. The integrated count was then compared with background radiation and the associated probabilities of detection and false alarm were then computed. Publications resulting from this research were published in PHYSOR 2012, presented at the 53rd annual Proceedings of the INMM, and at the Mathematics & Computation 2013 Conference.

Les canaux potassiques dépendants du voltage sont formés de quatre sous-unités, chacune possédant six segments transmembranaires (S1-S6) et une boucle (p-loop) qui se trouve entre le cinquième et le sixième segment au niveau du pore. Il est connu que le segment senseur du voltage (S1-S4) subit un mouvement lorsque le potentiel membranaire change. Pour ouvrir le canal, il est nécessaire de transférer l'énergie du senseur du voltage (généré par le mouvement des charges positives de S4) au pore. Le mécanisme exact de ce couplage électromécanique est encore sous étude. Un des points de liaison entre le senseur de voltage et le pore est le lien physique fait par le segment S4-S5 (S45L). Le but de cette étude est de déterminer l'influence de la flexibilité du segment S45L sur le processus de couplage. Dans le S45L, trois glycines sont distribuées dans des positions différentes. Elles sont responsables de la flexibilité des hélices-alpha. Ces glycines (mais pas leurs positions exactes) sont conservées pour tous les canaux potassiques dépendants de potentiel. En utilisant la technique de mutagènes dirigé, la glycine a été remplacée dans chacune de ces différentes positions par une alanine et dans une deuxième étape, par une proline (pour introduire un angle dans l'hélice). Pour étudier le comportement des canaux dans cette nouvelle conformation, on a appliqué la technique de « patch clamp » pour déterminer les effets lors de l'ouverture du pore (courant ionique). Avec le « cut-open oocyte voltage-clamp », nous avons étudié les effets sur le mouvement du senseur de voltage (courant “gating”) et la coordination temporelle avec l'ouverture du pore (courant ionique). Les données ont montré qu’en réduisant la flexibilité dans le S45L, il faut avoir plus d'énergie pour faire ouvrir le canal. Le changement pour une proline suggère que le mouvement du senseur est indépendant du pore pendant l'ouverture du canal. / Voltage-gated potassium channels are formed of four subunits, each one with six transmembrane segments (S1-S6) and a loop (p-loop) between S5 and S6 at the level of the pore. It is known that the voltage sensitive segment (S1-S4) undergoes a movement upon membrane potential changes. To open the channel, it is necessary to transfer the energy of the voltage sensor (generated by the displacement of the positive charges of S4) to the pore. The exact mechanism of this “electromechanical coupling” is still under investigation. The voltage sensor and pore are physically linked by the S4-S5 linker (S45L). The aim of this study is to determine the influence of S45L flexibility on the coupling process. In the S45L, three glycines are distributed at different positions and are responsible for the flexibility of the alpha-helix. These glycines (but not their exact position) are conserved within the potassium voltage-gated ion channels. The glycines were each replaced by an alanine using point mutagenesis. In a second step, a proline was introduced at the position in order to introduce a break in the helix. To study the behaviour of channels in this new conformation, we used the patch clamp technique to determine the effects during the pore opening (ionic current). With the cut-open voltage-clamp we determined the effects on voltage sensor movement (gating current) as well as the temporal correlation with the pore opening (ionic current). The data showed that when the flexibility of the S45L is reduced, the channel needs more energy to open. Exchange with proline suggests that the movement of the sensor is independent of pore opening.

Les canaux Ca2+ activés par le voltage (CaV) sont des protéines membranaires qui génèrent des courants Ca2+ dans les cellules excitables suite à une dépolarisation membranaire. Ces complexes oligomériques sont classifiés selon les propriétés structurelles de la sous-unité principale qui forme le pore du canal, soit la sous-unité CaVα1. La sous-unité auxiliaire CaVβ module l’expression membranaire et la dépendance au voltage du « gating » de la sous-unité CaVα1 des canaux HVA (« high-voltage-activated ») CaV1 et CaV2. La sous-unité CaVβ est formée par un domaine SH3 (« Src homology-3 ») connecté à un domaine GK (« guanylate kinase-like ») par le biais d’un domaine variable HOOK. Dans le but d’identifier les résidus dans la CaVβ3 qui sont responsables de la densité membranaire du CaV2.3, nous avons produit des mutants de la sous-unité auxiliaire le long de ses domaines fonctionnels. Cela dit, la délétion complète du domaine SH3 ainsi que la délétion du domaine HOOK n’ont pas modifié la densité membranaire de CaV2.3 ni ses propriétés d’activation. Cependant, la délétion de cinq résidus dans le domaine GK interrompt l’expression membranaire et l’expression fonctionnelle de CaV2.3. La mutation de résidus identifiés précédemment comme soutenant une affinité de liaison de l’ordre du nanomolaire dans le domaine GK de CaVβ n’a pas modifié de manière significative l’adressage membranaire de CaV2.3. Toutefois, les mutations de quatre résidus leucine dans les régions α3, α6, β10 et α9 du domaine GK ont grandement réduit l’adressage membranaire du canal CaV2.3. Nos résultats confirment que le domaine GK contient les déterminants moléculaires responsables de la fonction chaperone de CaVβ. Cela dit, l’adressage membranaire induit par CaVβ semble être déterminé par des éléments structuraux qui ne sont pas strictement dépendants d’une liaison à haute affinité de CaVβ sur CaVα1. / Voltage-activated Ca2+ channels (CaV) are membrane proteins that play a key role in promoting Ca2+ influx in response to membrane depolarization in excitable cells. They form oligomeric complexes that are classified according to the structural properties of the pore-forming CaVα1 subunit. Auxiliary CaVβ subunits modulate cell-surface expression and voltage-dependent gating of high-voltage-activated (HVA) CaV1 and CaV2 α1 subunits. CaVβ subunits are formed by a Src homology-3 (SH3) domain and a guanylate kinase-like (GK) domain connected through a variable HOOK-domain. In order to identify the residues responsible for the CaVβ3-induced membrane density of CaV2.3, we produced mutants along CaVβ3’s fonctionnal domains. Complete deletion of the SH3 domain as well as deletion of the HOOK domain did not alter plasma membrane targeting of CaV2.3 nor its typical activation gating. In contrast, 5-residue deletions in the GK domain disrupted cell surface trafficking and functional expression of CaV2.3. Mutations of residues known to carry nanomolar affinity binding in the GK domain of CaVβ did not significantly alter cell surface density. Mutations of a quartet of leucine residues in the α3, α6, β10, and α9 regions of the GK domain, each expected to curtail protein-protein interaction, were found to significantly impair cell surface targeting of CaV2.3 channels. Altogether, our results confirm that the GK domain includes the molecular determinants carrying the chaperone function of CaVβ. However, CaVβ-induced cell surface targeting appears to be determined by structural elements that are not strictly dominated by high-affinity binding of CaVβ onto CaVα1.

Štěpána Boukalová Mechanisms of activation and modulation of vanilloid TRP channels TRPV1 and TRPV3 are thermosensitive ion channels from the vanilloid subfamily of TRP receptors. TRPV1, which is primarily expressed in nociceptive sensory neurons, is an important transducer of painful stimuli and is also involved in the detection of noxious heat. TRPV3 is expressed mainly in the skin where it regulates proliferation and differentiation of keratinocytes. Similarly to voltage-dependent potassium (Kv) channels, TRP receptors are comprised of four subunits, each with six transmembrane segments (S1-S6). Using mutational approach, we tried to elucidate the role of S1 in TRPV1 functioning. Our results indicate that the extracellular portion of S1 plays a crucial role in TRPV1 gating. TRPV1 channels with a conservative mutation of positively charged residue in this region (R455K substitution) were overactive. However, they were neither activated nor potentiated by low pH; on the contrary, protons stabilized the closed conformation of this mutant channel. Very similar phenotypic properties were found in other TRPV1 mutants with substitution in S4/S5-S5 region and in the pore helix. In Kv channels, extracelular portion of S1 forms a small contact surface with the pore helix, which allows efficient transmission of...

L'objectif de cette thèse est d’étudier temporellement des phénomènes évolutifs à l'aide de la tomographie d'émission monophotonique (TEMP). La première partie de cette thèse traite le problème du mouvement respiratoire dans les images TEMP de souris. Nous présentons ici une méthode permettant de détecter ce mouvement respiratoire dans les images TEMP 4D, d'extraire un signal respiratoire intrinsèque, et de déterminer la phase du cycle respiratoire sans mouvement la plus large possible. Les données enregistrées durant ces phases sans mouvement sont alors utilisées pour reconstruire une seule image TEMP 3D sans artefact de mouvement par acquisition. Les images ainsi reconstruites présentent un bon compromis en terme de statistiques et de précision des mesures par rapport aux images TEMP 3D de base et TEMP 4D. Dans la deuxième partie, nous étudions la cinétique d'incorporation de l'iode dans l'estomac de souris à partir d'images TEMP 4D. Afin de comprendre le rôle biologique de cette accumulation dans l'estomac, nous avons modélisé le phénomène par une approche d'analyse compartimentale avec un modèle simplifiée à deux compartiments (paroi et cavité stomacale) et une entrée (sang). Les courbes temps-activité (TAC) de chaque compartiment sont déduites des observations et une première estimation des paramètres a été obtenue. / The aim of this thesis is to investigate temporally evolving phenomena with the use of single photon emission computed tomography (SPECT).The first part of this thesis addresses the problem of respiratory motion in SPECT images of mice. The presented method permits us to detect the respiratory motion in 4D SPECT images, to extract an intrinsic respiratory signal and to determine the widest possible phase of the respiratory cycle without movement. The data recorded during these motionless phases are then used to reconstruct a single 3D SPECT image without motion artefacts per acquisition. Reconstructed motionless SPECT images present a good compromise in terms of statistics and accuracy of the measurements with respect to basic 3D SPECT and 4D SPECT images. In the second part, we study the iodide uptake kinetics in the stomach 99mTc-pertechnetate biodistribution with the of mice through the study of use of 4D SPECT images. To understand the biological role of the iodide accumulation in the stomach, we modelled the phenomenon with a compartmental analysis approach using a simplified two-compartment (stomach wall and cavity) model with one input (blood). Time activity curves (TAC) of each compartment are deduced from observations and a first estimation of the parameters was obtained.

Ankyrin receptor TRPA1 is an ion channel widely expressed on primary afferent sensory neurons, where it acts as a polymodal sensor of nociceptive stimuli. Apart from pungent chemicals (e. g. isothiocyanates, cinnamaldehyde and its derivatives, acrolein, menthol), it could be activated by cold temperatures, depolarizing voltages or intracellular calcium ions. TRPA1 channel is a homotetramer in which each subunit consists of cytoplasmic N and C termini and a transmembrane region. The transmembrane part is organized into six alpha- helices connected by intra- and extracellular loops. The N terminus comprises a tandem set of 16 to 17 ankyrin repeats (AR), while the C terminus has a substantially shorter, dominantly helical structure. In 2015, a partial cryo-EM structure of TRPA1 was resolved; however, the functional roles of the individual regions of the receptor have not yet been fully understood. This doctoral thesis is concerned to elucidate the role of highly conserved sequence and structural motifs within the cytoplasmic termini and the S4-S5 region of TRPA1 in voltage- and chemical sensitivity of the receptor. The probable binding site for calcium ions that are the most important physiological modulators of TRPA1 was described by using homology modeling, molecular-dynamics simulations,...

La chambre réverbérante à brassage de modes (CRBM) est une cavité métallique fermée surdimensionnée, équipée d’un brasseur de modes. Le brassage de modes rend le champ électromagnétique homogène et isotrope à l’intérieur de la CRBM (dans son volume utile). Cette thèse illustre tout d’abord une nouvelle méthode pour évaluer les performances d’un brasseur de modes (via le spectre Doppler). Ensuite, elle présente une nouvelle méthode permettant de mesurer la surface équivalente radar (SER) d’un objet canonique en utilisant la technique de fenêtrage temporel ou time-gating. Enfin, elle présente une nouvelle méthode permettant de mesurer le diagramme de rayonnement d’une antenne dans une cavité surdimensionnée via la technique de time-gating. / The reverberation chamber (RC) is an oversized closed metal cavity, equipped with a mode-stirrer. The mode stirring makes the electromagnetic field homogeneous and isotropic inside the RC (in its useful volume). This thesis illustrates firstly a new method for evaluating the performance of a mode-stirrer (via the Doppler spectrum). Then, it presents a new method for measuring the radar cross section (RCS) of a canonical object using the time-gating technique. Finally, it presents a new method for measuring the antenna radiation pattern in an oversized cavity via the time-gating technique.