Добірка наукової літератури з теми "Modulateur bimodal"

Abstract Cochlear implant (CI) users have more difficulty understanding speech in temporally modulated noise than in steady-state (SS) noise. This is thought to be caused by the limited low-frequency information that CIs provide, as well as by the envelope coding in CIs that discards the temporal fine structure (TFS). Contralateral amplification with a hearing aid, referred to as bimodal hearing, can potentially provide CI users with TFS cues to complement the envelope cues provided by the CI signal. In this study, we investigated whether the use of a CI alone provides access to only envelope cues and whether acoustic amplification can provide additional access to TFS cues. To this end, we evaluated speech recognition in bimodal listeners, using SS noise and two amplitude-modulated noise types, namely babble noise and amplitude-modulated steady-state (AMSS) noise. We hypothesized that speech recognition in noise depends on the envelope of the noise, but not on its TFS when listening with a CI. Secondly, we hypothesized that the amount of benefit gained by the addition of a contralateral hearing aid depends on both the envelope and TFS of the noise. The two amplitude-modulated noise types decreased speech recognition more effectively than SS noise. Against expectations, however, we found that babble noise decreased speech recognition more effectively than AMSS noise in the CI-only condition. Therefore, we rejected our hypothesis that TFS is not available to CI users. In line with expectations, we found that the bimodal benefit was highest in babble noise. However, there was no significant difference between the bimodal benefit obtained in SS and AMSS noise. Our results suggest that a CI alone can provide TFS cues and that bimodal benefits in noise depend on TFS, but not on the envelope of the noise.

Abstract The serotonin molecule plays a multifunctional role in mammalian homeostasis serving as a neurotransmitter in the central nervous system, a gut-derived mediator of peristalsis, and a circulating hormone that regulates appetite, cardiovascular function, and hemostasis. Recent evidence from the clinic and the bench highlight an unexpected target for serotonin action, the skeleton. Clinically, two classes of drugs, the second generation antipsychotic drugs (SGAs) and selective serotonin reuptake inhibitors (SSRIs), which modulate central and peripheral serotonin signaling, have been shown to alter bone remodeling although the mechanism is not clear. In contrast, genetically engineered mouse models have demonstrated a bimodal control system whereby gut-derived serotonin under the control of the Wnt/Lrp/β-catenin system acts systemically to suppress bone formation, whereas CNS serotonin activated by leptin modulates sympathetic outflow to the skeleton. In this brief review, we will summarize recent findings linking serotonin to the skeleton and discuss future directions for this new but challenging aspect of this multidimensional molecule.

The serotonin molecule plays a multifunctional role in mammalian homeostasis serving as a neurotransmitter in the central nervous system, a gut-derived mediator of peristalsis, and a circulating hormone that regulates appetite, cardiovascular function, and hemostasis. Recent evidence from the clinic and the bench highlight an unexpected target for serotonin action, the skeleton. Clinically, two classes of drugs, the second generation antipsychotic drugs (SGAs) and selective serotonin reuptake inhibitors (SSRIs), which modulate central and peripheral serotonin signaling, have been shown to alter bone remodeling although the mechanism is not clear. In contrast, genetically engineered mouse models have demonstrated a bimodal control system whereby gut-derived serotonin under the control of the Wnt/Lrp/β-catenin system acts systemically to suppress bone formation, whereas CNS serotonin activated by leptin modulates sympathetic outflow to the skeleton. In this brief review, we will summarize recent findings linking serotonin to the skeleton and discuss future directions for this new but challenging aspect of this multidimensional molecule.

Purpose The objective of the study was to investigate the influence of noise (energetic) and speech (energetic plus informational) maskers on the head shadow (HS), squelch (SQ), and binaural summation (SU) effect in bilateral and bimodal cochlear implant (CI) users. Method Speech recognition was measured in the presence of either a competing talker or modulated speech-shaped noise in 10 bimodal and 10 bilateral adult CI users. HS, SQ, and SU effects were calculated. The interfering signals were manipulated with respect to F0 to consider the influence of different speaker voices. Results The effects HS, SQ, and SU differed depending on the type of masker. A detailed analysis of errors was used to dissociate energetic and informational masking effects. The analysis showed a release from energetic than from informational masking. Conclusion Noise interferers are not sufficient to reflect difficulties experienced with speech understanding in noise for bilateral and bimodal CI users.

Historically, the study of multisensory processing has examined the function of the definitive neuron type, the bimodal neuron. These neurons are excited by inputs from more than one sensory modality, and when multisensory stimuli are present, they can integrate their responses in a predictable manner. However, recent studies have revealed that multisensory processing in the cortex is not restricted to bimodal neurons. The present investigation sought to examine the potential for multisensory processing in nonbimodal (unimodal) neurons in the retinotopically organized posterolateral lateral suprasylvian (PLLS) area of the cat. Standard extracellular recordings were used to measure responses of all neurons encountered to both separate- and combined-modality stimulation. Whereas bimodal neurons behaved as predicted, the surprising result was that 16% of unimodal visual neurons encountered were significantly facilitated by auditory stimuli. Because these unimodal visual neurons did not respond to an auditory stimulus presented alone but had their visual responses modulated by concurrent auditory stimulation, they represent a new form of multisensory neuron: the subthreshold multisensory neuron. These data also demonstrate that bimodal neurons can no longer be regarded as the exclusive basis for multisensory processing.

La kallikréine humaine 6 (hK6) ou neurosine est la protéase à sérine la plus abondante du système nerveux central (SNC). Sa dualité de fonction dans les processus neurodégénératifs font d’elle une cible privilégiée pour la conception de modulateurs pharmacologiques de son activité. Cependant, il existe aujourd’hui très peu de composés répondant à cette attente. Aussi, le principal objectif de ces travaux de thèse a consisté à identifier des inhibiteurs et activateurs organiques de faible poids moléculaire (<500 Da) de la hK6, compatibles avec un développement clinique. L’étude de la hK6 sous ses différents aspects a permis d’établir son profil catalytique et dynamique et de mettre en évidence son rôle anti-agrégatif de l’α-synucléine endogène. L’exploration de diverses chimiothèques regroupant près de 1 200 molécules a permis d’identifier des molécules touches (hits) qui ont fait l’objet d’études mécanistiques approfondies. Des évaluations par modélisation moléculaire ont également été réalisées afin d’établir les bases structurales de la modulation et un profil de sélectivité de ces molécules vis-à-vis d’autres protéases à sérine concurrentes a pu être établi. Pour la première fois, un modulateur bimodal ainsi qu’un activateur, tous deux hautement sélectifs de la hK6, ont été identifiés et un modèle de régulation allostérique a pu être proposé. Plusieurs inhibiteurs originaux possédant un bon profil de sélectivité vis-à-vis de la hK6 ont également été sélectionnés. Ces molécules ne présentent pas d’effet cytotoxique sur des cultures primaires de neurones. Les composés identifiés au cours de cette thèse constituent ainsi une excellente base pour le développement d’agents pharmacologiques à visée neuroprotectrice et anti-inflammatoire et ouvre la voie à l’exploration de nouveaux sites allostériques au sein de cette enzyme et des protéases à sérine tryptiques
The human kallikrein 6 (hK6) or neurosin is the most abundant serine protease of the central nervous system (CNS). Its dual implication in neurodegenerative processes makes it an emerging target for the design of pharmacological modulators of its activity. Yet today there are only very few compounds that meet this expectation. Thus, the main aim of these thesis was to identify organic low molecular weight (<500 Da) inhibitors and activators of hK6 compatible with clinical development. The study ofhK6 through various aspects has established its catalytic and dynamic profile and highlights its anti-aggregative role of endogenous α-synuclein. Exploring the diverse libraries comprising nearly 1 200molecules led to the identification of key compounds (hits) that have been subjected to extensive mechanistic studies. Assessments by molecular modeling were also carried out to establish the structural basis for activity modulation and selectivity profiling toward competing serine proteases has also been established. For the first time, a bimodal modulator as well as an activator, both highly selective to hK6, were identified and an allosteric regulatory model was proposed. Several original inhibitors having a good selectivity profile toward hK6 were also selected. Furthermore, these molecules do not exhibit any cytotoxic effect on primary neuronal cultures. The compounds identified in this thesis provide an excellent basis for the development of pharmacological agents with neuroprotective and anti-inflammatory properties and pave the way for the exploration of new allosteric sites in hK6 and tryptic serine proteases in general

Small cantilevers with ultra-high resonant frequencies (1–3 MHz) have paved the way for high-speed atomic force microscopy. However, their potential for multi-frequency atomic force microscopy is unexplored. Because small cantilevers have small spring constants but large resonant frequencies, they are well-suited for the characterisation of delicate specimens with high imaging rates. We demonstrate their imaging capabilities in a bimodal frequency modulation mode in constant excitation on semi-crystalline polypropylene. The first two flexural modes of the cantilever were simultaneously excited. The detected frequency shift of the first eigenmode was held constant for topographical feedback, whereas the second eigenmode frequency shift was used to map the local properties of the specimen. High-resolution images were acquired depicting crystalline lamellae of approximately 12 nm in width. Additionally, dynamic force curves revealed that the contrast originated from different interaction forces between the tip and the distinct polymer regions. The technique uses gentle forces during scanning and quantified the elastic moduli Eam = 300 MPa and Ecr = 600 MPa on amorphous and crystalline regions, respectively. Thus, multimode measurements with small cantilevers allow one to map material properties on the nanoscale at high resolutions and increase the force sensitivity compared with standard cantilevers
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Multifrequency Atomic Force Microscopy (AFM) techniques, where the cantilever oscillation is measured and sometimes driven at multiple frequencies, have become an active research topic in recent years. This is in part because these methods can provide increased compositional contrast during surface characterization. Since 2004 bimodal AFM imaging has been used extensively to complement the information that can be obtained using the standard single-frequency tapping-mode operation. More recently we have implemented a trimodal tapping-mode scheme, in which we have incorporated a frequency-modulated third eigenmode into bimodal tapping-mode operation in order to acquire topography, phase and frequency shift information simultaneously. We have also studied numerically the effect of different levels of sample stiffness, tip-sample dissipative forces, oscillation amplitudes for each of the eigenmodes and cantilever rest positions above the sample on the frequency response of the higher eigenmodes in bimodal and trimodal operations. Here we explore the ability to separate conservative and dissipative effects using the different channels available in trimodal operation.

Semiconductor and magnetic nanoparticles hold unique optical and magnetic properties, and great promise for bio-imaging and therapeutic applications. As part of their stable synthesis, the nanocrystal surfaces are usually capped by long chain organic moieties such as trioctylphosphine oxide. This capping serves two purposes: it saturates dangling bonds at the exposed crystalline lattice, and it prevents irreversible aggregation by stabilizing the colloid through entropic repulsion. These nanocrystals can be rendered water-soluble by either ligand exchange or overcoating, which hampers their widespread use in biological imaging and biomedical therapeutics. Here, we report a novel scheme of synthesizing fluorescent PbS and magnetic Fe3O4 nanoparticles using DNA oligonucleotides. Our method of PbS synthesis includes addition of Na2S to the mixture solution of DNA sequence and Pb acetate (at a fixed molar ratio of DNA/S2−/Pb2+ of 1:2:4) in a standard TAE buffer at room temperature in the open air. In the case of Fe3O4 particle synthesis, ferric and ferrous chloride were mixed with DNA in DI water at a molar ratio of DNA/Fe2+/Fe3+ = 1:4:8 and the particles were formed via reductive precipitation, induced by increasing pH to ∼11 with addition of ammonium hydroxide. These nanocrystals are highly stable and water-soluble immediately after the synthesis, due to DNA termination. We examined the surface chemistry between oligonucleotides and nanocrystals using FTIR spectroscopy, and found that the different chemical moieties of nucleobases passivate the particle surface. Strong coordination of primary amine and carbonyl groups provides the chemical and colloidal stabilities, leading to high particle yields (Figure 1). The resulting PbS nanocrystals have a distribution of 3–6 nm in diameter, while a broader size distribution is observed with Fe3O4 nanoparticles as shown in Figure 1b and c, respectively. A similar observation was reported with the pH change-induced Fe3O4 particles of a bimodal size distribution where superparamagnetic and ferrimagnetic magnetites co-exist. In spite of the differences, FTIR measurements suggest that the chemical nature of the oligonucleotide stabilization in this case is identical to the PbS system. As a particular application, we demonstrate that aptamer-capped PbS QD can detect a target protein based on selective charge transfer, since the oligonucleotide-templated synthesis can also serve the additional purpose of providing selective binding to a molecular target. Here, we use thrombin and a thrombin-binding aptamer as a model system. These QD have diameters of 3∼6 nm and fluoresce around 1050 nm. We find that a DNA aptamer can passivate near IR fluorescent PbS nanocrystals, rendering them water-soluble and stable against aggregation, and retain the secondary conformation needed to selectively bind to its target, thrombin, as shown in Figure 2. Importantly, we find that when the aptamer-functionalized nanoparticles binds to its target (only the target), there is a highly systematic and selective quenching of the PL, even in high concentrations of interfering proteins as shown in Figure 3a and b. Thrombin is detected within one minute with a detection limit of ∼1 nM. This PL quenching is attributed to charge transfer from functional groups on the protein to the nanocrystals. A charge transfer can suppress optical transition mechanisms as we observe a significant decrease in QD absorption with target addition (Figure 3c). Here, we rule out other possibilities including Forster resonance energy transfer (FRET) and particle aggregation, because thrombin absorb only in the UV, and we did not observe any significant change in the diffusion coefficient of the particles with the target analyte, respectively. The charge transfer-induced photobleaching of QD and carbon nanotubes was observed with amine groups, Ru-based complexes, and azobenzene compounds. This selective detection of an unlabeled protein is distinct from previously reported schemes utilizing electrochemistry, absorption, and FRET. In this scheme, the target detection by a unique, direct PL transduction is observed even in the presence of high background concentrations of interfering negatively or positively charged proteins. This mechanism is the first to selectively modulate the QD PL directly, enabling new types of label free assays and detection schemes. This direct optical transduction is possible due to oligonucleotidetemplated surface passivation and molecular recognition. This chemistry may lead to more nanoparticle-based optical and magnetic probes that can be activated in a highly chemoselective manner.