411 research outputs found

    Biophysical modeling of a cochlear implant system: progress on closed-loop design using a novel patient-specific evaluation platform

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    The modern cochlear implant is one of the most successful neural stimulation devices, which partially mimics the workings of the auditory periphery. In the last few decades it has created a paradigm shift in hearing restoration of the deaf population, which has led to more than 324,000 cochlear implant users today. Despite its great success there is great disparity in patient outcomes without clear understanding of the aetiology of this variance in implant performance. Furthermore speech recognition in adverse conditions or music appreciation is still not attainable with today's commercial technology. This motivates the research for the next generation of cochlear implants that takes advantage of recent developments in electronics, neuroscience, nanotechnology, micro-mechanics, polymer chemistry and molecular biology to deliver high fidelity sound. The main difficulties in determining the root of the problem in the cases where the cochlear implant does not perform well are two fold: first there is not a clear paradigm on how the electrical stimulation is perceived as sound by the brain, and second there is limited understanding on the plasticity effects, or learning, of the brain in response to electrical stimulation. These significant knowledge limitations impede the design of novel cochlear implant technologies, as the technical specifications that can lead to better performing implants remain undefined. The motivation of the work presented in this thesis is to compare and contrast the cochlear implant neural stimulation with the operation of the physiological healthy auditory periphery up to the level of the auditory nerve. As such design of novel cochlear implant systems can become feasible by gaining insight on the question `how well does a specific cochlear implant system approximate the healthy auditory periphery?' circumventing the necessity of complete understanding of the brain's comprehension of patterned electrical stimulation delivered from a generic cochlear implant device. A computational model, termed Digital Cochlea Stimulation and Evaluation Tool (‘DiCoStET’) has been developed to provide an objective estimate of cochlear implant performance based on neuronal activation measures, such as vector strength and average activation. A patient-specific cochlea 3D geometry is generated using a model derived by a single anatomical measurement from a patient, using non-invasive high resolution computed tomography (HRCT), and anatomically invariant human metrics and relations. Human measurements of the neuron route within the inner ear enable an innervation pattern to be modelled which joins the space from the organ of Corti to the spiral ganglion subsequently descending into the auditory nerve bundle. An electrode is inserted in the cochlea at a depth that is determined by the user of the tool. The geometric relation between the stimulation sites on the electrode and the spiral ganglion are used to estimate an activating function that will be unique for the specific patient's cochlear shape and electrode placement. This `transfer function', so to speak, between electrode and spiral ganglion serves as a `digital patient' for validating novel cochlear implant systems. The novel computational tool is intended for use by bioengineers, surgeons, audiologists and neuroscientists alike. In addition to ‘DiCoStET’ a second computational model is presented in this thesis aiming at enhancing the understanding of the physiological mechanisms of hearing, specifically the workings of the auditory synapse. The purpose of this model is to provide insight on the sound encoding mechanisms of the synapse. A hypothetical mechanism is suggested in the release of neurotransmitter vesicles that permits the auditory synapse to encode temporal patterns of sound separately from sound intensity. DiCoStET was used to examine the performance of two different types of filters used for spectral analysis in the cochlear implant system, the Gammatone type filter and the Butterworth type filter. The model outputs suggest that the Gammatone type filter performs better than the Butterworth type filter. Furthermore two stimulation strategies, the Continuous Interleaved Stimulation (CIS) and Asynchronous Interleaved Stimulation (AIS) have been compared. The estimated neuronal stimulation spatiotemporal patterns for each strategy suggest that the overall stimulation pattern is not greatly affected by the temporal sequence change. However the finer detail of neuronal activation is different between the two strategies, and when compared to healthy neuronal activation patterns the conjecture is made that the sequential stimulation of CIS hinders the transmission of sound fine structure information to the brain. The effect of the two models developed is the feasibility of collaborative work emanating from various disciplines; especially electrical engineering, auditory physiology and neuroscience for the development of novel cochlear implant systems. This is achieved by using the concept of a `digital patient' whose artificial neuronal activation is compared to a healthy scenario in a computationally efficient manner to allow practical simulation times.Open Acces

    Lead identification and structure-activity relationships of heteroarylpyrazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists

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    A knowledge-based library of aryl 2,3-dichlorophenylsulfonamides was synthesised and screened as human CCR4 antagonists, in order to identify a suitable hit for the start of a lead-optimisation programme. X-ray diffraction studies were used to identify the pyrazole ring as a moiety that could bring about intramolecular hydrogen bonding with the sulfonamide NH and provide a clip or orthogonal conformation that was believed to be the preferred active conformation. Replacement of the core phenyl ring with a pyridine, and replacement of the 2,3-dichlorobenzenesulfonamide with 5- chlorothiophenesulfonamide provided compound 33 which has excellent physicochemical properties and represents a good starting point for a lead optimisation programme. Electronic structure calculations indicated that the preference for the clip or orthogonal conformation found in the small molecule crystal structures of 7 and 14 was in agreement with the order of potency in the biological assay

    Women’s Political Capabilities as Mediators of Leadership and People Satisfaction

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    Despite a much lower proportion than men, in both business and politics, a 2018 Pew Research Center survey shows that majorities in the U.S.A. say women leaders in comparison to men are more compassionate and empathetic in working out compromises and in standing up for their beliefs. Via the resource-based view tool, the researchers examine these specific capabilities (i.e., political proposals that benefit society, humanitarian causes, and political ideas) of U.S. women politicians and men politicians, while separately attempting to validate public perceptions of leadership. Using correlation analysis, the study tests the effect of each capability on leadership and people satisfaction. Data were collected from 80 U.S. politicians (40 women and 40 men) from State and Local Governments. The survey took place between 2 October and 5 December 2017. The results show that “women politicians’ ability to build humanitarian political proposals” has a statistically significant strong positive impact on “leadership”, while “women politicians’ ability to build political proposals to benefit society” has a statistically significant strong positive impact on “people satisfaction”. Putting the gender equality argument aside, the study suggests that women, in any case, deserve much more than a “one in four” political participation, even if only in the name of collective decision-making for the common good. Thus, it is important for more women voters to be actively involved and participate in politics and political decision-making in the context of democratic governments and elected politicians. Managerial implications and academic guidance are provided for future research

    Oxazoline Promoted Rh-Catalyzed C-H Amidation of Benzene Derivatives with Sulfonamides and Trifluoroacetamide. A Comparative Study.

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    A Rh-catalyzed ortho-amidation of 2-aryloxazolines offers an efficient and direct route to a range of sulfonamides. The scope of the reaction is very broad with respect to sulfonamide substrate, but the position and electronic nature of the substituents on the aryl moiety of the oxazoline lead to a surprising modulation of reactivity. The reactivity of sulfonamides in comparison to trifluoroacetamide is compared, the latter undergoing Rh-catalyzed amidation more rapidly

    The Thomistic Perception of the Person and Human Rights

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    The idea of human rights is connected to the modern perception of law founded on subjectivity, in the context of which rights are authorizations of individual action versus a higher authority, resulting in a subjectivity of law. The huge importance of the thomistic perception of the person is connected with the issue of relations between the individual and society, as well as relations between law and state, since Thomas Aquinas foresaw what we call ‘rights of man’. Thus, the person, in a metaphysical context, is associated with natural order, since natural sociability forms the basis of a person’s supernatural fulfillment. Because of his social nature, the person is also a carrier of social relations and a product of his own encounter with other persons. In this way, Thomas Aquinas makes a synthesis of man per se, as part of mankind, and man as a person vis-à-vis others in the sphere of justice, consisting ‘in rendering to each one his right’. Ius is a relation of justice concerning what is right (iustum) from the point of view of the other, “to whom something is due.” Aquinas can be considered a forerunner of human rights of the modern era, as demonstrated by the issue of natural equity, the issue of unjust law and obedience and the issue of political legitimization. In this framework, “human” or “natural” rights are considered moral rights. However, in the sphere of law they are perceived only within the community and common good, by no means constituting exclusive and absolute rights but only rights corresponding with duties and obligations. The Thomistic approach expresses both the free side of man vis-à-vis the state and its structures (in the spiritual level) and the egalitarian demand of law within social relations. Furthermore, it places the sphere of law on the background of common good and common interest. The Thomistic approach of the human person is a response to the modern perception of legal subjectivity and the priority of individuals, associated with the ideology of rights and leading to a confrontation of individual and society and a division of man to natural man and citizen, a product of the antithesis between society and state

    Processing plants for food: Experimental grinding within the ERC-project PLANTCULT

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    PlantCult Project aims to explore the role of culinary traditions and innovations through their impact on shaping the social landscape in ancient Europe over long time periods (from the Neolithic period to the Iron Age) and large territories. The experimental program is part of an integrated study of food products and associated equipment focusing on whether the introduction of new species or changes in social and economic organisation brought about changes in the food grinding technologies of the area. The experiments include tools operated by back and forth reciprocal motion and circular motion, and manufactured from different raw materials, with different morphologies and sizes. The tools design and the list of plant ingredients (cereals, legumes, acorns and oil-seeds) ground in the experiments are all based on the archaeological record of the studied area. In this paper we present the experimental protocol, the multi-scale methodology applied to the use-wear analysis of grinding stone tools, and the results of the experimental processing of the main plant ingredients detected in prehistoric European cuisine
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