Doctor of Philosophy(PhD) / Two recently identified transient receptor potential (TRP) channels, TRPM8 and TRPA1, have been proposed to play an important role in mammalian cool and cold peripheral sensory transduction. When expressed in cell-lines the cloned TRPM8 and TRPA1 receptors have distinct pharmacological and temperature response characteristics. Although these receptors are also transported to the central terminals of primary afferents, little is known about their centrally mediated actions. In this thesis, I use an in vitro electrophysiological approach to investigate the dorsal horn processing of cool afferent modalities and the role of TRP ion channels. The results of this thesis provide further information on thermal processing, indicate direction for further research and suggest possible therapeutic targets for the management of abnormal cold sensory processing. Initial experiments demonstrate that the cooling agents and known TRPM8 and TRPA1 agonists, menthol and icilin, inhibit primary afferent evoked excitatory postsynaptic currents (EPSCs) in rat spinal cord dorsal horn neurons. In addition, temperature reduction, menthol and icilin increase the frequency of miniature EPSCs without affecting amplitude distribution or kinetics. Little or no direct postsynaptic effect on dorsal horn neurons, GABAergic or glycinergic transmission was found. In combination, these observations demonstrate that temperature reduction, menthol and icilin act presynaptically to increase the probability of glutamate release from primary afferent fibres. Further examination of the changes in glutamatergic synaptic transmission induced by temperature reduction, menthol and icilin reveals a subset of neurons sensitive to innocuous cool (< 29 oC) and low concentrations of icilin (3-10 µM) which closely match the temperature activation and pharmacological profile of TRPM8. In addition, the majority of lamina I and II neurons displayed characteristics partly consistent with TRPA1-activation, including a concentration-dependent response to icilin and blockade by ruthenium red. The present experiments did not allow thermal characterisation of these TRPA1-like responses. Together these observations indicate that the effects of menthol and icilin on glutamatergic synaptic transmission in the superficial dorsal horn are mediated by TRPM8 and possibly by TRPA1. Examination of the anatomical location of neurons activated by temperature reduction, menthol, icilin and capsaicin allowed the central termination pattern of thermoreceptive primary afferent fibres with specific TRP-like response characteristics to be determined. TRPM8-like presynaptic activation was confined to a subpopulation of neurons located in lamina I and outer lamina II, while the majority of neurons throughout laminae I and II received inputs sensitive to menthol, high concentrations of icilin and capsaicin. These findings suggest that innocuous cool sensation projects to a specific subpopulation of superficial dorsal horn neurons unlike other modalities (mediated by TRPV1, possibly TRPA1 and other receptors), which non-selectively engage circuits within the entire superficial dorsal horn. No morphological specificity was identified for recovered neurons after electrophysiological characterisation. Finally, mu-opioids were shown to inhibit basal glutamatergic synaptic transmission as well as menthol- and icilin-induced transmission in the superficial dorsal horn. Of particular interest, delta-opioids selectively inhibited icilin-induced synaptic transmission within the same location. The selective effect of delta-opioids suggests a possible role in modulating receptors activated by icilin (TRPM8 and TRPA1). Overall, this thesis provides further evidence that TRPM8 is responsible for the transduction of innocuous cold sensation in mammals and is a potential therapeutic target in humans with cold hyperaesthesia secondary to abnormal thermal processing. The use of delta-opioid agonists warrants further investigation in cold hypersensitivity states and potentially other forms of pain.

This thesis concerns quadratic response properties and their application to properties in Jablonski diagrams such as resonant two-photon absorption and excited state absorption. Our main interest lies in optical power limiting applications, and in this context, molecules containing heavy metal atoms prove superior. Therefore, we are interested in how relativity affects these properties, and in order to assess this, a four-component relativistic framework is adopted. To properly address the molecular properties of interest, both relativistic effects and electron correlation need to be accounted for. These two properties are not additive, and, therefore, correlation needs to be incorporated into the four-component framework. We present the implementation of quadratic response properties at the four-component density functional level of theory. For second-harmonic generation, we have, with numerical examples, demonstrated that correlation and relativity are indeed not additive and that the inclusion of noncollinear magnetization is of little importance. We report that both electron correlation as well as relativity strongly affect results for second-harmonic generation. For example, relativity alone reduces the µβ-response signal by 62% and 75% for meta- and ortho-bromobenzene, respectively, and enhances the same response by 17% and 21% for meta- and ortho-iodobenzene, respectively. In the four-component framework, we present the implementations of single and double residues of the quadratic response function, which allows for the evaluation of resonant two-photon absorption cross sections and excited state properties. Using these tools, we discuss different levels of approximation to the relativistic Hamiltonian and we demonstrate that for two-photon absorption, a proper treatment of relativistic effects qualitatively alters the spectrum. For example, already for an element as light as neon, significant differences are seen between the relativistic and nonrelativistic spectra as triplet transitions acquire substantial absorption cross sections in the former case. Finally, quantum mechanics in conjunction with electrodynamics is applied to determine clamping levels in macroscopic samples. The microscopic properties of the optically active chromophores are determined by response theory, and then, electrodynamics is used to describe the interactions between the chromophores and incident laser pulses. Using this approach a series of molecules have been investigated and their performances have been compared and ranked in order to find novel materials for optical power limiting applications.

Extended periods of oxygen deprivation cause brain death in mammals but the western painted turtle overwinters in anoxic mud for months without damage. Neural protection is achieved through decreases in the whole cell currents of N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (NMDAR and AMPAR) that are dependent on a mild increase in intracellular calcium from the mitochondria. The goal of this research was to determine if natural anoxic decreases in reactive oxidative species (ROS) serve as the signal to bring about these changes. Reductions in cellular ROS levels were demonstrated to have no effect on AMPAR currents or intracellular calcium and produced massive increases in NMDAR currents, indicating that ROS depression does not directly mediate anoxic alterations. Interestingly, mammalian neural tissue also experiences a similar increase in NMDAR whole cell current in response to reducing agents suggesting a possible conserved mechanism for normoxic receptor control.

Extended periods of oxygen deprivation cause brain death in mammals but the western painted turtle overwinters in anoxic mud for months without damage. Neural protection is achieved through decreases in the whole cell currents of N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (NMDAR and AMPAR) that are dependent on a mild increase in intracellular calcium from the mitochondria. The goal of this research was to determine if natural anoxic decreases in reactive oxidative species (ROS) serve as the signal to bring about these changes. Reductions in cellular ROS levels were demonstrated to have no effect on AMPAR currents or intracellular calcium and produced massive increases in NMDAR currents, indicating that ROS depression does not directly mediate anoxic alterations. Interestingly, mammalian neural tissue also experiences a similar increase in NMDAR whole cell current in response to reducing agents suggesting a possible conserved mechanism for normoxic receptor control.

Doctor of Philosophy(PhD) / Two recently identified transient receptor potential (TRP) channels, TRPM8 and TRPA1, have been proposed to play an important role in mammalian cool and cold peripheral sensory transduction. When expressed in cell-lines the cloned TRPM8 and TRPA1 receptors have distinct pharmacological and temperature response characteristics. Although these receptors are also transported to the central terminals of primary afferents, little is known about their centrally mediated actions. In this thesis, I use an in vitro electrophysiological approach to investigate the dorsal horn processing of cool afferent modalities and the role of TRP ion channels. The results of this thesis provide further information on thermal processing, indicate direction for further research and suggest possible therapeutic targets for the management of abnormal cold sensory processing. Initial experiments demonstrate that the cooling agents and known TRPM8 and TRPA1 agonists, menthol and icilin, inhibit primary afferent evoked excitatory postsynaptic currents (EPSCs) in rat spinal cord dorsal horn neurons. In addition, temperature reduction, menthol and icilin increase the frequency of miniature EPSCs without affecting amplitude distribution or kinetics. Little or no direct postsynaptic effect on dorsal horn neurons, GABAergic or glycinergic transmission was found. In combination, these observations demonstrate that temperature reduction, menthol and icilin act presynaptically to increase the probability of glutamate release from primary afferent fibres. Further examination of the changes in glutamatergic synaptic transmission induced by temperature reduction, menthol and icilin reveals a subset of neurons sensitive to innocuous cool (< 29 oC) and low concentrations of icilin (3-10 µM) which closely match the temperature activation and pharmacological profile of TRPM8. In addition, the majority of lamina I and II neurons displayed characteristics partly consistent with TRPA1-activation, including a concentration-dependent response to icilin and blockade by ruthenium red. The present experiments did not allow thermal characterisation of these TRPA1-like responses. Together these observations indicate that the effects of menthol and icilin on glutamatergic synaptic transmission in the superficial dorsal horn are mediated by TRPM8 and possibly by TRPA1. Examination of the anatomical location of neurons activated by temperature reduction, menthol, icilin and capsaicin allowed the central termination pattern of thermoreceptive primary afferent fibres with specific TRP-like response characteristics to be determined. TRPM8-like presynaptic activation was confined to a subpopulation of neurons located in lamina I and outer lamina II, while the majority of neurons throughout laminae I and II received inputs sensitive to menthol, high concentrations of icilin and capsaicin. These findings suggest that innocuous cool sensation projects to a specific subpopulation of superficial dorsal horn neurons unlike other modalities (mediated by TRPV1, possibly TRPA1 and other receptors), which non-selectively engage circuits within the entire superficial dorsal horn. No morphological specificity was identified for recovered neurons after electrophysiological characterisation. Finally, mu-opioids were shown to inhibit basal glutamatergic synaptic transmission as well as menthol- and icilin-induced transmission in the superficial dorsal horn. Of particular interest, delta-opioids selectively inhibited icilin-induced synaptic transmission within the same location. The selective effect of delta-opioids suggests a possible role in modulating receptors activated by icilin (TRPM8 and TRPA1). Overall, this thesis provides further evidence that TRPM8 is responsible for the transduction of innocuous cold sensation in mammals and is a potential therapeutic target in humans with cold hyperaesthesia secondary to abnormal thermal processing. The use of delta-opioid agonists warrants further investigation in cold hypersensitivity states and potentially other forms of pain.

Made available in DSpace on 2014-06-11T19:27:13Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-02-26Bitstream added on 2014-06-13T20:16:16Z : No. of bitstreams: 1 souza_ap_me_ilha.pdf: 2793163 bytes, checksum: cac24da914ff0917c1d9438da0bc50f8 (MD5) / A Bioengenharia está cada vez mais presente em todo o mundo. Ela estuda problemas que tenham dificuldades em análise experimental em laboratório. Este trabalho determina a força exercida por um grampo cirúrgico quando o mesmo é aplicado em determinada região Arterial a fim de ocluir o fluxo sanguíneo. Esta força foi medida utilizado uma simulação computacional. Duas áreas foram consideradas: uma representando a parede Arterial e a outra, representando o sangue. Esta simulação realizou-se em regime de acoplamento entre os dois domínios utilizando interação fluido-estrutura. A modelagem foi feita considerando dois domínios distintos: estrutura e fluido. O fluido é considerado incompressível e Newtoniano e é governado pelas equações de Navier-Stokes. As paredes da estrutura são modeladas a partir da Lei de Hooke. A solução numérica calcula: os campos de pressão e velocidade do fluido, campo de deslocamento da estrutura e a força aplicada pelo grampo para que ocorra a obstrução do fluxo sanguíneo naquele local / The Bioengineering is increasingly present in the fields of scientific research throughout the world. It studies problems that have difficulty in experimental analysis in the laboratory. This work measures the force exerted by a surgical clip when it is applied in a given region Arterial to occlude blood flow. This force was measured using a computational simulation. It was modeled two cylinders, one representing the arterial wall and the other in this first, representing the blood. This simulation was carried out under the coupling between the two domains using fluid-structure interaction. Modeling was done in three-dimensions, considering two distinct areas: one as structure and other as fluid. The fluid was considered incompressible and Newtonian. It is governed by the Navier-Stokes equations. The walls of the structure were modeled from the Hooke's Law. The numerical solution calculate: pressure fields, and fluid velocity, displacement field of the structure and the force applied by the clip for the occurrence of obstruction of blood flow there

Die Auswertung von Unfallzahlen an Produktionsmaschinen der vergangenen Jahre zeigt, dass nach Jahren sinkender Unfallzahlen eine Stagnation eintritt (Mödden 2018). Der Unfallstatistik der Deutschen Gesetzlichen Unfallversicherung (DGUV) ist außerdem zu entnehmen, dass die Ursache für tödliche oder schwere Unfälle sehr häufig freigesetzte Werkstücke sind. In den meisten Fällen lagen mangelhafte Aufspannsituationen vor (Kesselkaul Meyer 2016). Wenn die Möglichkeiten der inhärent sicheren Konstruktion und der technischen Schutzmaßnahmen ausgeschöpft sind und trotzdem Restrisiken verbleiben, muss im Schritt 3 die Benutzerinformation, die als instruktive Sicherheit zusammengefasst wird, darauf hinweisen (Neudörfer 2014, ISO 12100 2011, MRL 2006). Das Problem ist hierbei, dass die Beachtung der instruktiven Sicherheit vom Bediener abhängig ist. Das Vertikal-Drehen auf Fräsbearbeitungszentren ist ein arbeitssicherheitstechnisch besonders kritischer Prozess, weil dafür die Maschine mit vollwertigen Rotationsachsen für das Werkstück ausgerüstet wird. Durch die hohen Drehzahlen der Werkstücke steigen deren kinetische Energie und damit das Gefährdungsrisiko gegenüber der reinen klassischen Fräsbearbeitung stark an. Im Stillstand und bei geringen Drehzahlen hat das Werkstück dagegen in der Regel einen sicheren Stand und vermittelt dem Maschinenbediener unter Umständen eine trügerische Sicherheit. Wird das Werkstück außerdem manuell gespannt, entstehen trotz ausreichender technischer Zuverlässigkeit des Systems 'Werkzeugmaschine-Spannmittel-Werkstück' Unwägbarkeiten, die rein auf das menschliche Handeln also die Mensch-Maschine-Interaktion zurückzuführen sind. Die auf einer bewährten Risikoabschätzung beruhende normungstechnische Konvention erfordert Überwachungsfunktionen und instruktive Sicherheit für die konkrete Werkstückspannung (ISO 16090 2017). Sie setzt also quasi einen idealen und z. B. nicht ermüdenden und immer richtig handelnden Maschinenbediener voraus. Die oben erwähnten Unfallzahlen sind ein Beweis, dass die reale Situation nicht befriedigend ist. Die wesentliche Frage ist: Wie kann die Mensch-Maschine-Interaktion (MMI) als Teil des Maschinendesigns sicherer gestaltet werden? Und auf das konkrete Beispiel bezogen: Wie kann die Instruktion so verbessert werden, dass schwere Unfälle verhindert werden? Um diese Frage zu beantworten, ist es im ersten Schritt notwendig, den Einfluss der menschlichen Unzuverlässigkeit zu quantifizieren, um ihn so sowohl in technisch-physikalische Auslegung als auch in die Bewertung der Maschinensicherheit einfließen zu lassen.

This thesis deals with the design and solving construction of devices for centering cargo tires. Another part of this work is a concept of the clamping head for fixation of tires by industrial robot and its following placement on a palette. Construction solution will be drawn up with access and without access of human operator. All structural variations will be reviewed by risk analysis and analysis of possible incidence and influence of defects.

Работа выполнена на основании данных АО «НПО автоматики». Дипломный проект состоит из трех частей: Технологической, которая включает: описание конструкции детали; определение типа производства; разработку концепции механической обработки детали; выбор вида заготовки и метода её получения; конструирование заготовки и определение общих припусков на обработку; составление планов обработки каждой поверхности в соответствии с этапами обработки; разработку маршрута, включающего назначение базовых поверхностей, выбор станочного оборудования и технологической оснастки; моделирование эскизов на каждую операцию; определение операционных допусков и припусков на обрабатываемые поверхности; определение операционных размеров на обрабатываемые поверхности; выбор режимов обработки; определение норм времени на каждую операцию; оформление рабочей технологической документации. Конструкторской, которая включает: определение потребной силы закрепления (силовой расчёт); выбор и расчёт механизированного привода; точностной анализ приспособления; эскизное конструирование общего вида приспособления; проектирование контрольного приспособления; оформление рабочей конструкторской документации. Научно-исследовательской, которая включает экспериментальное исследование влияния режима резания на качество обрабатываемой поверхности из алюминиевого сплава АМг6 с последующим выводом уравнения регрессии. Графическая часть – 15 листов формата А1; Таблиц – 89; Рисунков – 44; Количество используемых источников – 19. / The work was performed on the basis of the data of JSC "NPO Automation". The graduation project consists of three parts: 1. Technological, which includes: description of the construction details; determining the type of production; development of the concept of machining parts; selection of the type of workpiece and the method of its receipt; design of the workpiece and the definition of total allowances for processing; drawing up plans for the treatment of each surface in accordance with the processing steps; development of the route, including the assignment of base surfaces, the choice of machine equipment and tooling; modeling sketches for each operation; Determination of operating tolerances and allowances for machined surfaces; determination of the operating dimensions of the treated surface; selection of processing modes; determination of time norms for each operation; registration of working technological documentation. Design, which includes: determination of the required strength of fastening (force calculation); selection and calculation of a mechanized drive; accuracy analysis of the device; conceptual design of the general form of the device; design of the control device; design of working design documentation. 3. Research, which includes an experimental study of the influence of the cutting mode on the quality of the processed surface of aluminum alloy AMg6 with the subsequent derivation of the regression equation. - Graphic part - 15 sheets of A1 format; - Tables - 89; Figures -40; The number of sources used - 18.

his study explores clamp force estimation using Unscented Kalman Filtering (UKF) in torque-controlled tightening scenarios with various velocity profiles. Previous research has explored the impact of velocity levels on target torque and clamping force, but only using hand-held tools. Prior research is extended by implementing UKF in a fixed setup, using the QST42, to remove user errors. Four strategies, Continuous Drive, TurboTight, Accelerating Tightening, and Paused Tightening, are analyzed using error and quality factor metrics. In Continuous Drive, both hand-held and fixed rigshave mean errors of approximately 4.09% and 4.14%, with quality factors of 88.38% and 97.72%.UKF adapts well in TurboTight, with mean errors of 3.50% (hand-held) and 5.23% (fixed rigs), and quality factors of 93.02% and 94.44%, respectively. Dynamic strategies like Accelerating Tightening- yield higher mean errors (10.33%) and quality factors (94.86%), while Paused Tightening results in a mean error of 5.17% and a quality factor of 76.86%. Tailoring UKF calibration is crucial for accuracy. Overall, this research underscores the close correlation between UKF’s performance and the dynamics of the tightening strategy. The implications extend to industrial applications, advocating for strategy-specific adjustments to enhance clamp force estimation accuracy. This study contributes to advancing UKF’s applicability in real-world scenarios, providing a foundational framework to enhance the accuracy and reliability of clamp force estimations. / Denna studie utforskar kraftuppskattning för klammer i momentkontrollerade åtdragnings-scenarier med olika hastighetsprofiler med hjälp av Unscented Kalman Filtering (UKF). Tidigare forskning har utforskat påverkan av hastighetsnivåer på målmoment och klämkraft, men endast med användning av handhållna verktyg. Tidigare forskning utökas genom att implementera UKF i en fast inställning, med QST42 verktyget, för att eliminera användarfel. Fyra strategier, Continuous Drive, TurboTight, Accelerating Tightening och Paused Tight-ening, analyseras med hjälp av fel- och kvalitetsfaktormetoder. I Continuous Drive har både handhållna och fixta åtdragningar medelvärdesfel på cirka 4,09% och 4,14%, med kvalitetsfaktorer på 88,38% och 97,72%. UKF anpassar sig väl i TurboTight, med medelvärdesfel på 3,50% (handhållna) och 5,23%(fixt rig) och kvalitetsfaktorer på 93,02% och 94,44%, respektive. Dynamiska strategier som Accelerating Tightening ger högre medelvärdesfel (10,33%) och kvalitetsfaktorer (94,86%), medan Paused Tightening resulterar i ett medelvärdesfel på 5,17% och en kvalitetsfaktor på 76,86%. Sammanfattningsvis understryker denna forskning den nära korrelationen mellan UKF:s prestanda och dynamiken i åtdragningsstrategin. Implikationerna sträcker sig till industriella tillämpningar och förespråkar strategispecifika justeringar för att förbättra noggrannheten i klämkraftsuppskattningen. Denna studie bidrar till att främja användningen av UKF i verkliga scenarier och tillhandahåller en grundläggande ram för att förbättra noggrannheten och tillförlitligheten i klämkraftsuppskattning.