Function and Regulation of Cytochrome P450 4V2 and the Implications in Bietti’s Crystalline Dystrophy

Thesis (Ph.D.)--University of Washington, 2016-06

Changes in joint stability with muscle contraction measured from transmission of mechanical vibration

A non-invasive in vivo technique was developed to evaluate changes in wrist joint stability properties induced by increased co-activation of the forearm muscles in a gripping task. Mechanical vibration at 45, 50 and 55 Hz was applied to the radial head in ten healthy volunteers. Vibrations of the styloid process of the radius and the distal end of the metacarpal bone of the index finger were measured with triaxial accelerometers. Joint stability properties were quantified by the transfer function gain between accelerations on either side of the wrist-joint. Gain was calculated with the muscles at rest and at five force levels ranging from 5% to 25% of maximum grip force (%MF). During contraction the gain was significantly greater than in control trial (0%MF) for all contractions levels at 45 and 50 Hz and a trend for 15%MF and higher at 55 Hz. Group means of contraction force and gain were significantly correlated at 45 (R-2 = 0.98) and 50 Hz (R-2 = 0.72), but not at 55 Hz (R-2 = 0.10). In conclusion, vibration transmission gain may provide a method to evaluate changes in joint stability properties. (c) 2005 Published by Elsevier Ltd.

Distinct physiological mechanisms underlie altered glycinergic synaptic transmission in the murine mutants spastic, spasmodic, and oscillator

Spastic (spa), spasmodic (spd), and oscillator (ot) mice have naturally occurring glycine receptor ( GlyR) mutations, which manifest as motor deficits and an exaggerated startle response. Using whole-cell recording in hypoglossal motoneurons, we compared the physiological mechanisms by which each mutation alters GlyR function. Mean glycinergic miniature IPSC ( mIPSC) amplitude and frequency were dramatically reduced (> 50%) compared with controls for each mutant. mIPSC decay times were unchanged in spa/spa (4.5 +/- 0.3 vs 4.7 +/- 0.2 ms), reduced in spd/spd (2.7 +/- 0.2 vs 4.7 +/- 0.2 ms), and increased in ot/ot (12.3 +/- 1.2 vs 4.8 +/- 0.2 ms). Thus, in spastic, GlyRs are functionally normal but reduced in number, whereas in spasmodic, GlyR kinetics is faster. The oscillator mutation results in complete absence of alpha 1-containing GlyRs; however, some non-alpha 1-containing GlyRs persist at synapses. Fluctuation analysis of membrane current, induced by glycine application to outside-out patches, showed that mean single-channel conductance was increased in spa/spa (64.2 +/- 4.9 vs 36.1 +/- 1.4 pS), but unchanged in spd/spd (32.4 +/- 2.1 vs 35.3 +/- 2.1 pS). GlyR-mediated whole-cell currents in spa/spa exhibited increased picrotoxin sensitivity (27 vs 71% block for 100 mu M), indicating alpha 1 homomeric GlyR expression. The picrotoxin sensitivity of evoked glycinergic IPSCs and conductance of synaptic GlyRs, as determined by nonstationary variance analysis, were identical for spa/spa and controls. Together, these findings show the three mutations disrupt GlyR-mediated inhibition via different physiological mechanisms, and the spastic mutation results in compensatory alpha 1 homomeric GlyRs at extrasynaptic loci.

Genome reduction in Leptospira borgpetersenii reflects limited transmission potential

Leptospirosis is one of the most common zoonotic diseases in the world, resulting in high morbidity and mortality in humans and affecting global livestock production. Most infections are caused by either Leptospira borgpetersenii or Leptospira interrogans, bacteria that vary in their distribution in nature and rely on different modes of transmission. We report the complete genomic sequences of two strains of L. borgpetersenii serovar Hardjo that have distinct phenotypes and virulence. These two strains have nearly identical genetic content, with subtle frameshift and point mutations being a common form of genetic variation. Starkly limited regions of synteny are shared between the large chromosomes of L. borgpetersenii and L. interrogans, probably the result of frequent recombination events between insertion sequences. The L. borgpetersenii genome is ≈700 kb smaller and has a lower coding density than L. interrogans, indicating it is decaying through a process of insertion sequence-mediated genome reduction. Loss of gene function is not random but is centered on impairment of environmental sensing and metabolite transport and utilization. These features distinguish L. borgpetersenii from L. interrogans, a species with minimal genetic decay and that survives extended passage in aquatic environments encountering a mammalian host. We conclude that L. borgpetersenii is evolving toward dependence on a strict host-to-host transmission cycle.

Jobs, Unemployment, and Macroeconomic Transmission

Measuring Job Openings: Evidence from Swedish Plant Level Data. In modern macroeconomic models “job openings'' are a key component. Thus, when taking these models to the data we need an empirical counterpart to the theoretical concept of job openings. To achieve this, the literature relies on job vacancies measured either in survey or register data. Insofar as this concept captures the concept of job openings well we should see a tight relationship between vacancies and subsequent hires on the micro level. To investigate this, I analyze a new data set of Swedish hires and job vacancies on the plant level covering the period 2001-2012. I find that vacancies contain little power in predicting hires over and above (i) whether the number of vacancies is positive and (ii) plant size. Building on this, I propose an alternative measure of job openings in the economy. This measure (i) better predicts hiring at the plant level and (ii) provides a better fitting aggregate matching function vis-à-vis the traditional vacancy measure. Firm Level Evidence from Two Vacancy Measures. Using firm level survey and register data for both Sweden and Denmark we show systematic mis-measurement in both vacancy measures. While the register-based measure on the aggregate constitutes a quarter of the survey-based measure, the latter is not a super-set of the former. To obtain the full set of unique vacancies in these two databases, the number of survey vacancies should be multiplied by approximately 1.2. Importantly, this adjustment factor varies over time and across firm characteristics. Our findings have implications for both the search-matching literature and policy analysis based on vacancy measures: observed changes in vacancies can be an outcome of changes in mis-measurement, and are not necessarily changes in the actual number of vacancies. Swedish Unemployment Dynamics. We study the contribution of different labor market flows to business cycle variations in unemployment in the context of a dual labor market. To this end, we develop a decomposition method that allows for a distinction between permanent and temporary employment. We also allow for slow convergence to steady state which is characteristic of European labor markets. We apply the method to a new Swedish data set covering the period 1987-2012 and show that the relative contributions of inflows and outflows to/from unemployment are roughly 60/30. The remaining 10\% are due to flows not involving unemployment. Even though temporary contracts only cover 9-11\% of the working age population, variations in flows involving temporary contracts account for 44\% of the variation in unemployment. We also show that the importance of flows involving temporary contracts is likely to be understated if one does not account for non-steady state dynamics. The New Keynesian Transmission Mechanism: A Heterogeneous-Agent Perspective. We argue that a 2-agent version of the standard New Keynesian model---where a ``worker'' receives only labor income and a “capitalist'' only profit income---offers insights about how income inequality affects the monetary transmission mechanism. Under rigid prices, monetary policy affects the distribution of consumption, but it has no effect on output as workers choose not to change their hours worked in response to wage movements. In the corresponding representative-agent model, in contrast, hours do rise after a monetary policy loosening due to a wealth effect on labor supply: profits fall, thus reducing the representative worker's income. If wages are rigid too, however, the monetary transmission mechanism is active and resembles that in the corresponding representative-agent model. Here, workers are not on their labor supply curve and hence respond passively to demand, and profits are procyclical.

Numerically optimized implementations, mitigation and simulations of polarisation mode dispersion in real-time transmission systems

The aim of this thesis is to present numerical investigations of the polarisation mode dispersion (PMD) effect. Outstanding issues on the side of the numerical implementations of PMD are resolved and the proposed methods are further optimized for computational efficiency and physical accuracy. Methods for the mitigation of the PMD effect are taken into account and simulations of transmission system with added PMD are presented. The basic outline of the work focusing on PMD can be divided as follows. At first the widely-used coarse-step method for simulating the PMD phenomenon as well as a method derived from the Manakov-PMD equation are implemented and investigated separately through the distribution of a state of polarisation on the Poincaré sphere, and the evolution of the dispersion of a signal. Next these two methods are statistically examined and compared to well-known analytical models of the probability distribution function (PDF) and the autocorrelation function (ACF) of the PMD phenomenon. Important optimisations are achieved, for each of the aforementioned implementations in the computational level. In addition the ACF of the coarse-step method is considered separately, based on the result which indicates that the numerically produced ACF, exaggerates the value of the correlation between different frequencies. Moreover the mitigation of the PMD phenomenon is considered, in the form of numerically implementing Low-PMD spun fibres. Finally, all the above are combined in simulations that demonstrate the impact of the PMD on the quality factor (Q=factor) of different transmission systems. For this a numerical solver based on the coupled nonlinear Schrödinger equation is created which is otherwise tested against the most important transmission impairments in the early chapters of this thesis.

Soliton propagation through a disordered system:statistics of the transmission delay

We have studied the soliton propagation through a segment containing random pointlike scatterers. In the limit of small concentration of scatterers when the mean distance between the scatterers is larger than the soliton width, a method has been developed for obtaining the statistical characteristics of the soliton transmission through the segment. The method is applicable for any classical particle traversing through a disordered segment with the given velocity transformation after each act of scattering. In the case of weak scattering and relatively short disordered segment the transmission time delay of a fast soliton is mostly determined by the shifts of the soliton center after each act of scattering. For sufficiently long segments the main contribution to the delay is due to the shifts of the amplitude and velocity of a fast soliton after each scatterer. Corresponding crossover lengths for both cases of light and heavy solitons have been obtained. We have also calculated the exact probability density function of the soliton transmission time delay for a sufficiently long segment. In the case of weak identical scatterers the latter is a universal function which depends on a sole parameter—the mean number of scatterers in a segment.

Retinal and systemic vascular function in health and disease: the effect of smoking and coronary artery disease

The purpose of the following studies was to explore the effect of systemic vascular and endothelial dysfunction upon the ocular circulation and functionality of the retina. There are 6 principal sections to the present work. Retinal vessel activity in smokers and non-smokers: the principal findings of this work were: chronic smoking affects retinal vessel motion at baseline and during stimulation with flickering light; chronic smoking leads to a vaso-constrictory shift in retinal arteriolar reactivity to flicker; retinal arteriolar elasticity is decreased in chronic smokers. The effect of acute smoking on retinal vessel dynamics in smokers and non-smokers: the principal finding of this work was that retinal reactivity in chronic smokers is blunted when exposed to clicker light provocation immediately after smoking one cigarette. Ocular blood flow in coronary artery disease: The principal findings of this work were: retrobulbar and retinal blood flow is preserved in CAD patients, despite a change pulse wave transmission; arterial retinal response to flickering light provocation is significantly delayed in CAD patients; retinal venular diameters are significantly dilated in CAD patients. Autonomic nervous system function and peripheral circulation in CAD: The principal findings in this work were: CAD patients demonstrate a sympathetic overdrive during a 24 period; a delay in peripheral vascular reactivity (nail-fold capillaries) as observed in patients suffering from CAD could be caused by either arteriosclerotic changes of the vascular walls or due to systemic haemodynamic changes. Visual function in CAD: The principal findings in this work were: overall visual function in CAD patients is preserved, despite a decrease in contrast sensitivity; applying a filtering technique selecting those with greater coefficient of variance which in turn represents a decrease in reliability, some patients appear to have an impaired visual function as assessed using FDT visual field evaluation. Multiple functional, structural and biochemical vascular endothelial dysfunctions in patients suffering from CAD: relationships and possible implications: The principal findings of this work were: BMI significantly correlated with vWF (a marker of endothelial function) in CAD patients. Retinal vascular reactivity showed a significant correlation with peripheral reactivity parameters in controls which lacked in the CAD group and could reflect a loss in vascular endothelial integrity; visual field parameters as assessed by frequency doubling technology were strongly related with systemic vascular elasticity (ambulatory arterial stiffness index) in controls but not CAD patients.

Modulation of network oscillatory activity and GABAergic synaptic transmission by CB1 cannabinoid receptors in the rat medial entorhinal cortex

Cannabinoids modulate inhibitory GABAergic neurotransmission in many brain regions. Within the temporal lobe, cannabinoid receptors are highly expressed, and are located presynaptically at inhibitory terminals. Here, we have explored the role of type-1 cannabinoid receptors (CB1Rs) at the level of inhibitory synaptic currents and field-recorded network oscillations. We report that arachidonylcyclopropylamide, an agonist at CB1R, inhibits GABAergic synaptic transmission onto both superficial and deep medial entorhinal (mEC) neurones, but this has little effect on network oscillations in beta/gamma frequency bands. By contrast, the CB1R antagonist/inverse agonist LY320135 (500?nM), increased GABAergic synaptic activity and beta/gamma oscillatory activity in superficial mEC, was suppressed, whilst that in deep mEC was enhanced. These data indicate that cannabinoid-mediated effects on inhibitory synaptic activity may be constitutively active in vitro, and that modulation of CB1R activation using inverse agonists unmasks complex effects of CBR function on network activity.

Flat-top pulse generation based on a fiber Bragg grating in transmission

We propose and analyze a flat-top pulse generator based on a fiber Bragg grating (FBG) in transmission. As is shown in the examples, a uniform period FBG properly designed can exhibit a spectral response in transmission close to sinc function (in amplitude and phase) in a certain bandwidth, because of the logarithm Hilbert transform relations, which can be used to reshape a Gaussian-like input pulse into a flat-top pulse.

Polarization multiplexed 16QAM transmission employing modified digital back-propagation

We experimentally demonstrate performance enhancements enabled by weighted digital back propagation method for 28 Gbaud PM-16QAM transmission systems, over a 250 km ultra-large area fibre, using only one back-propagation step for the entire link, enabling up to 3 dB improvement in power tolerance with respect to linear compensation only. We observe that this is roughly the same improvement that can be obtained with the conventional, computationally heavy, non-weighted digital back propagation compensation with one step per span. As a further benchmark, we analyze performance improvement as a function of number of steps, and show that the performance improvement saturates at approximately 20 steps per span, at which a 5 dB improvement in power tolerance is obtained with respect to linear compensation only. Furthermore, we show that coarse-step self-phase modulation compensation is inefficient in wavelength division multiplexed transmission.

Picosecond soliton transmission using concatenated nonlinear optical loop-mirror intensity filters

The issues involved in employing nonlinear optical loop mirrors (NOLMs) as intensity filters in picosecond soliton transmission were examined in detail. It was shown that inserting NOLMs into a periodically amplified transmission line allowed picosecond solitons to be transmitted under conditions considered infeasible until now. The loop mirrors gave dual function, removing low-power background dispersive waves through saturable absorption and applying a negative feedback mechanism to control the amplitude of the solitons. The stochastic characteristics of the pulses that were due to amplifier spontaneous-emission noise were investigated, and a number of new properties were determined. In addition, the mutual interaction between pulses was also significantly different from that observed for longer-duration solitons. The impact of Raman scattering in the computations was included and it was shown that soliton self-frequency shifts may be eliminated by appropriate bandwidth restrictions.

Application of long period gratings sensors to respiratory function monitoring

A series of in-line curvature sensors on a garment are used to monitor the thoracic and abdominal movements of a human during respiration. These results are used to obtain volumetric tidal changes of the human torso showing reasonable agreement with a spirometer used simultaneously to record the volume at the mouth during breathing. The curvature sensors are based upon long period gratings written in a progressive three layered fibre that are insensitive to refractive index changes. The sensor platform consists of the long period grating laid upon a carbon fibre ribbon, which is encapsulated in a low temperature curing silicone rubber. An array of sensors is also used to reconstruct the shape changes of a resuscitation manikin during simulated respiration. The data for reconstruction is obtained by two methods of multiplexing and interrogation: firstly using the transmission spectral profile of the LPG's attenuation bands measured using an optical spectrum analyser; secondly using a derivative spectroscopy technique.

Comparison of bit error rate estimation methods for QPSK CO-OFDM transmission

In this letter, we experimentally study the statistical properties of a received QPSK modulated signal and compare various bit error rate (BER) estimation methods for coherent optical orthogonal frequency division multiplexing transmission. We show that the statistical BER estimation method based on the probability density function of the received QPSK symbols offers the most accurate estimate of the system performance.

Bit error rate estimation methods for QPSK CO-OFDM transmission

Coherent optical orthogonal frequency division multiplexing (CO-OFDM) is an attractive transmission technique to virtually eliminate intersymbol interference caused by chromatic dispersion and polarization-mode dispersion. Design, development, and operation of CO-OFDM systems require simple, efficient, and reliable methods of their performance evaluation. In this paper, we demonstrate an accurate bit error rate estimation method for QPSK CO-OFDM transmission based on the probability density function of the received QPSK symbols. By comparing with other known approaches, including data-aided and nondata-aided error vector magnitude, we show that the proposed method offers the most accurate estimate of the system performance for both single channel and wavelength division multiplexing QPSK CO-OFDM transmission systems. © 2014 IEEE.