Phenotypic properties and intrinsic currents of neurons involved in the neural generation of mammalian breathing

Breathing is essential for mammalian life. Although there is an emerging consensus that the inspiratory respiratory rhythm is generated in a lower brainstem region known as the preBotzinger Complex (preBotC), the mechanism of rhythmogenesis is still unclear. Additionally, the modulation of intrinsic currents within preBotC neurons has yet to be fully elucidated. This dissertation addresses both of these issues and relies on imaging, electrophysiological, and modeling techniques. The first chapter examines the size and composition of the preBotC. The chapter also decribes the means by which substance P (SP) excites the vast majority of preBotC neurons by illustrating the characteristics of the SP-activated current (/SP) in these neurons. In the subsequent chapter, we characterize a voltage-dependent potassium current that is involved in maintaining stable rhythms during normal fictive breathing. The third chapter presents a mathematical model of heterogeneous and rhythmogenic neurons that initiate network bursts. We show how this behavior relies on feedback synaptic connections within the network that reinforces activity, i.e., recurrent-excitation. We also compare model results to experimental data and make testable predictions. The final chapter elaborates on the discussion of /SP from the first chapter and presents evidence suggesting that a cyclic adenosine monophosphate (cAMP)-modulated non-specific cation channel may account for the depolarizing response in preBotC neurons from several neuromodulators. Altogether, this dissertation advances the field\u27s understanding on several fronts. We have distinguished possible functional roles of neurons from electrophysiological characteristics, estimated the number of neurons necessary for rhythmogenesis, characterized /SP , and clarified the distribution of SP-sensitive receptors among inspiratory neurons. We have identified and characterized a voltage-dependent potassium currrent important for inspiratory activity and analyzed its role. We have also described in detail how rhythmic bursts form from recurrent excitation and how this relates to experimental data. Finally, we have identified and begun characterizing a potentially important and novel mechanism for the modulation of membrane potentials in critical inspiratory neurons

AN ANALYSIS OF REGIONAL ECONOMIC GROWTH IN THE US MIDWEST

In this paper we examine more closely some of the forces that underlie economic growth at the county level. In an effort to describe a much more comprehensive regional economic growth model, we address a variety of different growth hypotheses by introducing a large number of growth related variables. When formulating our hypotheses and specifying our growth model we make liberal use of GIS mapping software to "paint" a picture of where growth spots exist and why. Our empirical estimation indicates amenities, state and local tax burdens, population, amount of agricultural activity, and demographics have important economic growth impacts.Community/Rural/Urban Development,

Automated cell-specific laser detection and ablation of neural circuits in neonatal brain tissue

Key points center dot We developed an automated system that detects neurons belonging to specific populations in vitro or in situ, maps their physical locations in three-dimensional tissue specimens and then laser ablates the cell targets\u27 one at a time, in sequence, while monitoring neural population activity electrophysiologically. center dot Two-photon Ca2+ imaging and image processing routines detect and validate target neurons based on rhythmic Ca2+ fluorescence activity patterns. center dot Visible-wavelength confocal imaging and image processing routines detect and validate target neurons that express genetically encoded fluorescent proteins. center dot High-intensity two-photon spot scanning vaporizes target neurons with specificity while minimizing damage to neighbouring tissue. center dot Physiological monitoring of network function is performed before, during and after the cell-specific laser ablations to measure the effects on network functionality in real time. Abstract A key feature of neurodegenerative disease is the pathological loss of neurons that participate in generating behaviour. To investigate network properties of neural circuits and provide a complementary tool to study neurodegeneration in vitro or in situ, we developed an automated cell-specific laser detection and ablation system. The instrument consists of a two-photon and visible-wavelength confocal imaging setup, controlled by executive software, that identifies neurons in preparations based on genetically encoded fluorescent proteins or Ca2+ imaging, and then sequentially ablates cell targets while monitoring network function concurrently. Pathological changes in network function can be directly attributed to ablated cells, which are logged in real time. Here, we investigated brainstem respiratory circuits to demonstrate single-cell precision in ablation during physiological network activity, but the technique could be applied to interrogate network properties in neural systems that retain network functionality in reduced preparations in vitro or in situ

EXPERIMENTAL METHODS IN CONSUMER PREFERENCE STUDIES

Controlled experimental auctions can be used to elicit preferences for food products. We describe results from two series of experiments in which subjects revealed their willingness-to-pay for safer food. In one series, the risk reduction technology was not specified; in the other, it was identified as food irradiation. The results provide some evidence on the acceptability of food irradiation as a risk reduction technology.Consumer/Household Economics,

The Keap1/Nrf2 pathway in health and disease:from the bench to the clinic

The transcription factor nuclear factor-erythroid 2 p45-related factor 2 (Nrf2, with gene called NFE2L2) is a master regulator of the antioxidant response. In the last decade, interest has intensified in this research area as its importance in several physiological and pathological processes has become widely recognized; these include redox signalling and redox homoeostasis, drug metabolism and disposition, intermediary metabolism, cellular adaptation to stress, chemoprevention and chemoresistance, toxicity, inflammation, neurodegeneration, lipogenesis and aging. Regulation of Nrf2 is complex and although much attention has focussed on its repression by Kelch-like ECH-associated protein-1 (Keap1), recently it has become increasingly apparent that it is also controlled by cross-talk with other signalling pathways including the glycogen synthase kinase-3 (GSK-3) - β-transducin repeat-containing protein (β-TrCP) axis, ERAD (endoplasmic reticulum-associated degradation)-associated E3 ubiquitin-protein ligase (Hrd1, also called synoviolin), nuclear factor-kappa B (NF-κB), Notch and AMP kinase. Due to its beneficial role in several diseases, Nrf2 has become a major therapeutic target, with novel natural, synthetic and targeted small molecules currently under investigation to modulate the pathway and in clinical trials.</p

Contrarian Technical Trading Rules: Evidence From Nairobi Stock Index

We apply several popular technical trading rules in the normal way and a contrarian way to daily data of the Nairobi Stock Index from 9/12/2006 to 4/18/2013. The contrarian usage of popular technical trading rules implies that when a technical trading indicator emits buy (sell) signals, we do the opposite and sell (buy) the index. Results from the study support the predictive power of contrarian technical trading rules. We also investigate whether a trader can use the predictive power of contrarian technical rules to beat the profitability of the buy-and-hold strategy considering both transaction costs and risk. Designing four strategies of various contrarian trading rules, we conclude that it is possible to beat the buy-and-hold strategy even considering transaction costs and risk

What Explains the Incidence of the Use of a Common Sediment Control on Lots with Houses Under Construction?

To analyze compliance with one aspect of the regulation of stormwater discharge, we estimate a random-utility model of the probability that a builder uses a silt fence to control sediments on a lot with a house under construction in an urbanizing county of South Carolina. The probability increases if the builder is responsible to the subdivision’s developer or if a homeowners association exists. The probability also increases as the cost to install a silt fence decreases or the number of houses under construction per built house in a subdivision increases. The results can help county officials target inspection to improve compliance.compliance with regulation, erosion and sediment control, filter fabric, management of stormwater runoff, random-utility model, silt fence, storm water pollution prevention plan, Agribusiness, Community/Rural/Urban Development, Demand and Price Analysis, Environmental Economics and Policy, Industrial Organization, Land Economics/Use, Q01, Q24, Q53, Q58,

Cumulative Lesioning of Respiratory Interneurons Disrupts and Precludes Motor Rhythms in Vitro

How brain functions degenerate in the face of progressive cell loss is an important issue that pertains to neurodegenerative diseases and basic properties of neural networks. We developed an automated system that uses two-photon microscopy to detect rhythmic neurons from calcium activity, and then individually laser ablates the targets while monitoring network function in real time. We applied this system to the mammalian respiratory oscillator located in the pre-Bötzinger Complex (preBötC) of the ventral medulla, which spontaneously generates breathing-related motor activity in vitro. Here, we show that cumulatively deleting preBötC neurons progressively decreases respiratory frequency and the amplitude of motor output. On average, the deletion of 120 ± 45 neurons stopped spontaneous respiratory rhythm, and our data suggest ≈82% of the rhythm-generating neurons remain unlesioned. Cumulative ablations in other medullary respiratory regions did not affect frequency but diminished the amplitude of motor output to a lesser degree. These results suggest that the preBötC can sustain insults that destroy no more than ≈18% of its constituent interneurons, which may have implications for the onset of respiratory pathologies in disease states

Costs of delivering human papillomavirus vaccination to schoolgirls in Mwanza Region, Tanzania.

BACKGROUND: Cervical cancer is the leading cause of female cancer-related deaths in Tanzania. Vaccination against human papillomavirus (HPV) offers a new opportunity to control this disease. This study aimed to estimate the costs of a school-based HPV vaccination project in three districts in Mwanza Region (NCT ID: NCT01173900), Tanzania and to model incremental scaled-up costs of a regional vaccination program. METHODS: We first conducted a top-down cost analysis of the vaccination project, comparing observed costs of age-based (girls born in 1998) and class-based (class 6) vaccine delivery in a total of 134 primary schools. Based on the observed project costs, we then modeled incremental costs of a scaled-up vaccination program for Mwanza Region from the perspective of the Tanzanian government, assuming that HPV vaccines would be delivered through the Expanded Programme on Immunization (EPI). RESULTS: Total economic project costs for delivering 3 doses of HPV vaccine to 4,211 girls were estimated at about US$349,400 (including a vaccine price of US$5 per dose). Costs per fully-immunized girl were lower for class-based delivery than for age-based delivery. Incremental economic scaled-up costs for class-based vaccination of 50,290 girls in Mwanza Region were estimated at US$1.3 million. Economic scaled-up costs per fully-immunized girl were US$26.41, including HPV vaccine at US$5 per dose. Excluding vaccine costs, vaccine could be delivered at an incremental economic cost of US$3.09 per dose and US$9.76 per fully-immunized girl. Financial scaled-up costs, excluding costs of the vaccine and salaries of existing staff were estimated at US$1.73 per dose. CONCLUSIONS: Project costs of class-based vaccination were found to be below those of age-based vaccination because of more eligible girls being identified and higher vaccine uptake. We estimate that vaccine can be delivered at costs that would make HPV vaccination a very cost-effective intervention. Potentially, integrating HPV vaccine delivery with cost-effective school-based health interventions and a reduction of vaccine price below US$5 per dose would further reduce the costs per fully HPV-immunized girl