Axon Initial Segment Plasticity in Mouse Models of Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a debilitating and fatal neurodegenerative disease affecting upper and lower motor neurons. Though studied for over two decades since the first ALS-associated genetic mutation was discovered, researchers have yet to uncover the pathological processes that lead to progressive degeneration of motor neurons in ALS, or to develop effective treatments. One prominent hypothesis proposes that excitotoxicity caused by increased motor neuron firing plays a role in ALS pathogenesis. While prior studies reported increased action potential firing in early postnatal ALS-model motor neurons in vivo, it remains unknown whether the increased activity stems from increased intrinsic excitability of ALS motor neurons or from increased excitatory drive, and whether these changes are transient or persist into adulthood, when ALS symptoms emerge. In this thesis, I circumvented the difficulties in standard measurement of electrophysiological properties of adult spinal motor neurons in vivo by relying on the visualization of the axon initial segment, a subcellular structure known to undergo compensatory structural changes in response to perturbations in excitatory input. I discovered that cultured motor neurons derived from stem cells of the SOD1G93A mouse model of ALS display shortened axon initial segments and hypoexcitable electrophysiological properties. The shortening of the axon initial segment is compensatory, as ALS motor neurons receive increased numbers of excitatory inputs and manifest increased spontaneous activity. Remarkably, similar shortening of the axon initial segment was detected in early presymptomatic spinal motor neurons in vivo. The shortened axon initial segment persists into the symptomatic stages and is particularly pronounced in motor neurons containing p62 immunoreactive aggregates and neurons exhibiting swollen mitochondria, two signs of stress and neurodegeneration in the disease. Based on these observations I propose that early in the presymptomatic stages of the disease, spinal motor neurons recruit excessive excitatory inputs, resulting in their increased activity that is in part compensated by shortening of the axon initial segment. This state persists and becomes even more pronounced in motor neurons exhibiting biochemical changes preceding neurodegeneration. While these observations support the potential role for excitotoxic stress in spinal ALS motor neurons, I paradoxically observed the opposite phenotype in ALS-vulnerable cranial motor neurons in the brainstem of the SOD1G93A animals, raising the possibility that the cellular stress that drives the neurodegeneration in ALS is motor neuron subtype specific

Detection of human influence on a new, validated 1500-Year temperature reconstruction

Climate records over the last millennium place the twentieth-century warming in a longer historical context. Reconstructions of millennial temperatures show a wide range of variability, raising questions about the reliability of currently available reconstruction techniques and the uniqueness of late-twentieth-century warming. A calibration method is suggested that avoids the loss of low-frequency variance. A new reconstruction using this method shows substantial variability over the last 1500 yr. This record is consistent with independent temperature change estimates from borehole geothermal records, compared over the same spatial and temporal domain. The record is also broadly consistent with other recent reconstructions that attempt to fully recover low-frequency climate variability in their central estimate. High variability in reconstructions does not hamper the detection of greenhouse gas-induced climate change, since a substantial fraction of the variance in these reconstructions from the beginning of the analysis in the late thirteenth century to the end of the records can be attributed to external forcing. Results from a detection and attribution analysis show that greenhouse warming is detectable in all analyzed high-variance reconstructions (with the possible exception of one ending in 1925), and that about a third of the warming in the first half of the twentieth century can be attributed to anthropogenic greenhouse gas emissions. The estimated magnitude of the anthropogenic signal is consistent with most of the warming in the second half of the twentieth century being anthropogenic

The Influence of Soil Moisture Upon the Geothermal Climate Signal

Estimates of regional climate warming over the past few hundred years are being obtained from profiles of borehole temperature versus depth. The assumptions in recovering mean annual Surface Air Temperature (SAT) are that the relationship between the Ground Surface Temperature (GST) and the temperature-depth profile is purely conductive, and that SAT is uniquely coupled to GST. While these assumptions have been demonstrated to be approximately valid, they ignore the role of moisture transport in soil between soil and atmosphere. In this study we examine the influence of climatic changes in precipitation upon mean annual GST with climatic SAT held constant. We use the most recent version of our Prairie SVAT model for a set of 80 years simulations. Our findings are 10 increasing precipitation reduces mean annual GST, 2) phasing maximum precipitation to occur during the warmest months reduces mean annual GST, and 3) increasing the variance of precipitation reduces mean annual GST. The amplitudes of the effects are small but potentially not insignificant fractions of the geothermal climate signal. One of the long-term objectives of this investigation is to use global EOS SAT and remotely sensed soil moisture to link region-specific, geothermal climate signal histories to evolution of regional climate

A model study of the effects of climatic precipitation changes on ground temperatures

Temperature changes at the Earth surface propagate into the subsurface and leave a thermal signature in the underlying soil and rock. Inversions of subsurface temperature measurements yield reconstructions of ground surface temperature (GST) histories that provide estimates of climatic changes. A question remaining in the interpretation of reconstructed GST histories is the extent to which GST changes reflect changes principally in surface air temperature (SAT), or whether other factors may be significant. Here we use a Land Surface Processes (LSP) model to examine the influence of precipitation changes on GST and subsurface temperature and moisture fields on annual to decadal timescales. We model soil and vegetation conditions representative of a prairie region in the southern Great Plains of North America and force the model with meteorological data synthesized from a typical year in the region. Model responses are observed after changes in the amount of daily precipitation, the intensity and frequency of daily precipitation, and the diurnal and seasonal timing of precipitation. We show that: (1) increasing daily precipitation cools mean annual GST, (2) increasing the intensity and reducing the frequency of daily precipitation, while holding the annual amount of precipitation constant, cools mean annual GST, and (3) shifting maximum precipitation to occur in the warmest months cools mean annual GST. We compare modeled results to observed precipitation changes during the 20th century and conclude that the observed precipitation changes would cause only small changes to GST within the modeled region, on the order of 0.1 K or less

Improving Surge Flow Irrigation Efficiency Based on Analysis of Infiltration and Hydrodynamic Effects

This research investigated the movement of a surface flow profile over an infiltrating soil under conditions of surge flow, and theory related thereto, for use in preliminary design procedures for surge irrigation systems. Four specific research areas were: a) development of a surge flow infiltration model; b) the effect Or wetted perimeter on infiltration in furrow; c) design, construction, and calibration of a physical model of an irrigation border/furrow; and d) development of a surge flow furrow irrigation computer model for use in designing surge flow irrigation systems. The effect Or wetted perimeter on infiltration in furrows was investigated using field data. Overall, the Kostiakov cumulative infiltration equation, modified to include wetted perimeter raised to a power greater than unity, appeared to satisfactorily represent the effect of wetted perimeter on infiltration in furrows. The effect of surge flow cycle time and cycle ratio on infiltration in furrows was investigated using a recirculating furrow infiltrometer which simulates surge flow irrigation for various cycle times and cycle ratios. The data collected were used to evaluate two empirical surge flow infiltration models. The effects Of furrow geometry, surface storage, and recession time were considered. The results indicated that infiltration during surge flow irrigation can be effectively described using an empirical model based on the Kostiakov cumulative infiltration equation, the surge cycle ratio, and the surge cycle time. A physical model of an irrigation border/furrow was constructed using a 61 meter long by 0.76 meter wide tilting flume with a 0.09 meter deep infiltrating gravel bed. The model was partitioned into 15 sections of equal length. Each section contained a small computer controlled submersible pump by which water was uniformly withdrawn from the section through the gravel bed. Real time predictor/corrector computer algorithms were developed to simulate discrete spatially and temporally varying nonlinear infiltration. Each partitioned section also contained an electronic water depth sensor. All 15 water depth sensors are connected to a real time data acquisition system which relays depth of flow information to the computer simulating infiltration. The hydraulic effects of the infiltration simulator partitions, the effect of downstream boundaries on upstream flow depths, and the effect of flow depth and velocity distribution on energy loss were investigated. A computer model Or surge flow hydraulics and infiltration was developed for the preliminary design of surge flow systems. The model is based on the kinematic wave assumptions for overland flow, and the cycle ratio-time infiltration model developed during this research project. Hypothetical irrigation simulations indicate that for some high intake rate soils, surge flow has potential for markedly improving distribution efficiency over conventional continuous irrigation. However, the model also indicated that an improperly operated surge flow system can actually have lower efficiency than a continuous flow system; this factor is seldom mentioned in literature on surge irrigation

The surface science of quasicrystals

The surfaces of quasicrystals have been extensively studied since about 1990. In this paper we review work on the structure and morphology of clean surfaces, and their electronic and phonon structure. We also describe progress in adsorption and epitaxy studies. The paper is illustrated throughout with examples from the literature. We offer some reflections on the wider impact of this body of work and anticipate areas for future development. (Some figures in this article are in colour only in the electronic version

Surface Geometry of C60 on Ag(111)

The geometry of adsorbed C60 influences its collective properties. We report the first dynamical low-energy electron diffraction study to determine the geometry of a C60 monolayer, Ag(111)-(23×23)30°-C60, and related density functional theory calculations. The stable monolayer has C60 molecules in vacancies that result from the displacement of surface atoms. C60 bonds with hexagons down, with their mirror planes parallel to that of the substrate. The results indicate that vacancy structures are the rule rather than the exception for C60 monolayers on close-packed metal surfaces. © 2009 The American Physical Society

Altered cellular redox homeostasis and redox responses under standard oxygen cell culture conditions versus physioxia.

In vivo, mammalian cells reside in an environment of 0.5-10% O2 (depending on the tissue location within the body), whilst standard in vitro cell culture is carried out under room air. Little is known about the effects of this hyperoxic environment on treatment-induced oxidative stress, relative to a physiological oxygen environment. In the present study we investigated the effects of long-term culture under hyperoxia (air) on photodynamic treatment. Upon photodynamic irradiation, cells which had been cultured long-term under hyperoxia generated higher concentrations of mitochondrial reactive oxygen species, compared with cells in a physioxic (2% O2) environment. However, there was no significant difference in viability between hyperoxic and physioxic cells. The expression of genes encoding key redox homeostasis proteins and the activity of key antioxidant enzymes was significantly higher after the long-term culture of hyperoxic cells compared with physioxic cells. The induction of antioxidant genes and increased antioxidant enzyme activity appear to contribute to the development of a phenotype that is resistant to oxidative stress-induced cellular damage and death when using standard cell culture conditions. The results from experiments using selective inhibitors suggested that the thioredoxin antioxidant system contributes to this phenotype. To avoid artefactual results, in vitro cellular responses should be studied in mammalian cells that have been cultured under physioxia. This investigation provides new insights into the effects of physioxic cell culture on a model of a clinically relevant photodynamic treatment and the associated cellular pathways

North American megadroughts in the Common Era: reconstructions and simulations

During the Medieval Climate Anomaly (MCA), Western North America experienced episodes of intense aridity that persisted for multiple decades or longer. These megadroughts are well documented in many proxy records, but the causal mechanisms are poorly understood. General circulation models (GCMs) simulate megadroughts, but do not reproduce the temporal clustering of events during the MCA, suggesting they are not caused by the time history of volcanic or solar forcing. Instead, GCMs generate megadroughts through (1) internal atmospheric variability, (2) sea-surface temperatures, and (3) land surface and dust aerosol feedbacks. While no hypothesis has been definitively rejected, and no GCM has accurately reproduced all features (e.g., timing, duration, and extent) of any specific megadrought, their persistence suggests a role for processes that impart memory to the climate system (land surface and ocean dynamics). Over the 21st century, GCMs project an increase in the risk of megadrought occurrence through greenhouse gas forced reductions in precipitation and increases in evaporative demand. This drying is robust across models and multiple drought indicators, but major uncertainties still need to be resolved. These include the potential moderation of vegetation evaporative losses at higher atmospheric [CO₂], variations in land surface model complexity, and decadal to multidecadal modes of natural climate variability that could delay or advance onset of aridification over the the next several decades. Because future droughts will arise from both natural variability and greenhouse gas forced trends in hydroclimate, improving our understanding of the natural drivers of persistent multidecadal megadroughts should be a major research priority

Daily, seasonal, and annual relationships between air and subsurface temperatures

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95285/1/jgrd11942.pd