Doctor of Philosophy

dissertationIntegration of sensory inputs by the central nervous system (CNS) is necessary for adequate postural stability, but diminishes with age and is further impaired in Parkinson disease (PD). As a result, the CNS cannot appropriately weight sensory stimuli to facilitate postural responses to sudden changes in sensory input. Training the sensorimotor system to ignore or rapidly adapt to aberrant postural cues may improve postural control in PD. We evaluated the influence of acute and repeated exposure to galvanic vestibular stimulation (GVS) on postural responses during static and dynamic tasks to determine whether training improved these responses. We hypothesized that individuals with PD would demonstrate impaired postural recovery responses to acute GVS relative to healthy controls and that individuals with PD and healthy elders would demonstrate diminished adaptive responses to repeated GVS compared to young adults. Twelve individuals with PD (PD group), 15 healthy young adults (HY group), and 11 healthy elders (HE group) participated. Timing of GVS was randomly applied during each task. Fifteen acquisition and nine retention trials with GVS were compared to assess learning. The PD group took longer to stabilize their center of pressure (COP) in quiet stance following GVS acutely compared to controls. The PD and HE groups had lower sample entropy (SaEn) compared to the HY. Neither the PD nor HE groups demonstrated changes in SaEn or meaningful improvements in postural control during acquisition or retention. SaEn in the HY group acutely decreased and then increased at retention which coincided with a meaningful improvement in postural control. The PD group had impaired motor planning, postural preparation, and postural stability during a rise to toes task following acute GVS, but these constructs returned to baseline at later acquisition and retention time points. Controls suppressed GVS acutely Postural coordination decreased acutely in the PD group during tether release. This persisted and an adaptive trend in BOS transition was noted with repeated GVS exposure in this group. No changes were observed in the control groups. Taken together, these results demonstrated that acute GVS differentially affects postural control in individuals with PD. Our results support the hypothesis that reweighting of sensory stimuli is impaired in PD. We also show that individuals with PD are able to suppress attention to a vestibular illusion and demonstrate adaptive responses to a postural threat

The Great Geospace Observatory and Simultaneous Missions of Opportunity

A predictive understanding of the sun to geospace environment is one of the main goals of ILWS. This can only be achieved through a "system-level" approach, meaning long-term, simultaneous, continuous observations across the relevant scales of the magnetosphere and ionosphere/thermosphere (IT). To date such an approach, which must involve simultaneous, multi-scale, global imaging of different geospace regions, has not been carried out for a complete geomagnetic storm. Such imagery, now routine for the Solar community, is of critical scientific importance and captures public imagination. Its absence in geospace studies has limited the growth and impact of geospace science. In this presentation, we discuss a concept called the Great Geospace Observatory, which would involve coordinated geospace imaging through an international effort of multiple, simultaneous Missions of Opportunity. In this way, the cost would be spread among different agencies as well as putting remote sensors in vantage points optimized for each type of imaging. 24/7 auroral imaging from weather satellites on Molniya (or similar) orbits, EUV imaging of the plasmasphere from high-inclination orbits, continuous and global ENA imaging from geosynchronous commercial satellites, and continuous X-ray imaging of the cusp and magnetosheath from a high-altitude dedicated probe would quantitatively track system-level dynamics at through substorms, sawtooth events, steady magnetospheric convection, and storms; studying energy and mass coupling between the solar wind, magnetosphere, and the upper atmosphere. In our minds, The Great Geospace Observatory represents the next strategic step for ILWS and needs to be seriously considered

Search for plant biomagnetism with a sensitive atomic magnetometer

We report what we believe is the first experimental limit placed on plant biomagnetism. Measurements with a sensitive atomic magnetometer were performed on the Titan arum (Amorphophallus titanum) inflorescence, known for its fast bio-chemical processes while blooming. We find that the surface magnetic field from these processes, projected along the Earth's magnetic field, and measured at the surface of the plant, is less then ~0.6uG.Comment: 5 pages, 5 figures, to be published - modified one sentence in abstract + reformatted fi

An Analysis of Private School Closings

We add to the small literature on private school supply by exploring exits of K-12 private schools. We find that the closure of private schools is not an infrequent event, and use national survey data from the National Center for Education Statistics to study closures of private schools. We assume that the probability of an exit is a function of excess supply of private schools over the demand, as well as the school's characteristics such as age, size, and religious affiliation. Our empirical results generally support the implications of the model. Working Paper 07-0

Adam Smith’s Green Thumb and Malthus’ Three Horsemen: Cautionary tales from classical political economy

This essay identifies a contradiction between the flourishing interest in the environmental economics of the classical period and a lack of critical parsing of the works of its leading representatives. Its focus is the work of Adam Smith and Thomas Malthus. It offers a critical analysis of their contribution to environmental thought and surveys the work of their contemporary devotees. It scrutinizes Smith's contribution to what Karl Polanyi termed the "economistic fallacy," as well as his defenses of class hierarchy, the "growth imperative" and consumerism. It subjects to critical appraisal Malthus's enthusiasm for private property and the market system, and his opposition to market regulation. While Malthus's principal attraction to ecological economists lies in his having allegedly broadened the scope of economics, and in his narrative of scarcity, this article shows that he, in fact, narrowed the scope of the discipline and conceptualized scarcity in a reified and pseudo-scientific way

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Judicial Review, Irrationality, and the Limits of Intervention by the Courts

When exercising judicial review, the courts, on occasions, have intervened in circumstances where administrative decisions were not irrational. However, these low standards of judicial intervention are arguably constitutional, especially since the enactment of the Human Rights Act 1998 (HRA). To this end, this article seeks to establish a zone of executive decision-making, for reasons of democracy, where the courts are clearly excluded. But it is unable to do so. Does this mean, therefore, that judicial intervention on the grounds of irrationality exists without limit? Assuming this to be the case, it is suggested that the courts should show greater respect to the administrative branch of the state where it has genuinely sought to engage with the legal process in arriving at its decisions

The James Webb Space Telescope Mission: Optical Telescope Element Design, Development, and Performance

The James Webb Space Telescope (JWST) is a large, infrared space telescope that has recently started its science program which will enable breakthroughs in astrophysics and planetary science. Notably, JWST will provide the very first observations of the earliest luminous objects in the Universe and start a new era of exoplanet atmospheric characterization. This transformative science is enabled by a 6.6 m telescope that is passively cooled with a 5-layer sunshield. The primary mirror is comprised of 18 controllable, low areal density hexagonal segments, that were aligned and phased relative to each other in orbit using innovative image-based wavefront sensing and control algorithms. This revolutionary telescope took more than two decades to develop with a widely distributed team across engineering disciplines. We present an overview of the telescope requirements, architecture, development, superb on-orbit performance, and lessons learned. JWST successfully demonstrates a segmented aperture space telescope and establishes a path to building even larger space telescopes.Comment: accepted by PASP for JWST Overview Special Issue; 34 pages, 25 figure

Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women

Background: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. Methods: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. Results: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC. Conclusions: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2