This dissertation is concerned with several problems of instrumentation and data analysis encountered by the Apache Point Observatory Lunar Laser-ranging Operation. Chapter 2 considers crosstalk between elements of a single -photon avalanche photodiode detector. Experimental and analytic methods were developed to determine crosstalk rates, and empirical findings are presented. Chapter 3 details electronics developments that have improved the quality of data collected by detectors of the same type. Chapter 4 explores the challenges of estimating gravitational parameters on the basis of ranging data collected by this and other experiments and presents resampling techniques for the derivation of standard errors for estimates of such parameters determined by the Planetary Ephemeris Program (PEP), a solar-system model and data-fitting code. Possible directions for future work are discussed in Chapter 5. A manual of instructions for working with PEP is presented as an appendix

Palpable migratory arciform erythema (PMAE) is an uncommon T cell pseudolymphoma characterized by erythematous, annular-to-arciform papules and plaques. Although the eruption is self-limited in most cases, recurrences are routine. Diagnosis requires attention to clinical history as well as histopathologic analysis, which allow for differentiation from other T cell pseudolymphomas and gyrate erythemas. A common triggering factor has not been identified. We report a 60-year-old man who developed PMAE after IVIg infusion. Interestingly, although the individual eruptions were self-limited and resolved after several weeks, subsequent infusions predictably resulted in recurrence of PMAE, confirming the association. To our knowledge, this is the first reported case of recurrent PMAE in association with IVIg infusions.

Targeted therapy (BRAF/MEK inhibitors) is frequently employed in the treatment of metastatic melanoma following immune checkpoint inhibitor therapy inefficacy or intolerance. Although BRAF inhibitors are commonly associated with cutaneous eruptions, they rarely cause severe cutaneous adverse drug reactions such as drug-induced hypersensitivity syndrome (DIHS). Drug-induced hypersensitivity syndrome is a severe drug reaction characterized by extensive eruption often seen in conjunction with fever, facial edema, lymphadenopathy, eosinophilia, atypical lymphocytosis, and variable visceral organ injury characteristically beginning 2-8 weeks after initiating the causative drug. We report a case of atypical DIHS with reduced latency, mucosal involvement, lymphopenia, normal eosinophils, and no lymphadenopathy that occurred secondary to vemurafenib and cobimetinib therapy following melanoma progression while on pembrolizumab. Previous immune checkpoint inhibitor therapy has been associated with atypical DIHS in patients on BRAF/MEK inhibitors. Early recognition of the atypical clinical features of this hypersensitivity reaction is important so that drug discontinuation and corticosteroids can be initiated early.

Linear porokeratosis is a rare variant of porokeratosis that is characterized by unilateral lesions along the lines of Blaschko. Like all variants of porokeratosis, linear porokeratosis is characterized by the histopathologic finding of cornoid lamellae bracketing the lesion. The underlying pathophysiology involves a two-hit post-zygotic knockdown of genes involved in mevalonate biosynthesis in embryonic keratinocytes. Although there is currently no standard or effective treatment, therapies targeted to rescue this pathway and restore keratinocyte cholesterol availability are promising. Presented here is a patient with a rare, extensive case of linear porokeratosis treated with compounded 2% lovastatin/2% cholesterol cream leading to partial resolution of the plaques.

Fast-acting smart inverters that utilize preset operating conditions to determine real and reactive power injection/consumption can create voltage instabilities (over-voltage, voltage oscillations and more) in an electrical distribution network if set-points are not properly configured. In this work, linear distribution power flow equations and droop-based Volt–Var and Volt–Watt control curves are used to analytically derive a stability criterion using Lyapunov analysis that includes the network operating condition. The methodology is generally applicable for control curves that can be represented as Lipschitz functions. The derived Lipschitz constants account for smart inverter hardware limitations for reactive power generation. A local policy is derived from the stability criterion that allows inverters to adapt their control curves by monitoring only local voltage, thus avoiding centralized control or information sharing with other inverters. The criterion is independent of the internal time-delays of smart inverters. Simulation results for inverters with and without the proposed stabilization technique demonstrate how smart inverters can mitigate voltage oscillations locally and mitigate real and reactive power flow disturbances at the substation under multiple scenarios. The study concludes with illustrations of how the control policy can dampen oscillations caused by solar intermittency and cyberattacks.

Volt-VAR and Volt-Watt functionality in photovoltaic (PV) smart inverters provide mechanisms to ensure system voltage magnitudes and power factors remain within acceptable limits. However, these control functions can become unstable, introducing oscillations in system voltages when not appropriately configured or maliciously altered during a cyberattack. In the event that Volt-VAR and Volt-Watt control functions in a portion of PV smart inverters in a distribution grid are unstable, the proposed adaptation scheme utilizes the remaining and stably-behaving PV smart inverters and other Distributed Energy Resources to mitigate the effect of the instability. The adaptation mechanism is entirely decentralized, model-free, communication-free, and requires virtually no external configuration. We provide a derivation of the adaptive control approach and validate the algorithm in experiments on the IEEE 37 and 8500 node test feeders.

The increasing penetration of DER with smart-inverter functionality is set to transform the electrical distribution network from a passive system, with fixed injection/consumption, to an active network with hundreds of distributed controllers dynamically modulating their operating setpoints as a function of system conditions. This transition is being achieved through standardization of functionality through grid codes and/or international standards. DER, however, are unique in that they are typically neither owned nor operated by distribution utilities and, therefore, represent a new emerging attack vector for cyber-physical attacks. Within this work we consider deep reinforcement learning as a tool to learn the optimal parameters for the control logic of a set of uncompromised DER units to actively mitigate the effects of a cyber-attack on a subset of network DER.

Cognitive impairments are a common consequence of traumatic brain injury (TBI). The hippocampus is a subcortical structure that plays a key role in the formation of declarative memories and is highly vulnerable to TBI. The α7 nicotinic acetylcholine receptor (nAChR) is highly expressed in the hippocampus and reduced expression and function of this receptor are linked with cognitive impairments in Alzheimer's disease and schizophrenia. Positive allosteric modulation of α7 nAChRs with AVL-3288 enhances receptor currents and improves cognitive functioning in naïve animals and healthy human subjects. Therefore, we hypothesized that targeting the α7 nAChR with the positive allosteric modulator AVL-3288 would enhance cognitive functioning in the chronic recovery period of TBI. To test this hypothesis, adult male Sprague Dawley rats received moderate parasagittal fluid-percussion brain injury or sham surgery. At 3 months after recovery, animals were treated with vehicle or AVL-3288 at 30 min prior to cue and contextual fear conditioning and the water maze task. Treatment of TBI animals with AVL-3288 rescued learning and memory deficits in water maze retention and working memory. AVL-3288 treatment also improved cue and contextual fear memory when tested at 24 hr and 1 month after training, when TBI animals were treated acutely just during fear conditioning at 3 months post-TBI. Hippocampal atrophy but not cortical atrophy was reduced with AVL-3288 treatment in the chronic recovery phase of TBI. AVL-3288 application to acute hippocampal slices from animals at 3 months after TBI rescued basal synaptic transmission deficits and long-term potentiation (LTP) in area CA1. Our results demonstrate that AVL-3288 improves hippocampal synaptic plasticity, and learning and memory performance after TBI in the chronic recovery period. Enhancing cholinergic transmission through positive allosteric modulation of the α7 nAChR may be a novel therapeutic to improve cognition after TBI.

Background

Heterodera glycines, commonly referred to as the soybean cyst nematode (SCN), is an obligatory and sedentary plant parasite that causes over a billion-dollar yield loss to soybean production annually. Although there are genetic determinants that render soybean plants resistant to certain nematode genotypes, resistant soybean cultivars are increasingly ineffective because their multi-year usage has selected for virulent H. glycines populations. The parasitic success of H. glycines relies on the comprehensive re-engineering of an infection site into a syncytium, as well as the long-term suppression of host defense to ensure syncytial viability. At the forefront of these complex molecular interactions are effectors, the proteins secreted by H. glycines into host root tissues. The mechanisms of effector acquisition, diversification, and selection need to be understood before effective control strategies can be developed, but the lack of an annotated genome has been a major roadblock.

Results

Here, we use PacBio long-read technology to assemble a H. glycines genome of 738 contigs into 123 Mb with annotations for 29,769 genes. The genome contains significant numbers of repeats (34%), tandem duplicates (18.7 Mb), and horizontal gene transfer events (151 genes). A large number of putative effectors (431 genes) were identified in the genome, many of which were found in transposons.

Conclusions

This advance provides a glimpse into the host and parasite interplay by revealing a diversity of mechanisms that give rise to virulence genes in the soybean cyst nematode, including: tandem duplications containing over a fifth of the total gene count, virulence genes hitchhiking in transposons, and 107 horizontal gene transfers not reported in other plant parasitic nematodes thus far. Through extensive characterization of the H. glycines genome, we provide new insights into H. glycines biology and shed light onto the mystery underlying complex host-parasite interactions. This genome sequence is an important prerequisite to enable work towards generating new resistance or control measures against H. glycines.