Many complex systems in Nature are multifractal, a feature closely related to scale invariance. Multifractality is ubiquitous and so it can be found in systems as diverse as marine turbulence, econometric series, heartbeat dynamics and the solar magnetic field. In recent years, there has been growing interest in modelling the multifractal structure in these systems. This has improved our understanding of certain phenomena and has opened the way for applications such as reduction of coding redundancy, reconstruction of data gaps and forecasting of multifractal variables. Exhaustive multifractal characterization of experimental data is needed for tuning parameters of the models. The design of appro- priate algorithms to achieve this purpose remains a major challenge, since discretization, gaps, noise and long-range correlations require ad- vanced processing, especially since multifractal signals are not smooth: due to scale invariance, they are intrinsically uneven and intermittent. In the present study, we introduce a formalism for multifractal data based on microcanonical cascades. We show that with appropri- ate selection of the representation basis, we greatly improve inference capabilities in a robust fashion. In addition, we show two applications of microcanonical cascades: first, forecasting of stock market series; and second, detection of interscale heat transfer in the ocean.

A study into the reconstruction of cascade like events in the IceCube neutrino detector was performed by utilizing in-situ flasher devices. Reconstruction analysis was done with two different flasher settings at each optical module on string 63 at varying depths in the ice. Three different reconstruction algorithms were used to estimate the characteristics of these cascade type events. The characteristics included the estimated vertex position, and the number of photons produced by each flasher. The number of photons produced can be related to the energy for the cascade event via the detailed knowledge of the cascade physics. Results from the analysis show the strengths of using the center of gravity type approaches to estimating the vertex positions of very bright events, and the inability to reconstruct to an accurate position in z which can occur when using more complicated vertex algorithms on the same events. Analysis using the energy reconstruction modules demonstrated the strengths of using methods that take into account the ice properties inside the detector.

Proteolytic processes are often mediated by highly orchestrated cascades, through which protease enzymes function coordinately to ensure a stepwise activation. This thesis presents experimental data which supports and complements the previously postulated mechanism of KLK (kallikrein-related protease) activation through proteolytic cascades. Further examination of the seminal KLK cascade has revealed several of its key (patho) physiological roles in human reproductive system. Multiple members of the seminal KLK cascade, in particular KLK14, were shown to play a pivotal role in regulating semen liquefaction. The cascade was further shown to be tightly regulated through a series of highly orchestrated feedback loops, to prevent deleterious effects due to aberrant protease activation. Accordingly, a strong association was observed between the expression level of several seminal KLKs, delayed liquefaction, and other markers of semen quality, including semen hyperviscosity. Furthermore, a strong association was found between delayed liquefaction and abnormal sperm motility. Therefore, dysregulated KLK expressions and/or activities were proposed as an underlying cause of male subfertility. Finally, this thesis has provided initial insights into a novel potential function of multiple members of the seminal KLK cascade in activation of the key immune-deviating agent, TGFβ1, in seminal plasma. TGFβ1 activation is postulated to be mediated directly through complete fragmentation or indirectly through partial cleavage and conformational changes of the LAP propeptide motif of the latent TGFβ1. KLK- mediate proteolytic cleavage of the TGFβ1 binding protein, LTBP1, is also suggested as a potential physiological mechanism for release of the membrane-bound latent TGFβ1. Overall, the data provided here may suggest a common regulatory mechanism, involved co-temporally in the two key processes of semen liquefaction and immune-suppression. This might be critical in protecting motile sperms following their release from semen coagulum. Understanding KLK-mediated proteolytic events in seminal plasma can shed light not only on the physiological role of this family of enzymes, but also on some of causes of male subfertility. Accordingly, therapeutic induction of this cascade may be utilized to supplement the current clinical treatment of male subfertility. Conversely, targeted inhibition of key components of the cascade may have potential pharmaceutical utility as a novel topical contraceptive strategy.

Plant-derived natural products continue to be a valuable source of useful therapies for cancer as well as other diseases. As part of a continuing mission to obtain anticancer agents from natural sources, researchers at the National Cancer Institute (NCI) established the 60 human tumor cell line anticancer screen. The schweinfurthins are one family of unique natural products discovered through this screening process. Most of these natural compounds exhibit potent and differential activity in the 60-cell screen. Importantly, the pattern of activity displayed by the schweinfurthins shows no correlation to any clinically used anticancer drug, indicating that this family of natural products probably acts via a novel mechanism or at a novel target. Our group has conducted extensive structure-activity relationship studies in an effort to illuminate the mechanism of action of the schweinfurthins. In this thesis, the preparation and biological activity of a number of new schweinfurthin F analogues possessing variations in the D-ring alkyl chain and stilbene moiety will be discussed. These studies have clarified the importance of the D-ring to the schweinfurthins' pharmacophore. Based on the results obtained from the exploration of the structural requirements of these natural products, it was determi-ned that the right-half of the schweinfurthins would be an appropriate site for attachment of a molecular probe to be used in affinity experiments. The synthesis of these biotinylated probes will be examined in detail, and their use in pull-down assays will be summarized. The preparation of key schweinfurthin intermediates has involved the extensive use of Lewis acid-mediated cationic cascade cyclizations terminated by MOM-protected phenols. Those successes have inspired investigations of additional applications of these cyclizations. In particular, a variant of these cyclizations using "MOM-protected" enol ethers as reasonable substitutes for β-keto ester terminating moieties has been studied. These interrelated studies involving the synthesis of schweinfurthin analogues and the exploration of cascade cyclizations will be discussed in detail.

Atypical hemolytic uremic syndrome (aHUS) is characterized by acute renal failure, thrombocytopenia, and microangiopathic hemolytic anemia. aHUS is far less common and more severe than typical HUS, which is caused by E. coli infection and manifests as diarrheal illness. The pathogenesis of the disease is linked to dysregulation of the alternative pathway of the complement cascade. Mutations in the complement regulators factor H (CFH), membrane cofactor protein (MCP), factor B (CFB), and factor I (CFI) have been implicated in aHUS. These loss or gain of function mutations lead to uncontrolled complement activity and immune-mediated host cell damage. Establishing a genetic etiology is important as it helps to direct treatment during the acute phase of disease and when transplantation is considered. It has been shown in previous studies that the age of onset as well the severity of the disease is correlated with the type of mutation a patient is found to carry. In forty percent of aHUS patients a mutation in CFH, MCP, CFB, CFI, C3 or THBD is not detected. These data strongly suggest that other genetic factors are involved in the pathogenesis of aHUS and that comprehensive mutation detection in aHUS patients is essential to provide diagnostic and prognostic information, and improve their clinical care. My thesis work has aimed to identify the other genetic contributors to this disease. To achieve this goal we began by screening the largest American cohort of aHUS patients for mutations in CFH, MCP, CFB, CFI, C3, THBD as well as CFHR5. This study identified over thirty novel mutations and suggests a more comprehensive genetic screening method that would better serve patients. To complement these studies multiplex ligation-dependent probe amplification was used to detect genetic rearrangements within the factor H related genes. A number of unique fusion proteins were seen in aHUS patients, all of which are predicted to affect the function of CFH. To discover mutations in novel genes that are causally related to aHUS, we have optimized a platform called CASCADE (Capture and Sequencing of Complement-Associated Disease Exons), which is based on targeted-genome capture and next-generation sequencing. This study revealed an unexpected role for ADAMTS13 and other genes in the coagulation pathway as modifiers of aHUS. Using functional assays we show two of the ADAMTS13 variants alter the behavior of this protein. This work has changed how we view this disease by identifying several novel candidate genes, for which we hope future analysis will lead to a better understanding of their role in aHUS. Using this knowledge we can provide better and more personalized treatments for patients.

This thesis quantitatively investigates gaseous electron-ion recombination in an environmental scanning electron microscope (ESEM) at a transient level by utilizing the dark shadows/streaks seen in gaseous secondary electron detector (GSED) images immediately after a region of enhanced secondary electron (SE) emission is encountered by a scanning electron beam. The investigation firstly derives a theoretical model of gaseous electron-ion recombination that takes into consideration transients caused by the time constant of the GSED electronics and external circuitry used to generate images. Experimental data of pixel intensity versus time of the streaks is then simulated using the model enabling the relative magnitudes of (i) ionization and recombination rates, (ii) recombination coefficients, and (iii) electron drift velocities, as well as absolute values of the total time constant of the detection system, to be determined as a function of microscope operating parameters. Results reveal the exact dependence that the effects of SE-ion recombination on signal formation have on reduced electric field intensity and time in ESEM. Furthermore, the model implicitly demonstrates that signal loss as a consequence of field retardation due to ion space charges, although obviously present, is not the foremost phenomenon causing streaking in images, as previously thought. Following that the generation and detection of gaseous scintillation and electro- luminescence produced via electron-gas molecule excitation reactions in ESEM is investigated. Here a novel gaseous scintillation detection (GSD) system is developed to efficiently detect photons produced. Images acquired using GSD are compared to those obtained using conventional GSED detection, and demonstrate that images rich in SE contrast can be achieved using such systems. A theoretical model is developed that describes the generation of photon signals by cascading SEs, high energy backscattered electrons (BSEs) and primary beam electrons (PEs). Photon amplification, or the total number of photons produced per sample emissive electron, is then investigated, and compared to conventional electronic amplification, over a wide range of microscope operating parameters, imaging gases and photon collection geometries. The main findings of the investigation revealed that detected electroluminescent signals exhibit larger SE signal-to-background levels than that of conventional electronic signals detected via GSED. Also, dragging the electron cascade towards the light pipe assemblage of GSD systems, or electrostatic focusing, dramatically increases photon collection efficiencies. The attainment of such an improvement being a direct consequence of increasing the `effective' solid angle for photon collection. Finally, in attempt to characterize the scintillating wavelengths arising from sample emissive SEs, PEs, BSEs, and their respective cascaded electrons, such that future photon filtering techniques can be employed to extract nominated GSD imaging signals, the emission spectra of commonly utilized electroluminescent gases in ESEM, such as argon (Ar) and nitrogen (N2), were collected and investigated. Spectra of Ar and N2 reveal several major emission lines that occur in the ultraviolet (UV) to near infrared (NIR) regions of the electromagnetic spectrum. The major photon emissions discovered in Ar are attributed to occur via atomic de-excitation transitions of neutral Ar (Ar I), whilst for N2, major emissions are attributed to be a consequence of second positive band vibrational de-excitation reactions. Major wavelength intensity versus gas pressure data, for both Ar and N2, illustrate that wavelength intensities increase with decreasing pressure. This phenomenon strongly suggesting that quenching effects and reductions in excitation mean free paths increase with imaging gas pressure.

Gravity measurements made during 1979 and 1980, combined with existing gravity measurements, provide data for the interpretation of upper crustal structures relevant to the assessment of the geothermal potential of south-central Oregon. West of Upper Klamath Lake, free-air gravity anomalies trend north-south and average near 35 mgals. East of Upper Klamath Lake, free-air gravity anomalies trend west to northwest, and average near ten mgals. The complete Bouguer anomaly field exhibits a regional gradient of nearly .4 mgals/km, which is attributed to the existence of a low-density upper mantle layer beneath the Basin and Range province. The large northwest-trending negative anomaly associated with the Klamath graben suggests a depth of low-density fill of up to 2300 m (7500 feet). The regional gravity field exhibits a broad regional high over the area surrounding Klamath Falls which may be caused by a shallow mantle or a large intrusive body at depth, or may simply be due to intense silicification of the area by thermal waters. The residual anomaly field exhibits broad bands of positive anomalies which enclose the negative anomaly associated with the Klamath graben. The easternmost of these broad, positive trends may correspond to the eastern flank of an anticline which may have existed prior to graben faulting. Positive anomalies west of the graben coincide with the Mount McLoughlin lineament. A large positive anomaly located south of Sprague River is interpreted to be a volcanic center and the heat source for thermal waters found in the Sprague River Valley. A two-dimensional cross section near 42°26' N. latitude suggests that step-like faults form the west side of the Klamath graben. The model indicates the presence of a high density body south of Sprague River that is interpreted to be a buried volcanic source for local extrusive volcanic rocks. Northwest-trending gravity anomalies west of Upper Klamath Lake indicate that structural trends of the Basin and Range province extend into the Cascade Mountains, and suggest that a heat source for thermal waters may exist beneath the High Cascades, rather than beneath the areas which exhibit geothermal activity. / Graduation date: 1982

Graduation date: 1982

This thesis examines factors limiting understory herb presence and flowering in young second-growth Douglas-fir (Pseudotsuga menziesii) forests on the west side of the Cascade Mountains, Oregon, USA. I studied the belowground effects of canopy trees on understory herbs and shrubs in old-growth forests using trenched plots from which tree roots were excluded. Effects of tree density and stand age were tested by comparing the understory community composition of old-growth stands and pre-commercially thinned and unthinned young second-growth stands. I also examined the effect of conifer basal area on understory herb presence and flowering within one young second-growth watershed. In young stands, I focused on three groups of understory herb species: disturbance-responsive (release), forest generalist and old-growth associated. The effects of root trenching on vegetation and soil moisture were tested in closed-canopy and gap locations in two old-growth Douglas-fir (Pseudotsuga menziesii) forests. Ten years after installation, trenched plots averaged 92% total understory cover while untrenched plots averaged 47% cover. Trenched plots under closed canopies were moister than control plots throughout the growing season; the trenching effect on soil moisture became apparent in the generally wetter gaps only at the end of the growing season. Vegetation responses to trenching were concomitantly larger under closed canopies than in gaps. Stands that had been pre-commercially thinned 20 years earlier exhibited understory composition more similar to old growth than did unthinned stands. Thinned stands exhibited higher frequencies, abundances and density of flowering of old-growth associated herbs than did unthinned stands, but lower than did old-growth stands. Forest generalist and release species showed mixed responses to thinning. I used both general linear models and classification and regression tree models to explore the association of herb species presence and flowering with conifer basal area and abiotic variables. Both modeling approaches yielded similar biological insights. Flowering was more sensitive than presence to current stand basal area. Flowering of old-growth associated and release species was negatively correlated with conifer basal area. Linear models allowed clearer hypothesis tests, while tree-based models had greater explanatory power and provided information about interactions between variables. / Graduation date: 2004

This study presents the development of a cell-based routing model. The model developed is a two parameter hydrological routing model that uses a coarse resolution stream network to route runoff from each cell in the watershed to the outlet. The watershed is divided into a number of equal cells, which are approximated as cascade of linear reservoirs or tanks. Water is routed from a cell downstream, depending on the flow direction of the cell, using the cascade of tanks. The routing model consists of two phases, first is the overland flow routing, which is followed by the channel flow routing. In this study, the cell-to-cell stream flow routing model is applied to the Brazos River Basin to demonstrate the impact of the cascade of tanks on the flow over a simple linear reservoir method. This watershed was tested with a uniform runoff depth in absence of observed runoff data. A case study on Waller Creek in Austin, Texas with observed runoff depths and stream flow is used to demonstrate the calibration and validation of model parameters.