Aseismic deformation in subduction megathrusts : central Andes and north-east Japan

We aim to characterize fault slip behavior during all stages of the seismic cycle in subduction megathrust environments with the eventual goal of understanding temporal and spatial variations of fault zone rheology, and to infer possible causal relationships between inter-, co- and post-seismic slip, as well as implications for earthquake and tsunami hazard. In particular we focus on analyzing aseismic deformation occurring during inter-seismic and post-seismic periods of the seismic cycle. We approach the problem using both Bayesian and optimization techniques. The Bayesian approach allows us to completely characterize the model parameter space by searching a posteriori estimates of the range of allowable models, to easily implement any kind of physically plausible a priori information and to perform the inversion without regularization other than that imposed by the parameterization of the model. However, the Bayesian approach computational expensive and not currently viable for quick response scenarios. Therefore, we also pursue improvements in the optimization inference scheme. We present a novel, robust and yet simple regularization technique that allows us to infer robust and somewhat more detailed models of slip on faults. We apply such methodologies, using simple quasi-static elastic models, to perform studies of inter- seismic deformation in the Central Andes subduction zone, and post-seismic deformation induced by the occurrence of the 2011 Mw 9.0 Tohoku-Oki earthquake in Japan. For the Central Andes, we present estimates of apparent coupling probability of the subduction interface and analyze its relationship to past earthquakes in the region. For Japan, we infer high spatial variability in material properties of the megathrust offshore Tohoku. We discuss the potential for a large earthquake just south of the Tohoku-Oki earthquake where our inferences suggest dominantly aseismic behavior.

Single cell proteomics microchip to profile immune function, with applications in stem cell biology, translational disease mechanism study and clinical therapeutics monitoring

In response to infection or tissue dysfunction, immune cells develop into highly heterogeneous repertoires with diverse functions. Capturing the full spectrum of these functions requires analysis of large numbers of effector molecules from single cells. However, currently only 3-5 functional proteins can be measured from single cells. We developed a single cell functional proteomics approach that integrates a microchip platform with multiplex cell purification. This approach can quantitate 20 proteins from >5,000 phenotypically pure single cells simultaneously. With a 1-million fold miniaturization, the system can detect down to ~100 molecules and requires only ~104 cells. Single cell functional proteomic analysis finds broad applications in basic, translational and clinical studies. In the three studies conducted, it yielded critical insights for understanding clinical cancer immunotherapy, inflammatory bowel disease (IBD) mechanism and hematopoietic stem cell (HSC) biology.

To study phenotypically defined cell populations, single cell barcode microchips were coupled with upstream multiplex cell purification based on up to 11 parameters. Statistical algorithms were developed to process and model the high dimensional readouts. This analysis evaluates rare cells and is versatile for various cells and proteins. (1) We conducted an immune monitoring study of a phase 2 cancer cellular immunotherapy clinical trial that used T-cell receptor (TCR) transgenic T cells as major therapeutics to treat metastatic melanoma. We evaluated the functional proteome of 4 antigen-specific, phenotypically defined T cell populations from peripheral blood of 3 patients across 8 time points. (2) Natural killer (NK) cells can play a protective role in chronic inflammation and their surface receptor – killer immunoglobulin-like receptor (KIR) – has been identified as a risk factor of IBD. We compared the functional behavior of NK cells that had differential KIR expressions. These NK cells were retrieved from the blood of 12 patients with different genetic backgrounds. (3) HSCs are the progenitors of immune cells and are thought to have no immediate functional capacity against pathogen. However, recent studies identified expression of Toll-like receptors (TLRs) on HSCs. We studied the functional capacity of HSCs upon TLR activation. The comparison of HSCs from wild-type mice against those from genetics knock-out mouse models elucidates the responding signaling pathway.

In all three cases, we observed profound functional heterogeneity within phenotypically defined cells. Polyfunctional cells that conduct multiple functions also produce those proteins in large amounts. They dominate the immune response. In the cancer immunotherapy, the strong cytotoxic and antitumor functions from transgenic TCR T cells contributed to a ~30% tumor reduction immediately after the therapy. However, this infused immune response disappeared within 2-3 weeks. Later on, some patients gained a second antitumor response, consisted of the emergence of endogenous antitumor cytotoxic T cells and their production of multiple antitumor functions. These patients showed more effective long-term tumor control. In the IBD mechanism study, we noticed that, compared with others, NK cells expressing KIR2DL3 receptor secreted a large array of effector proteins, such as TNF-α, CCLs and CXCLs. The functions from these cells regulated disease-contributing cells and protected host tissues. Their existence correlated with IBD disease susceptibility. In the HSC study, the HSCs exhibited functional capacity by producing TNF-α, IL-6 and GM-CSF. TLR stimulation activated the NF-κB signaling in HSCs. Single cell functional proteome contains rich information that is independent from the genome and transcriptome. In all three cases, functional proteomic evaluation uncovered critical biological insights that would not be resolved otherwise. The integrated single cell functional proteomic analysis constructed a detail kinetic picture of the immune response that took place during the clinical cancer immunotherapy. It revealed concrete functional evidence that connected genetics to IBD disease susceptibility. Further, it provided predictors that correlated with clinical responses and pathogenic outcomes.

Dynamic response of structures with uncertain parameters

This thesis presents a technique for obtaining the response of linear structural systems with parameter uncertainties subjected to either deterministic or random excitation. The parameter uncertainties are modeled as random variables or random fields, and are assumed to be time-independent. The new method is an extension of the deterministic finite element method to the space of random functions.

First, the general formulation of the method is developed, in the case where the excitation is deterministic in time. Next, the application of this formulation to systems satisfying the one-dimensional wave equation with uncertainty in their physical properties is described. A particular physical conceptualization of this equation is chosen for study, and some engineering applications are discussed in both an earthquake ground motion and a structural context.

Finally, the formulation of the new method is extended to include cases where the excitation is random in time. Application of this formulation to the random response of a primary-secondary system is described. It is found that parameter uncertainties can have a strong effect on the system response characteristics.

Earthquake response of steel braces and braced steel frames

This thesis consists of three parts. Chapter 2 deals with the dynamic buckling behavior of steel braces under cyclic axial end displacement. Braces under such a loading condition belong to a class of "acceleration magnifying" structural components, in which a small motion at the loading points can cause large internal acceleration and inertia. This member-level inertia is frequently ignored in current studies of braces and braced structures. This chapter shows that, under certain conditions, the inclusion of the member-level inertia can lead to brace behavior fundamentally different from that predicted by the quasi-static method. This result is to have significance in the correct use of the quasi-static, pseudo-dynamic and static condensation methods in the simulation of braces or braced structures under dynamic loading. The strain magnitude and distribution in the braces are also studied in this chapter.

Chapter 3 examines the effect of column uplift on the earthquake response of braced steel frames and explores the feasibility of flexible column-base anchoring. It is found that fully anchored braced-bay columns can induce extremely large internal forces in the braced-bay members and their connections, thus increasing the risk of failures observed in recent earthquakes. Flexible braced-bay column anchoring can significantly reduce the braced bay member force, but at the same time also introduces large story drift and column uplift. The pounding of an uplifting column with its support can result in very high compressive axial force.

Chapter 4 conducts a comparative study on the effectiveness of a proposed non-buckling bracing system and several conventional bracing systems. The non-buckling bracing system eliminates buckling and thus can be composed of small individual braces distributed widely in a structure to reduce bracing force concentration and increase redundancy. The elimination of buckling results in a significantly more effective bracing system compared with the conventional bracing systems. Among the conventional bracing systems, bracing configurations and end conditions for the bracing members affect the effectiveness.

The studies in Chapter 3 and Chapter 4 also indicate that code-designed conventionally braced steel frames can experience unacceptably severe response under the strong ground motions recorded during the recent Northridge and Kobe earthquakes.

A theoretical and empirical study of addiction

Consumption of addictive substances poses a challenge to economic models of rational, forward-looking agents. This dissertation presents a theoretical and empirical examination of consumption of addictive goods.

The theoretical model draws on evidence from psychology and neurobiology to improve on the standard assumptions used in intertemporal consumption studies. I model agents who may misperceive the severity of the future consequences from consuming addictive substances and allow for an agent's environment to shape her preferences in a systematic way suggested by numerous studies that have found craving to be induced by the presence of environmental cues associated with past substance use. The behavior of agents in this behavioral model of addiction can mimic the pattern of quitting and relapsing that is prevalent among addictive substance users.

Chapter 3 presents an empirical analysis of the Becker and Murphy (1988) model of rational addiction using data on grocery store sales of cigarettes. This essay empirically tests the model's predictions concerning consumption responses to future and past price changes as well as the prediction that the response to an anticipated price change differs from the response to an unanticipated price change. In addition, I consider the consumption effects of three institutional changes that occur during the time period 1996 through 1999.

Model systems for the study of drug hypersensitivity

I. It was not possible to produce anti-tetracycline antibody in laboratory animals by any of the methods tried. Tetracycline protein conjugates were prepared and characterized. It was shown that previous reports of the detection of anti-tetracycline antibody by in vitro-methods were in error. Tetracycline precipitates non-specifically with serum proteins. The anaphylactic reaction reported was the result of misinterpretation, since the observations were inconsistent with the known mechanism of anaphylaxis and the supposed antibody would not sensitize guinea pig skin. The hemagglutination reaction was not reproducible and was extremely sensitive to minute amounts of microbial contamination. Both free tetracyclines and the conjugates were found to be poor antigens.

II. Anti-aspiryl antibodies were produced in rabbits using 3 protein carriers. The method of inhibition of precipitation was used to determine the specificity of the antibody produced. ε-Aminocaproate was found to be the most effective inhibitor of the haptens tested, indicating that the combining hapten of the protein is ε-aspiryl-lysyl. Free aspirin and salicylates were poor inhibitors and did not combine with the antibody to a significant extent. The ortho group was found to participate in the binding to antibody. The average binding constants were measured.

Normal rabbit serum was acetylated by aspirin under in vitro conditions, which are similar to physiological conditions. The extent of acetylation was determined by immunochemical tests. The acetylated serum proteins were shown to be potent antigens in rabbits. It was also shown that aspiryl proteins were partially acetylated. The relation of these results to human aspirin intolerance is discussed.

III. Aspirin did not induce contact sensitivity in guinea pigs when they were immunized by techniques that induce sensitivity with other reactive compounds. The acetylation mechanism is not relevant to this type of hypersensitivity, since sensitivity is not produced by potent acetylating agents like acetyl chloride and acetic anhydride. Aspiryl chloride, a totally artificial system, is a good sensitizer. Its specificity was examined.

IV. Protein conjugates were prepared with p-aminosalicylic acid and various carriers using azo, carbodiimide and mixed anhydride coupling. These antigens were injected into rabbits and guinea pigs and no anti-hapten IgG or IgM response was obtained. Delayed hypersensitivity was produced in guinea pigs by immunization with the conjugates, and its specificity was determined. Guinea pigs were not sensitized by either injections or topical application of p-amino-salicylic acid or p-aminosalicylate.

Response of linear, viscous damped systems to excitations having time-varying frequency

The response of linear, viscous damped systems to excitations having time-varying frequency is the subject of exact and approximate analyses, which are supplemented by an analog computer study of single degree of freedom system response to excitations having frequencies depending linearly and exponentially on time.

The technique of small perturbations and the methods of stationary phase and saddle-point integration, as well as a novel bounding procedure, are utilized to derive approximate expressions characterizing the system response envelope—particularly near resonances—for the general time-varying excitation frequency.

Descriptive measurements of system resonant behavior recorded during the course of the analog study—maximum response, excitation frequency at which maximum response occurs, and the width of the response peak at the half-power level—are investigated to determine dependence upon natural frequency, damping, and the functional form of the excitation frequency.

The laboratory problem of determining the properties of a physical system from records of its response to excitations of this class is considered, and the transient phenomenon known as “ringing” is treated briefly.

It is shown that system resonant behavior, as portrayed by the above measurements and expressions, is relatively insensitive to the specifics of the excitation frequency-time relation and may be described to good order in terms of parameters combining system properties with the time derivative of excitation frequency evaluated at resonance.

One of these parameters is shown useful for predicting whether or not a given excitation having a time-varying frequency will produce strong or subtle changes in the response envelope of a given system relative to the steady-state response envelope. The parameter is shown, additionally, to be useful for predicting whether or not a particular response record will exhibit the “ringing” phenomenon.

Studies of response to earthquake ground motion

A study is made of the accuracy of electronic digital computer calculations of ground displacement and response spectra from strong-motion earthquake accelerograms. This involves an investigation of methods of the preparatory reduction of accelerograms into a form useful for the digital computation and of the accuracy of subsequent digital calculations. Various checks are made for both the ground displacement and response spectra results, and it is concluded that the main errors are those involved in digitizing the original record. Differences resulting from various investigators digitizing the same experimental record may become as large as 100% of the maximum computed ground displacements. The spread of the results of ground displacement calculations is greater than that of the response spectra calculations. Standardized methods of adjustment and calculation are recommended, to minimize such errors.

Studies are made of the spread of response spectral values about their mean. The distribution is investigated experimentally by Monte Carlo techniques using an electric analog system with white noise excitation, and histograms are presented indicating the dependence of the distribution on the damping and period of the structure. Approximate distributions are obtained analytically by confirming and extending existing results with accurate digital computer calculations. A comparison of the experimental and analytical approaches indicates good agreement for low damping values where the approximations are valid. A family of distribution curves to be used in conjunction with existing average spectra is presented. The combination of analog and digital computations used with Monte Carlo techniques is a promising approach to the statistical problems of earthquake engineering.

Methods of analysis of very small earthquake ground motion records obtained simultaneously at different sites are discussed. The advantages of Fourier spectrum analysis for certain types of studies and methods of calculation of Fourier spectra are presented. The digitizing and analysis of several earthquake records is described and checks are made of the dependence of results on digitizing procedure, earthquake duration and integration step length. Possible dangers of a direct ratio comparison of Fourier spectra curves are pointed out and the necessity for some type of smoothing procedure before comparison is established. A standard method of analysis for the study of comparative ground motion at different sites is recommended.

A Multiwavelength Study of the Intracluster Medium and the Characterization of the Multiwavelength Sub/millimeter Inductance Camera

The first part of this thesis combines Bolocam observations of the thermal Sunyaev-Zel’dovich (SZ) effect at 140 GHz with X-ray observations from Chandra, strong lensing data from the Hubble Space Telescope (HST), and weak lensing data from HST and Subaru to constrain parametric models for the distribution of dark and baryonic matter in a sample of six massive, dynamically relaxed galaxy clusters. For five of the six clusters, the full multiwavelength dataset is well described by a relatively simple model that assumes spherical symmetry, hydrostatic equilibrium, and entirely thermal pressure support. The multiwavelength analysis yields considerably better constraints on the total mass and concentration compared to analysis of any one dataset individually. The subsample of five galaxy clusters is used to place an upper limit on the fraction of pressure support in the intracluster medium (ICM) due to nonthermal processes, such as turbulent and bulk flow of the gas. We constrain the nonthermal pressure fraction at r500c to be less than 0.11 at 95% confidence, where r500c refers to radius at which the average enclosed density is 500 times the critical density of the Universe. This is in tension with state-of-the-art hydrodynamical simulations, which predict a nonthermal pressure fraction of approximately 0.25 at r500c for the clusters in this sample.

The second part of this thesis focuses on the characterization of the Multiwavelength Sub/millimeter Inductance Camera (MUSIC), a photometric imaging camera that was commissioned at the Caltech Submillimeter Observatory (CSO) in 2012. MUSIC is designed to have a 14 arcminute, diffraction-limited field of view populated with 576 spatial pixels that are simultaneously sensitive to four bands at 150, 220, 290, and 350 GHz. It is well-suited for studies of dusty star forming galaxies, galaxy clusters via the SZ Effect, and galactic star formation. MUSIC employs a number of novel detector technologies: broadband phased-arrays of slot dipole antennas for beam formation, on-chip lumped element filters for band definition, and Microwave Kinetic Inductance Detectors (MKIDs) for transduction of incoming light to electric signal. MKIDs are superconducting micro-resonators coupled to a feedline. Incoming light breaks apart Cooper pairs in the superconductor, causing a change in the quality factor and frequency of the resonator. This is read out as amplitude and phase modulation of a microwave probe signal centered on the resonant frequency. By tuning each resonator to a slightly different frequency and sending out a superposition of probe signals, hundreds of detectors can be read out on a single feedline. This natural capability for large scale, frequency domain multiplexing combined with relatively simple fabrication makes MKIDs a promising low temperature detector for future kilopixel sub/millimeter instruments. There is also considerable interest in using MKIDs for optical through near-infrared spectrophotometry due to their fast microsecond response time and modest energy resolution. In order to optimize the MKID design to obtain suitable performance for any particular application, it is critical to have a well-understood physical model for the detectors and the sources of noise to which they are susceptible. MUSIC has collected many hours of on-sky data with over 1000 MKIDs. This work studies the performance of the detectors in the context of one such physical model. Chapter 2 describes the theoretical model for the responsivity and noise of MKIDs. Chapter 3 outlines the set of measurements used to calibrate this model for the MUSIC detectors. Chapter 4 presents the resulting estimates of the spectral response, optical efficiency, and on-sky loading. The measured detector response to Uranus is compared to the calibrated model prediction in order to determine how well the model describes the propagation of signal through the full instrument. Chapter 5 examines the noise present in the detector timestreams during recent science observations. Noise due to fluctuations in atmospheric emission dominate at long timescales (less than 0.5 Hz). Fluctuations in the amplitude and phase of the microwave probe signal due to the readout electronics contribute significant 1/f and drift-type noise at shorter timescales. The atmospheric noise is removed by creating a template for the fluctuations in atmospheric emission from weighted averages of the detector timestreams. The electronics noise is removed by using probe signals centered off-resonance to construct templates for the amplitude and phase fluctuations. The algorithms that perform the atmospheric and electronic noise removal are described. After removal, we find good agreement between the observed residual noise and our expectation for intrinsic detector noise over a significant fraction of the signal bandwidth.