Non-contiguous protein recombination

Swapping sequence elements among related proteins can produce chimeric proteins with novel behaviors and improved properties such as enhanced stability. Although homologous mutations are much more conservative than random mutations, chimeras of distantly-related proteins have a low probability of retaining fold and function. Here, I introduce a new tool for protein recombination that identifies structural blocks that can be swapped among homologous proteins with minimal disruption. This non-contiguous recombination approach enables design of chimeras and libraries of chimeras with less disruption than can be achieved by swapping blocks of sequence. Less disruption means that one can generate libraries with higher fractions of functional enzymes and enables recombination of more distant homologs.

Using this new tool I design and construct many functional chimeric cellulases. I illustrate the structurally conservative nature of this recombination by creating a functional prokaryotic-eukaryotic chimera and solving its structure. I also show how non-contiguous recombination can be used to efficiently identify stabilizing mutations that have been incorporated into homologs in nature.

The central nervous control of walking in the locust, Schistocerca Americana

Rhythmic motor behaviors in all animals appear to be under the control of "central pattern generator" circuits, neural circuits which can produce output patterns appropriate for behavior even when isolated from their normal peripheral inputs. Insects have been a useful model system in which to study the control of legged terrestrial locomotion. Much is known about walking in insects at the behavioral level, but to date there has been no clear demonstration that a central pattern generator for walking exists. The focus of this thesis is to explore the central neural basis for locomotion in the locust, Schistocerca americana.

Rhythmic motor patterns could be evoked in leg motor neurons of isolated thoracic ganglia of locusts by the muscarinic agonist pilocarpine. These motor patterns would be appropriate for the movement of single legs during walking. Rhythmic patterns could be evoked in all three thoracic ganglia, but the segmental rhythms differed in their sensitivities to pilocarpine, their frequencies, and the phase relationships of motor neuron antagonists. These different patterns could be generated by a simple adaptable model circuit, which was both simulated and implemented in VLSI hardware. The intersegmental coordination of leg motor rhythms was then examined in preparations of isolated chains of thoracic ganglia. Correlations between motor patterns in different thoracic ganglia indicated that central coupling between segmental pattern generators is likely to contribute to the coordination of the legs during walking.

The work described here clearly demonstrates that segmental pattern generators for walking exist in insects. The pattern generators produce motor outputs which are likely to contribute to the coordination of the joints of a limb, as well as the coordination of different limbs. These studies lay the groundwork for further studies to determine the relative contributions of central and sensory neural mechanisms to terrestrial walking.

Pharmacology and pore-forming domains of the cystic fibrosis transmembrane conductance regulator

The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel member of the ATP-binding cassette (ABC) superfamily of membrane proteins. CFTR has two homologous halves, each consisting of six transmembrane spanning domains (TM) followed by a nucleotide binding fold, connected by a regulatory (R) domain. This thesis addresses the question of which domains are responsible for Cl^- selectivity, i.e., which domains line the channel pore.

To address this question, novel blockers of CFTR were characterized. CFTR was heterologously expressed in Xenopus oocytes to study the mechanism of block by two closely related arylaminobenzoates, diphenylamine-2-carboxylic acid (DPC) and flufenamic acid (FFA). Block by both is voltage-dependent, with a binding site ≈ 40% through the electric field of the membrane. DPC and FFA can both reach their binding site from either side of the membrane to produce a flickering block of CFTR single channels. In addition, DPC block is influenced by Cl^- concentration, and DPC blocks with a bimolecular forward binding rate and a unimolecular dissociation rate. Therefore, DPC and FFA are open-channel blockers of CFTR, and a residue of CFTR whose mutation affects their binding must line the pore.

Screening of site-directed mutants for altered DPC binding affinity reveals that TM-6 and TM-12 line the pore. Mutation of residue 5341 in TM-6 abolishes most DPC block, greatly reduces single-channel conductance, and alters the direction of current rectification. Additional residues are found in TM-6 (K335) and TM-12 (T1134) whose mutations weaken or strengthen DPC block; other mutations move the DPC binding site from TM-6 to TM-12. The strengthened block and lower conductance due to mutation T1134F is quantitated at the single-channel level. The geometry of DPC and of the residues mutated suggest α-helical structures for TM-6 and TM-12. Evidence is presented that the effects of the mutations are due to direct side-chain interaction, and not to allosteric effects propagated through the protein. Mutations are also made in TM-11, including mutation S1118F, which gives voltage-dependent current relaxations. The results may guide future studies on permeation through ABC transporters and through other Cl^- channels.

Topics in gravitational-wave science : macroscopic quantum mechanics and black hole physics

The theories of relativity and quantum mechanics, the two most important physics discoveries of the 20th century, not only revolutionized our understanding of the nature of space-time and the way matter exists and interacts, but also became the building blocks of what we currently know as modern physics. My thesis studies both subjects in great depths --- this intersection takes place in gravitational-wave physics.

Gravitational waves are "ripples of space-time", long predicted by general relativity. Although indirect evidence of gravitational waves has been discovered from observations of binary pulsars, direct detection of these waves is still actively being pursued. An international array of laser interferometer gravitational-wave detectors has been constructed in the past decade, and a first generation of these detectors has taken several years of data without a discovery. At this moment, these detectors are being upgraded into second-generation configurations, which will have ten times better sensitivity. Kilogram-scale test masses of these detectors, highly isolated from the environment, are probed continuously by photons. The sensitivity of such a quantum measurement can often be limited by the Heisenberg Uncertainty Principle, and during such a measurement, the test masses can be viewed as evolving through a sequence of nearly pure quantum states.

The first part of this thesis (Chapter 2) concerns how to minimize the adverse effect of thermal fluctuations on the sensitivity of advanced gravitational detectors, thereby making them closer to being quantum-limited. My colleagues and I present a detailed analysis of coating thermal noise in advanced gravitational-wave detectors, which is the dominant noise source of Advanced LIGO in the middle of the detection frequency band. We identified the two elastic loss angles, clarified the different components of the coating Brownian noise, and obtained their cross spectral densities.

The second part of this thesis (Chapters 3-7) concerns formulating experimental concepts and analyzing experimental results that demonstrate the quantum mechanical behavior of macroscopic objects - as well as developing theoretical tools for analyzing quantum measurement processes. In Chapter 3, we study the open quantum dynamics of optomechanical experiments in which a single photon strongly influences the quantum state of a mechanical object. We also explain how to engineer the mechanical oscillator's quantum state by modifying the single photon's wave function.

In Chapters 4-5, we build theoretical tools for analyzing the so-called "non-Markovian" quantum measurement processes. Chapter 4 establishes a mathematical formalism that describes the evolution of a quantum system (the plant), which is coupled to a non-Markovian bath (i.e., one with a memory) while at the same time being under continuous quantum measurement (by the probe field). This aims at providing a general framework for analyzing a large class of non-Markovian measurement processes. Chapter 5 develops a way of characterizing the non-Markovianity of a bath (i.e.,whether and to what extent the bath remembers information about the plant) by perturbing the plant and watching for changes in the its subsequent evolution. Chapter 6 re-analyzes a recent measurement of a mechanical oscillator's zero-point fluctuations, revealing nontrivial correlation between the measurement device's sensing noise and the quantum rack-action noise.

Chapter 7 describes a model in which gravity is classical and matter motions are quantized, elaborating how the quantum motions of matter are affected by the fact that gravity is classical. It offers an experimentally plausible way to test this model (hence the nature of gravity) by measuring the center-of-mass motion of a macroscopic object.

The most promising gravitational waves for direct detection are those emitted from highly energetic astrophysical processes, sometimes involving black holes - a type of object predicted by general relativity whose properties depend highly on the strong-field regime of the theory. Although black holes have been inferred to exist at centers of galaxies and in certain so-called X-ray binary objects, detecting gravitational waves emitted by systems containing black holes will offer a much more direct way of observing black holes, providing unprecedented details of space-time geometry in the black-holes' strong-field region.

The third part of this thesis (Chapters 8-11) studies black-hole physics in connection with gravitational-wave detection.

Chapter 8 applies black hole perturbation theory to model the dynamics of a light compact object orbiting around a massive central Schwarzschild black hole. In this chapter, we present a Hamiltonian formalism in which the low-mass object and the metric perturbations of the background spacetime are jointly evolved. Chapter 9 uses WKB techniques to analyze oscillation modes (quasi-normal modes or QNMs) of spinning black holes. We obtain analytical approximations to the spectrum of the weakly-damped QNMs, with relative error O(1/L^2), and connect these frequencies to geometrical features of spherical photon orbits in Kerr spacetime. Chapter 11 focuses mainly on near-extremal Kerr black holes, we discuss a bifurcation in their QNM spectra for certain ranges of (l,m) (the angular quantum numbers) as a/M → 1. With tools prepared in Chapter 9 and 10, in Chapter 11 we obtain an analytical approximate for the scalar Green function in Kerr spacetime.

Tissue engineering active biological machines : bio-inspired design, directed self-assembly, and characterization of muscular pumps simulating the embryonic heart

Biological machines are active devices that are comprised of cells and other biological components. These functional devices are best suited for physiological environments that support cellular function and survival. Biological machines have the potential to revolutionize the engineering of biomedical devices intended for implantation, where the human body can provide the required physiological environment. For engineering such cell-based machines, bio-inspired design can serve as a guiding platform as it provides functionally proven designs that are attainable by living cells. In the present work, a systematic approach was used to tissue engineer one such machine by exclusively using biological building blocks and by employing a bio-inspired design. Valveless impedance pumps were constructed based on the working principles of the embryonic vertebrate heart and by using cells and tissue derived from rats. The function of these tissue-engineered muscular pumps was characterized by exploring their spatiotemporal and flow behavior in order to better understand the capabilities and limitations of cells when used as the engines of biological machines.

Transceiver designs and analysis for LTI, LTV and broadcast channels - new matrix decompositions and majorization theory

Signal processing techniques play important roles in the design of digital communication systems. These include information manipulation, transmitter signal processing, channel estimation, channel equalization and receiver signal processing. By interacting with communication theory and system implementing technologies, signal processing specialists develop efficient schemes for various communication problems by wisely exploiting various mathematical tools such as analysis, probability theory, matrix theory, optimization theory, and many others. In recent years, researchers realized that multiple-input multiple-output (MIMO) channel models are applicable to a wide range of different physical communications channels. Using the elegant matrix-vector notations, many MIMO transceiver (including the precoder and equalizer) design problems can be solved by matrix and optimization theory. Furthermore, the researchers showed that the majorization theory and matrix decompositions, such as singular value decomposition (SVD), geometric mean decomposition (GMD) and generalized triangular decomposition (GTD), provide unified frameworks for solving many of the point-to-point MIMO transceiver design problems.

In this thesis, we consider the transceiver design problems for linear time invariant (LTI) flat MIMO channels, linear time-varying narrowband MIMO channels, flat MIMO broadcast channels, and doubly selective scalar channels. Additionally, the channel estimation problem is also considered. The main contributions of this dissertation are the development of new matrix decompositions, and the uses of the matrix decompositions and majorization theory toward the practical transmit-receive scheme designs for transceiver optimization problems. Elegant solutions are obtained, novel transceiver structures are developed, ingenious algorithms are proposed, and performance analyses are derived.

The first part of the thesis focuses on transceiver design with LTI flat MIMO channels. We propose a novel matrix decomposition which decomposes a complex matrix as a product of several sets of semi-unitary matrices and upper triangular matrices in an iterative manner. The complexity of the new decomposition, generalized geometric mean decomposition (GGMD), is always less than or equal to that of geometric mean decomposition (GMD). The optimal GGMD parameters which yield the minimal complexity are derived. Based on the channel state information (CSI) at both the transmitter (CSIT) and receiver (CSIR), GGMD is used to design a butterfly structured decision feedback equalizer (DFE) MIMO transceiver which achieves the minimum average mean square error (MSE) under the total transmit power constraint. A novel iterative receiving detection algorithm for the specific receiver is also proposed. For the application to cyclic prefix (CP) systems in which the SVD of the equivalent channel matrix can be easily computed, the proposed GGMD transceiver has K/log_2(K) times complexity advantage over the GMD transceiver, where K is the number of data symbols per data block and is a power of 2. The performance analysis shows that the GGMD DFE transceiver can convert a MIMO channel into a set of parallel subchannels with the same bias and signal to interference plus noise ratios (SINRs). Hence, the average bit rate error (BER) is automatically minimized without the need for bit allocation. Moreover, the proposed transceiver can achieve the channel capacity simply by applying independent scalar Gaussian codes of the same rate at subchannels.

In the second part of the thesis, we focus on MIMO transceiver design for slowly time-varying MIMO channels with zero-forcing or MMSE criterion. Even though the GGMD/GMD DFE transceivers work for slowly time-varying MIMO channels by exploiting the instantaneous CSI at both ends, their performance is by no means optimal since the temporal diversity of the time-varying channels is not exploited. Based on the GTD, we develop space-time GTD (ST-GTD) for the decomposition of linear time-varying flat MIMO channels. Under the assumption that CSIT, CSIR and channel prediction are available, by using the proposed ST-GTD, we develop space-time geometric mean decomposition (ST-GMD) DFE transceivers under the zero-forcing or MMSE criterion. Under perfect channel prediction, the new system minimizes both the average MSE at the detector in each space-time (ST) block (which consists of several coherence blocks), and the average per ST-block BER in the moderate high SNR region. Moreover, the ST-GMD DFE transceiver designed under an MMSE criterion maximizes Gaussian mutual information over the equivalent channel seen by each ST-block. In general, the newly proposed transceivers perform better than the GGMD-based systems since the super-imposed temporal precoder is able to exploit the temporal diversity of time-varying channels. For practical applications, a novel ST-GTD based system which does not require channel prediction but shares the same asymptotic BER performance with the ST-GMD DFE transceiver is also proposed.

The third part of the thesis considers two quality of service (QoS) transceiver design problems for flat MIMO broadcast channels. The first one is the power minimization problem (min-power) with a total bitrate constraint and per-stream BER constraints. The second problem is the rate maximization problem (max-rate) with a total transmit power constraint and per-stream BER constraints. Exploiting a particular class of joint triangularization (JT), we are able to jointly optimize the bit allocation and the broadcast DFE transceiver for the min-power and max-rate problems. The resulting optimal designs are called the minimum power JT broadcast DFE transceiver (MPJT) and maximum rate JT broadcast DFE transceiver (MRJT), respectively. In addition to the optimal designs, two suboptimal designs based on QR decomposition are proposed. They are realizable for arbitrary number of users.

Finally, we investigate the design of a discrete Fourier transform (DFT) modulated filterbank transceiver (DFT-FBT) with LTV scalar channels. For both cases with known LTV channels and unknown wide sense stationary uncorrelated scattering (WSSUS) statistical channels, we show how to optimize the transmitting and receiving prototypes of a DFT-FBT such that the SINR at the receiver is maximized. Also, a novel pilot-aided subspace channel estimation algorithm is proposed for the orthogonal frequency division multiplexing (OFDM) systems with quasi-stationary multi-path Rayleigh fading channels. Using the concept of a difference co-array, the new technique can construct M^2 co-pilots from M physical pilot tones with alternating pilot placement. Subspace methods, such as MUSIC and ESPRIT, can be used to estimate the multipath delays and the number of identifiable paths is up to O(M^2), theoretically. With the delay information, a MMSE estimator for frequency response is derived. It is shown through simulations that the proposed method outperforms the conventional subspace channel estimator when the number of multipaths is greater than or equal to the number of physical pilots minus one.

Electrical and optical interconnects for high-performance computing

Technology scaling has enabled drastic growth in the computational and storage capacity of integrated circuits (ICs). This constant growth drives an increasing demand for high-bandwidth communication between and within ICs. In this dissertation we focus on low-power solutions that address this demand. We divide communication links into three subcategories depending on the communication distance. Each category has a different set of challenges and requirements and is affected by CMOS technology scaling in a different manner. We start with short-range chip-to-chip links for board-level communication. Next we will discuss board-to-board links, which demand a longer communication range. Finally on-chip links with communication ranges of a few millimeters are discussed.

Electrical signaling is a natural choice for chip-to-chip communication due to efficient integration and low cost. IO data rates have increased to the point where electrical signaling is now limited by the channel bandwidth. In order to achieve multi-Gb/s data rates, complex designs that equalize the channel are necessary. In addition, a high level of parallelism is central to sustaining bandwidth growth. Decision feedback equalization (DFE) is one of the most commonly employed techniques to overcome the limited bandwidth problem of the electrical channels. A linear and low-power summer is the central block of a DFE. Conventional approaches employ current-mode techniques to implement the summer, which require high power consumption. In order to achieve low-power operation we propose performing the summation in the charge domain. This approach enables a low-power and compact realization of the DFE as well as crosstalk cancellation. A prototype receiver was fabricated in 45nm SOI CMOS to validate the functionality of the proposed technique and was tested over channels with different levels of loss and coupling. Measurement results show that the receiver can equalize channels with maximum 21dB loss while consuming about 7.5mW from a 1.2V supply. We also introduce a compact, low-power transmitter employing passive equalization. The efficacy of the proposed technique is demonstrated through implementation of a prototype in 65nm CMOS. The design achieves up to 20Gb/s data rate while consuming less than 10mW.

An alternative to electrical signaling is to employ optical signaling for chip-to-chip interconnections, which offers low channel loss and cross-talk while providing high communication bandwidth. In this work we demonstrate the possibility of building compact and low-power optical receivers. A novel RC front-end is proposed that combines dynamic offset modulation and double-sampling techniques to eliminate the need for a short time constant at the input of the receiver. Unlike conventional designs, this receiver does not require a high-gain stage that runs at the data rate, making it suitable for low-power implementations. In addition, it allows time-division multiplexing to support very high data rates. A prototype was implemented in 65nm CMOS and achieved up to 24Gb/s with less than 0.4pJ/b power efficiency per channel. As the proposed design mainly employs digital blocks, it benefits greatly from technology scaling in terms of power and area saving.

As the technology scales, the number of transistors on the chip grows. This necessitates a corresponding increase in the bandwidth of the on-chip wires. In this dissertation, we take a close look at wire scaling and investigate its effect on wire performance metrics. We explore a novel on-chip communication link based on a double-sampling architecture and dynamic offset modulation technique that enables low power consumption and high data rates while achieving high bandwidth density in 28nm CMOS technology. The functionality of the link is demonstrated using different length minimum-pitch on-chip wires. Measurement results show that the link achieves up to 20Gb/s of data rate (12.5Gb/s/$\mu$m) with better than 136fJ/b of power efficiency.

Interacting single atoms with nanophotonics for chip-integrated quantum networks

Underlying matter and light are their building blocks of tiny atoms and photons. The ability to control and utilize matter-light interactions down to the elementary single atom and photon level at the nano-scale opens up exciting studies at the frontiers of science with applications in medicine, energy, and information technology. Of these, an intriguing front is the development of quantum networks where N >> 1 single-atom nodes are coherently linked by single photons, forming a collective quantum entity potentially capable of performing quantum computations and simulations. Here, a promising approach is to use optical cavities within the setting of cavity quantum electrodynamics (QED). However, since its first realization in 1992 by Kimble et al., current proof-of-principle experiments have involved just one or two conventional cavities. To move beyond to N >> 1 nodes, in this thesis we investigate a platform born from the marriage of cavity QED and nanophotonics, where single atoms at ~100 nm near the surfaces of lithographically fabricated dielectric photonic devices can strongly interact with single photons, on a chip. Particularly, we experimentally investigate three main types of devices: microtoroidal optical cavities, optical nanofibers, and nanophotonic crystal based structures. With a microtoroidal cavity, we realized a robust and efficient photon router where single photons are extracted from an incident coherent state of light and redirected to a separate output with high efficiency. We achieved strong single atom-photon coupling with atoms located ~100 nm near the surface of a microtoroid, which revealed important aspects in the atom dynamics and QED of these systems including atom-surface interaction effects. We present a method to achieve state-insensitive atom trapping near optical nanofibers, critical in nanophotonic systems where electromagnetic fields are tightly confined. We developed a system that fabricates high quality nanofibers with high controllability, with which we experimentally demonstrate a state-insensitive atom trap. We present initial investigations on nanophotonic crystal based structures as a platform for strong atom-photon interactions. The experimental advances and theoretical investigations carried out in this thesis provide a framework for and open the door to strong single atom-photon interactions using nanophotonics for chip-integrated quantum networks.

Plate tectonic constraints on flat subduction and paleomagnetic constraints on rifting

Plate tectonics shapes our dynamic planet through the creation and destruction of lithosphere. This work focuses on increasing our understanding of the processes at convergent and divergent boundaries through geologic and geophysical observations at modern plate boundaries. Recent work had shown that the subducting slab in central Mexico is most likely the flattest on Earth, yet there was no consensus about what caused it to originate. The first chapter of this thesis sets out to systematically test all previously proposed mechanisms for slab flattening on the Mexican case. What we have discovered is that there is only one model for which we can find no contradictory evidence. The lack of applicability of the standard mechanisms used to explain flat subduction in the Mexican example led us to question their applications globally. The second chapter expands the search for a cause of flat subduction, in both space and time. We focus on the historical record of flat slabs in South America and look for a correlation between the shallowing and steepening of slab segments with relation to the inferred thickness of the subducting oceanic crust. Using plate reconstructions and the assumption that a crustal anomaly formed on a spreading ridge will produce two conjugate features, we recreate the history of subduction along the South American margin and find that there is no correlation between the subduction of a bathymetric highs and shallow subduction. These studies have proven that a subducting crustal anomaly is neither a sufficient or necessary condition of flat slab subduction. The final chapter in this thesis looks at the divergent plate boundary in the Gulf of California. Through geologic reconnaissance mapping and an intensive paleomagnetic sampling campaign, we try to constrain the location and orientation of a widespread volcanic marker unit, the Tuff of San Felipe. Although the resolution of the applied magnetic susceptibility technique proved inadequate to contain the direction of the pyroclastic flow with high precision, we have been able to detect the tectonic rotation of coherent blocks as well as rotation within blocks.

Developing peptide based capture agents for diagnostics and therapeutics

Iterative in situ click chemistry (IISCC) is a robust general technology for development of high throughput, inexpensive protein detection agents. In IISCC, the target protein acts as a template and catalyst, and assembles its own ligand from modular blocks of peptides. This process of ligand discovery is iterated to add peptide arms to develop a multivalent ligand with increased affinity and selectivity. The peptide based protein capture agents (PCC) should ideally have the same degree of selectivity and specificity as a monoclonal antibody, along with improved chemical stability. We had previously reported developing a PCC agent against bovine carbonic anhydrase II (bCAII) that could replace a polyclonal antibody. To further enhance the affinity or specificity of the PCC agent, I explore branching the peptide arms to develop branched PCC agents against bCAII. The developed branched capture agents have two to three fold higher affinities for the target protein. In the second part of my thesis, I describe the epitope targeting strategy, a strategy for directing the development of a peptide ligand against specific region or fragment of the protein. The strategy is successfully demonstrated by developing PCC agents with low nanomolar binding affinities that target the C-terminal hydrophobic motif of Akt2 kinase. One of the developed triligands inhibits the kinase activity of Akt. This suggests that, if targeted against the right epitope, the PCC agents can also influence the functional properties of the protein. The exquisite control of the epitope targeting strategy is further demonstrated by developing a cyclic ligand against Akt2. The cyclic ligand acts as an inhibitor by itself, without any iteration of the ligand discovery process. The epitope targeting strategy is a cornerstone of the IISCC technology and opens up new opportunities, leading to the development of protein detection agents and of modulators of protein functions.

I. Geology of the Southwest quarter of the Elsinore Quadrangle. II. Geochemical properties of the waters of the Elsinore Quadrangle [= Geology of the Lake Elsinore Quadrangle, California. Mineral deposits of Lake Elsinore Quadrangle, California]

The Lake Elsinore quadrangle covers about 250 square miles and includes parts of the southwest margin of the Perris Block, the Elsinore trough, the southeastern end of the Santa Ana Mountains, and the Elsinore Mountains.

The oldest rocks consist of an assemblage of metamorphics of igneous effusive and sedimentary origin, probably, for the most part, of Triassic age. They are intruded by diorite and various hypabyssal rocks, then in turn by granitic rocks, which occupy over 40 percent of the area. Following this last igneous activity of probable Lower Cretaceous age, an extended period of sedimentation started with the deposition of the marine Upper Cretaceous Chico formation and continued during the Paloecene under alternating marine and continental conditions on the margins of the blocks. A marine regression towards the north, during the Neocene, accounts for the younger Tertiary strata in the region under consideration.

Outpouring of basalts to the southeast indicates that igneous activity was resumed toward the close of the Tertiary. The fault zone, which characterizes the Elsinor trough, marks one of the major tectonic lines of southem California. It separates the upthrown and tilted block of the Santa Ana Mountains to the south from the Perris Block to the north.

Most of the faults are normal in type and nearly parallel to the general trend of the trough, or intersect each other at an acute angle. Vertical displacements generally exceed the horizontal ones and several periods of activity are recognized.

Tilting of Tertiary and older Quaternary sediments in the trough have produced broad synclinal structures which have been modified by subsequent faulting.

Five old surfaces of erosion are exposed on the highlands.

The mineral resources of the region are mainly high-grade clay deposits and mineral waters.

Resetting asynchronous QDI systems

Quasi Delay-Insensitive (QDI) systems must be reset into a valid initial state before normal operation can start. Otherwise, deadlock may occur due to wrong handshake communication between processes. This thesis first reviews the traditional Global Reset Schemes (GRS). It then proposes a new Wave Reset Schemes (WRS). By utilizing the third possible value of QDI data codes - reset value, WRS propagates the data with reset value and triggers Local Reset (LR) sequentially. The global reset network for GRS can be removed and all reset signals are generated locally for each process. Circuits templates as well as some special blocks are modified to accommodate the reset value in WRS. An algorithm is proposed to choose the proper Local Reset Input (LRI) in order to shorten reset time. WRS is then applied to an iterative multiplier. The multiplier is proved working under different operating conditions.

Dating and characterizing late holocene earthquakes using paleomagnetics

In this thesis I apply paleomagnetic techniques to paleoseismological problems. I investigate the use of secular-variation magnetostratigraphy to date prehistoric earthquakes; I identify liquefaction remanent magnetization (LRM), and I quantify coseismic deformation within a fault zone by measuring the rotation of paleomagnetic vectors.

In Chapter 2 I construct a secular-variation reference curve for southern California. For this curve I measure three new well-constrained paleomagnetic directions: two from the Pallett Creek paleoseismological site at A.D. 1397-1480 and A.D. 1465-1495, and one from Panum Crater at A.D. 1325-1365. To these three directions I add the best nine data points from the Sternberg secular-variation curve, five data points from Champion, and one point from the A.D. 1480 eruption of Mt. St. Helens. I derive the error due to the non-dipole field that is added to these data by the geographical correction to southern California. Combining these yields a secular variation curve for southern California covering the period A.D. 670 to 1910, with the best coverage in the range A.D. 1064 to 1505.

In Chapter 3 I apply this curve to a problem in southern California. Two paleoseismological sites in the Salton trough of southern California have sediments deposited by prehistoric Lake Cahuilla. At the Salt Creek site I sampled sediments from three different lakes, and at the Indio site I sampled sediments from four different lakes. Based upon the coinciding paleomagnetic directions I correlate the oldest lake sampled at Salt Creek with the oldest lake sampled at Indio. Furthermore, the penultimate lake at Indio does not appear to be present at Salt Creek. Using the secular variation curve I can assign the lakes at Salt Creek to broad age ranges of A.D. 800 to 1100, A.D. 1100 to 1300, and A.D. 1300 to 1500. This example demonstrates the large uncertainties in the secular variation curve and the need to construct curves from a limited geographical area.

Chapter 4 demonstrates that seismically induced liquefaction can cause resetting of detrital remanent magnetization and acquisition of a liquefaction remanent magnetization (LRM). I sampled three different liquefaction features, a sandbody formed in the Elsinore fault zone, diapirs from sediments of Mono Lake, and a sandblow in these same sediments. In every case the liquefaction features showed stable magnetization despite substantial physical disruption. In addition, in the case of the sandblow and the sandbody, the intensity of the natural remanent magnetization increased by up to an order of magnitude.

In Chapter 5 I apply paleomagnetics to measuring the tectonic rotations in a 52 meter long transect across the San Andreas fault zone at the Pallett Creek paleoseismological site. This site has presented a significant problem because the brittle long-term average slip-rate across the fault is significantly less than the slip-rate from other nearby sites. I find sections adjacent to the fault with tectonic rotations of up to 30°. If interpreted as block rotations, the non-brittle offset was 14.0+2.8, -2.1 meters in the last three earthquakes and 8.5+1.0, -0.9 meters in the last two. Combined with the brittle offset in these events, the last three events all had about 6 meters of total fault offset, even though the intervals between them were markedly different.

In Appendix 1 I present a detailed description of my standard sampling and demagnetization procedure.

In Appendix 2 I present a detailed discussion of the study at Panum Crater that yielded the well-constrained paleomagnetic direction for use in developing secular variation curve in Chapter 2. In addition, from sampling two distinctly different clast types in a block-and-ash flow deposit from Panum Crater, I find that this flow had a complex emplacement and cooling history. Angular, glassy "lithic" blocks were emplaced at temperatures above 600° C. Some of these had cooled nearly completely, whereas others had cooled only to 450° C, when settling in the flow rotated the blocks slightly. The partially cooled blocks then finished cooling without further settling. Highly vesicular, breadcrusted pumiceous clasts had not yet cooled to 600° C at the time of these rotations, because they show a stable, well clustered, unidirectional magnetic vector.

Synthesis and potency of long end-associative polymers for mist control

Long linear polymers that are end-functionalized with associative groups were studied as additives to hydrocarbon fluids to mitigate the fire hazard associated with the presence of mist in a crash scenario. These polymers were molecularly designed to overcome both the shear-degradation of long polymer chains in turbulent flows, and the chain collapse induced by the random placement of associative groups along polymer backbones. Architectures of associative groups on the polymer chain ends that were tested included clusters of self-associative carboxyl groups and pairs of hetero-complementary associative units.

Linear polymers with clusters of discrete numbers of carboxyl groups on their chain ends were investigated first: an innovative synthetic strategy was devised to achieve unprecedented backbone lengths and precise control of the number of carboxyl groups on chain ends (N). We found that a very narrow range of N allows the co-existence of sufficient end-association strength and polymer solubility in apolar media. Subsequent steady-flow rheological study on solution behavior of such soluble polymers in apolar media revealed that the end-association of very long chains in apolar media leads to the formation of flower-like micelles interconnected by bridging chains, which trap significant fraction of polymer chains into looped structures with low contribution to mist-control. The efficacy of very long 1,4-polybutadiene chains end-functionalized with clusters of four carboxyl groups as mist-control additives for jet fuel was further tested. In addition to being shear-resistant, the polymer was found capable of providing fire-protection to jet fuel at concentrations as low as 0.3wt%. We also found that this polymer has excellent solubility in jet fuel over a wide range of temperature (-30 to +70°C) and negligible interference with dewatering of jet fuel. It does not cause an adverse increase in viscosity at concentrations where mist-control efficacy exists.

Four pairs of hetero-complementary associative end-groups of varying strengths were subsequently investigated, in the hopes of achieving supramolecular aggregates with both mist-control ability and better utilization of polymer building blocks. Rheological study of solutions of the corresponding complementary associative polymer pairs in apolar media revealed the strength of complementary end-association required to achieve supramolecular aggregates capable of modulating rheological properties of the solution.

Both self-associating and complementary associating polymers have therefore been found to resist shear degradation. The successful strategy of building soluble, end-associative polymers with either self-associative or complementary associative groups will guide the next generation of mist-control technology.

Sequence specific complexation of b DNA at sites containing g,c base pairs

A series of eight related analogs of distamycin A has been synthesized. Footprinting and affinity cleaving reveal that only two of the analogs, pyridine-2- car box amide-netropsin (2-Py N) and 1-methylimidazole-2-carboxamide-netrops in (2-ImN), bind to DNA with a specificity different from that of the parent compound. A new class of sites, represented by a TGACT sequence, is a strong site for 2-PyN binding, and the major recognition site for 2-ImN on DNA. Both compounds recognize the G•C bp specifically, although A's and T's in the site may be interchanged without penalty. Additional A•T bp outside the binding site increase the binding affinity. The compounds bind in the minor groove of the DNA sequence, but protect both grooves from dimethylsulfate. The binding evidence suggests that 2-PyN or 2-ImN binding induces a DNA conformational change.

In order to understand this sequence specific complexation better, the Ackers quantitative footprinting method for measuring individual site affinity constants has been extended to small molecules. MPE•Fe(II) cleavage reactions over a 10^5 range of free ligand concentrations are analyzed by gel electrophoresis. The decrease in cleavage is calculated by densitometry of a gel autoradiogram. The apparent fraction of DNA bound is then calculated from the amount of cleavage protection. The data is fitted to a theoretical curve using non-linear least squares techniques. Affinity constants at four individual sites are determined simultaneously. The distamycin A analog binds solely at A•T rich sites. Affinities range from 10^(6)- 10^(7)M^(-1) The data for parent compound D fit closely to a monomeric binding curve. 2-PyN binds both A•T sites and the TGTCA site with an apparent affinity constant of 10^(5) M^(-1). 2-ImN binds A•T sites with affinities less than 5 x 10^(4) M^(-1). The affinity of 2-ImN for the TGTCA site does not change significantly from the 2-PyN value. At the TGTCA site, the experimental data fit a dimeric binding curve better than a monomeric curve. Both 2-PyN and 2-ImN have substantially lower DNA affinities than closely related compounds.

In order to probe the requirements of this new binding site, fourteen other derivatives have been synthesized and tested. All compounds that recognize the TGTCA site have a heterocyclic aromatic nitrogen ortho to the N or C-terminal amide of the netropsin subunit. Specificity is strongly affected by the overall length of the small molecule. Only compounds that consist of at least three aromatic rings linked by amides exhibit TGTCA site binding. Specificity is only weakly altered by substitution on the pyridine ring, which correlates best with steric factors. A model is proposed for TGTCA site binding that has as its key feature hydrogen bonding to both G's by the small molecule. The specificity is determined by the sequence dependence of the distance between G's.

One derivative of 2-PyN exhibits pH dependent sequence specificity. At low pH, 4-dimethylaminopyridine-2-carboxamide-netropsin binds tightly to A•T sites. At high pH, 4-Me_(2)NPyN binds most tightly to the TGTCA site. In aqueous solution, this compound protonates at the pyridine nitrogen at pH 6. Thus presence of the protonated form correlates with A•T specificity.

The binding site of a class of eukaryotic transcriptional activators typified by yeast protein GCN4 and the mammalian oncogene Jun contains a strong 2-ImN binding site. Specificity requirements for the protein and small molecule are similar. GCN4 and 2-lmN bind simultaneously to the same binding site. GCN4 alters the cleavage pattern of 2-ImN-EDTA derivative at only one of its binding sites. The details of the interaction suggest that GCN4 alters the conformation of an AAAAAAA sequence adjacent to its binding site. The presence of a yeast counterpart to Jun partially blocks 2-lmN binding. The differences do not appear to be caused by direct interactions between 2-lmN and the proteins, but by induced conformational changes in the DNA protein complex. It is likely that the observed differences in complexation are involved in the varying sequence specificity of these proteins.