Search

Tissue resident memory CD8+ T (TRM) cells reside in nonlymphoid tissues and provide enhanced local protection against reinfections. While it is known that TRM cells and circulating memory CD8+ T (TCIRCM) cells arise from a memory precursor population, where and when these cells receive specific instructions to initiate their respective memory programming is not completely understood. Here, we delineated siIEL-TRM-precursor cells and TCIRCM-precursor cells in the mesenteric lymph node, prior to the peak of CD8+ T cell response, as CCR9hiCD62Llo and CD62LhiCCR9lo respectively, and demonstrated that the two populations are phenotypically distinct. While the DNA-binding protein inhibitor Id3 was previously shown to be required for the formation and survival of memory cells, we found that Id3 promotes formation of siIEL-TRM-precursor cells and represses formation of TCIRCM-precursor cells. Thus, these data suggest that the fates of siIEL-TRM cells and TCIRCM cells diverge in the mesenteric lymph node at an early effector timepoint and clarify the role of Id3 in the formation of siIEL-TRM-precursor and TCIRCM-precursor precursor populations.

Intracellular pH dynamics is increasingly recognized to regulate myriad cell behaviors. We report a finding that intracellular pH dynamics also regulates adult stem cell lineage specification. We identify an intracellular pH gradient in mouse small intestinal crypts, lowest in crypt stem cells and increasing along the crypt column. Disrupting this gradient by inhibiting H+ efflux by Na+/H+ exchanger 1 abolishes crypt budding and blocks differentiation of Paneth cells, which are rescued with exogenous WNT. Using single-cell RNA sequencing and lineage tracing we demonstrate that intracellular pH dynamics acts downstream of ATOH1, with increased pH promoting differentiation toward the secretory lineage. Our findings indicate that an increase in pH is required for the lineage specification that contributes to crypt maintenance, establishing a role for intracellular pH dynamics in cell fate decisions within an adult stem cell lineage.

The oceans play an important role in regulating atmospheric CO2 levels and the climate system. Since the beginning of the Industrial Revolution, the ocean has absorbed more than 25% of anthropogenic CO2 emissions, and the carbon sink is expected to grow over the next several centuries as atmospheric CO2 concentrations rise. Multiple ocean processes, however, affect the amount of anthropogenic carbon that the ocean absorbs from the atmosphere. This thesis combines Earth System Models (ESM) from the sixth phase Coupled Model Intercomparison Project (CMIP6) with an offline inverse biogeochemical model to answer a fundamental question: What mechanisms control the size of the ocean carbon sink in a warming climate?First, I use the CMIP6 models to investigate the role of meridional overturning circulation in ocean carbon uptake (Chapter 2). Slowing MOC reduces anthropogenic carbon uptake by the solubility pump while increasing deep ocean carbon and nutrient storage by the biological pump. The net effect is a reduction in the ocean carbon sink. I then used an offline inverse biogeochemical model to conduct a series of sensitivity experiments to better understand how changes in circulation affect the ocean carbon sink (Chapter 3). The results show that slowing MOC reduces anthropogenic carbon uptake by decreasing biological productivity. The slowing MOC sequesters more nutrients in the deep ocean, reducing nutrient replenishment to the upper ocean and thus lowering biological productivity. This increases ocean surface CO2 saturation and reduces the ocean's ability to absorb anthropogenic CO2 from the atmosphere. However, without taking into account changes in biological productivity, the slowing MOC contributes little to the ocean carbon sink. In Chapter 4, I examine the ocean ventilation timescales and patterns in a time-evolving circulation in the context of climate change. I found that slowing meridional overturning circulation causes a 110-year increase in global-averag

This dissertation exams how psychology theory can be implemented into experimentaleconomics and studies the effects of human cognitive activities on their economics behaviors. It also studies how people react to job applicants with misdemeanor records and how economics outcomes can affect lying behaviors. The data used for this dissertation include self-collected data from laboratory experiments and publicly available data from U.S. government agencies. In the first chapter, I show that people with anxious attachment style tend to make economics decisions appealing to others yet people with avoidant attachment style care more about their own economics well-beings. In the second chapter, I show that marijuana possession-related misdemeanor significantly hinders one’s employment outcomes and expungement could help the situation. Although the legalization of marijuana is still an on-going process, without expunging the previous misdemeanor records related to marijuana, the legalization itself is not enough to improve the employment outcomes. In the third chapter, I show that constant moral reminders decrease dishonest behaviors whereas higher rewards lead to more deception. Moral reminders can only work to certain extent and as the rewards go higher, the effect of moral reminders gradually diminish.

Change-point detection investigates whether there are abrupt changes in distributions in sequences of observations. The goal is to partition a sequence of observations into homogeneous subsequences, which provides essential screening information for follow-up studies. As we enter the era of big data, it is commonplace to encounter sequences of high-dimensional/non-Euclidean observations. Parametric methods are often limited to those data where the parametric assumptions are reasonable. Nonparametric methods are usually more broadly applicable, but it is often hard to conduct theoretical analysis on them, such as to provide an analytic $p$-value approximation to facilitate the application to large datasets. The graph-based framework, which utilizes the edge-count information on the similarity graphs constructed on the observations, is the first kind that can be applied to these data with analytic $p$-value approximates. In this dissertation, we work out three advancements of the graph-based framework to meet the needs for modern data analysis. First, we improve the time efficiency of the algorithms by incorporating the approximate directed $k$-Nearest Neighbor ($k$-NN) graphs into the framework. Our new method is many folds faster to run and has power higher than or competitive with state-of-the-art nonparametric methods under various settings. The effectiveness of the new method is illustrated by real applications to fMRI and Neuropixels data sequences. Second, when data are autocorrelated, existing methods that assume independence could result in a higher false discovery rate. Therefore, we use the circular block permutation (CBP) framework that preserves the locally dependent structure among observations. The new framework provides proper controls on the false discovery rate when data have weak serial correlations. Third, we investigate the problem of multiple sequences of high-dimensional/non-Euclidean observations. We propose a new scan statistic that is powerfu

Despite the rise of social studies to address craft economy or production in modern society, how the value can be added to a craft-made product is poorly explained. By exploring the global context of the guitar-making industry in the 1960s and interviewing guitar makers in four different countries, in this dissertation, I argue that the rise of the craft-made guitar industry since the 1980s resulted from the invented tradition of "vintage" and the dependence on advanced technology. Additionally, by exploring various guitar builders' life stories, labor processes, and business networks, I create a concept, the ladder towards luthiers, to describe how an inexperienced apprentice may become an independent luthier in a hierarchical structure in the industry. Furthermore, I argue that the traditional definition of craft overvalues male luthiers' role in adding value to a craft-made guitar and overlooks female workers' contributions in the craft industry. In order to highlight different actors' contributions in the craft industry, we need a new definition of craft to help consumers understand that the value of a craft product is also made in a social process rather than by an independent luthier. Finally, this study also sheds light on the relationship between craft production and mass production and figures out that the rise of craft production could reflect a reskilling process of industrial capitalism rather than the opposite of the deskilled mass production.

NAND flash memory has become a widely used data storage technology. It uses rectangular arrays, or blocks of floating-gate transistors (commonly referred to as cells) to store information. The flash memory cells gradually wear out with repeated writing and erasing, referred to as program/erase (P/E) cycling, but the damage caused by P/E cycling is dependent on the programmed cell level. For example, in SLC flash memory, each cell has two different states, erased and programmed, represented by 1 and 0, respectively. Storing 1 in a cell causes less damage, or wear, than storing 0. More generally, in multilevel flash memories, the cell wear is an increasing function of the programmed cell level. The main research goal of this dissertation is to design new coding techniques that can extend the lifetime of flahs memories. The damage caused by programming the cell is usually modeled as a cost, and increasing the lifetime of flash memories can be converted to the problem of encoding information for use on channels with a cost constraint. This type of code is often referred to as a shaping code. Therefore in this dissertation we study rate-constrained shaping codes for noiseless costly channels. We systematically investigate the fundamental performance limits of fixed-to-variable length shaping codes from a rate and distribution perspective for a memoryless channel. Then, we study a recently proposed rate-1 direct shaping code and study its error propagation property. In addition, we consider shaping codes for finite-state noiseless costly channels. One observation from the above analysis is that an optimal shaping code for a memoryless channel generates a codeword sequence that approximates an i.i.d. process, and an optimal shaping code for a finite-state channel generates a codeword sequence that approximates a stationary Markov process. In this dissertation, we study the connection between shaping codes and distribution matching codes that map a sequence of i.i.d. source

Euryarchaeal lineages have been believed to have a methanogenic last common ancestor. However, members of euryarchaeal Archaeoglobi have long been considered nonmethanogenic and their evolutionary history remains elusive. Here, three high-quality metagenomic-assembled genomes (MAGs) retrieved from high-temperature oil reservoir and hot springs, together with three newly assembled Archaeoglobi MAGs from previously reported hot spring metagenomes, are demonstrated to represent a novel genus of Archaeoglobaceae, "Candidatus Methanomixophus." All "Ca Methanomixophus" MAGs encode an M methyltransferase (MTR) complex and a traditional type of methyl-coenzyme M reductase (MCR) complex, which is different from the divergent MCR complexes found in "Ca Polytropus marinifundus." In addition, "Ca Methanomixophus dualitatem" MAGs preserve the genomic capacity for dissimilatory sulfate reduction. Comparative phylogenetic analysis supports a laterally transferred origin for an MCR complex and vertical heritage of the MTR complex in this lineage. Metatranscriptomic analysis revealed concomitant in situ activity of hydrogen-dependent methylotrophic methanogenesis and heterotrophic fermentation within populations of "Ca Methanomixophus hydrogenotrophicum" in a high-temperature oil reservoir.IMPORTANCE Current understanding of the diversity, biology, and ecology of Archaea is very limited, especially considering how few of the known phyla have been cultured or genomically explored. The reconstruction of "Ca Methanomixophus" MAGs not only expands the known range of metabolic versatility of the members of Archaeoglobi but also suggests that the phylogenetic distribution of MCR and MTR complexes is even wider than previously anticipated.

Point-of-care (POC) testing has demonstrated great transformative potential in personalized medicine. In particular, patients undergoing transplantation require POC testing to ensure appropriate serum immunosuppressant levels so as to maintain adequate graft function and survival. However, no suitable POC device for monitoring immunosuppressant levels is currently available. Exploiting the latest advances in metamaterials can lead to a breakthrough in POC testing. A high-contrast grating (HCG) biosensor is a low-cost, compact, simple-to-fabricate, and easy-to-operate structure. It is highly sensitive and robust in surface-based biomarker detection, which is favorable for the efficiency of a POC device. In this study, the feasibility of using an HCG as a POC sensor for therapeutic drug monitoring of immunosuppressants was evaluated. The detection efficiency of the most commonly prescribed immunosuppressive medication cyclosporine A by using this sensor was demonstrated to be comparable to those of conventional commercial kits, suggesting that the sensor has the potential to be used as a rapid detection and feedback platform for increasing drug compliance and improving new organ transplant survival.

The International Society of Cancer Metabolism (ISCaM) meeting on Cancer Metabolic Rewiring, held in Braga Portugal in October 2019, provided an outstanding forum for investigators to present current findings and views, and discuss ideas and future directions on fundamental biology as well as clinical translations. The first session on Cancer pH Dynamics was preceded by the opening keynote presentation from our group entitled Intracellular pH Regulation of Protein Dynamics: From Cancer to Stem Cell Behaviors. In this review we introduce a brief background on intracellular pH (pHi) dynamics, including how it is regulated as well as functional consequences, summarize key findings included in our presentation, and conclude with perspectives on how understanding the role of pHi dynamics in stem cells can be relevant for understanding how pHi dynamics enables cancer progression.

In this article, the capabilities of soft and hard X-ray techniques, including X-ray absorption (XAS), soft X-ray emission spectroscopy (XES), resonant inelastic soft X-ray scattering (RIXS), X-ray photoelectron spectroscopy (XPS), and X-ray diffraction (XRD), and their application to solid-state hydrogen storage materials are presented. These characterization tools are indispensable for interrogating hydrogen storage materials at the relevant length scales of fundamental interest, which range from the micron scale to nanometer dimensions. Since nanostructuring is now well established as an avenue to improve the thermodynamics and kinetics of hydrogen release and uptake, due to properties such as reduced mean free paths of transport and increased surface-to-volume ratio, it becomes of critical importance to explicitly identify structure-property relationships on the nanometer scale. X-ray diffraction and spectroscopy are effective tools for probing size-, shape-, and structure-dependent material properties at the nanoscale. This article also discusses the recent development of in-situ soft X-ray spectroscopy cells, which enable investigation of critical solid/liquid or solid/gas interfaces under more practical conditions. These unique tools are providing a window into the thermodynamics and kinetics of hydrogenation and dehydrogenation reactions and informing a quantitative understanding of the fundamental energetics of hydrogen storage processes at the microscopic level. In particular, in-situ soft X-ray spectroscopies can be utilized to probe the formation of intermediate species, byproducts, as well as the changes in morphology and effect of additives, which all can greatly affect the hydrogen storage capacity, kinetics, thermodynamics, and reversibility. A few examples using soft X-ray spectroscopies to study these materials are discussed to demonstrate how these powerful characterization tools could be helpful to further understand the hydrogen storage systems.

Twinning structures and their interfacial segregation play a key role in strengthening of magnesium alloys. Micro-steps are frequently existed in the incoherent twin boundaries, while the effect of them on interface and interfacial segregation is still not clear. In this work, we performed an atomic-scale microstructure analysis using high-angle annular dark field scanning transmission electron microscopy (HAADF-STEM) to explore the effect of micro-steps on twin and its interfacial segregation in Mg-Ag alloy. Diffraction pattern of the incoherent {10 1 ¯ 1} twin shows that the misorientation has a slight tilt of 5° from its theoretical angle of 125° due to the accumulated effects of the micro-steps and their misfit dislocations in twin boundaries. Most of the micro-steps in {10 1 ¯ 1} twin boundary are in the height of 2 d ( 10 1 ¯ 1 ) and 4 d ( 10 1 ¯ 1 ) , respectively, and both of them have two types according to whether there are dislocations on the micro-steps. The twin boundary is interrupted by many micro-steps, which leads to a step-line distributed interfacial segregation. Moreover, the Ag tends to segregate to dislocation cores, which results in the interruption of interfacial segregation at the micro-steps with dislocations.

The Large Hadron Collider (LHC) is the world’s largest and most powerful particle accelerator. It found the Higgs particle in 2012. In order to fully exploit the potential of the LHC, it is planned to upgrade to the High-Luminosity LHC (HL-LHC), reaching a peak luminosity of 5−7.5×1034 cm−2s−1. The Compact Muon Solenoid (CMS) detector, as one of four detectors at the LHC, will be upgraded to operate at the HL-LHC. One of the most important aspects of this upgrade will be the addition of track information in the Level-1 trigger system. In this thesis, we will present the concept of the CMS tracker and trigger system upgrade including the limitations of the current trigger system. The implementation ofthetracktriggerviaaHoughtransformwillbediscussed. Simulationsofthetrack trigger system show that more than 90% of tracking particles can be reconstructed over the full acceptance. We also discuss the relationship between the tracker layout and the number of reconstructed tracks. The performance of the track trigger for tracks generated at different positions in the z-direction is shown. By changing the cell size of the Hough transform, the performance of the track trigger system changes. The best performance is obtained with a granularity of 32x64 cells per sector. The effect in the performance of the Hough transform due to dense track environments will be discussed last.

We use 3-D cloud-resolving model (CRM) simulations of two mesoscale convective systems at mid-latitudes and a simple statistical ensemble method to diagnose the scale dependency of convective momentum transport (CMT) and CMT-related properties, and evaluate a parameterization scheme for convection-induced pressure gradient (CIPG) developed by Gregory et al. (GKI97). GKI97 relates CIPG to a constant coefficient multiplied by mass flux and vertical mean wind shear. CRM results show that mass fluxes and CMT exhibit strong scale dependency in temporal evolution and vertical structure. The prevalent understandings of CMT characteristics in terms of upgradient/downgradient transport are applicable to updrafts but not downdrafts across a wide range of grid spacings (4-512 km). For the small-to-median grid spacings (4~64 km), GKI97 reproduces some aspects of CIPG scale dependency except for underestimating the variations of CIPG as grid spacing decreases. However, for large grid spacings (128~512 km), GKI97 might even less adequately parameterize CIPG because it omits the contribution from either the nonlinear shear or buoyancy forcings. Further diagnosis of CRM results suggests that inclusion of nonlinear shear forcing in GKI97 is needed for the large grid spacings, and use of the three-updraft and one downdraft approach proposed in an earlier study may help a modified GKI97 capture more variations of CIPG as grid spacing decreases for the small-to-median grid spacings. Further, the optimal coefficients used in GKI97 seems insensitive to grid spacings, but they might be different for updrafts and downdrafts, for different MCS types, and for zonal and meridional components.

BackgroundMicroorganisms have long been associated with oxic and anoxic degradation of hydrocarbons in oil reservoirs and oil production facilities. While we can readily determine the abundance of microorganisms in the reservoir and study their activity in the laboratory, it has been challenging to resolve what microbes are actively participating in crude oil degradation in situ and to gain insight into what metabolic pathways they deploy.ResultsHere, we describe the metabolic potential and in situ activity of microbial communities obtained from the Jiangsu Oil Reservoir (China) by an integrated metagenomics and metatranscriptomics approach. Almost complete genome sequences obtained by differential binning highlight the distinct capability of different community members to degrade hydrocarbons under oxic or anoxic condition. Transcriptomic data delineate active members of the community and give insights that Acinetobacter species completely oxidize alkanes into carbon dioxide with the involvement of oxygen, and Archaeoglobus species mainly ferment alkanes to generate acetate which could be consumed by Methanosaeta species. Furthermore, nutritional requirements based on amino acid and vitamin auxotrophies suggest a complex network of interactions and dependencies among active community members that go beyond classical syntrophic exchanges; this network defines community composition and microbial ecology in oil reservoirs undergoing secondary recovery.ConclusionOur data expand current knowledge of the metabolic potential and role in hydrocarbon metabolism of individual members of thermophilic microbial communities from an oil reservoir. The study also reveals potential metabolic exchanges based on vitamin and amino acid auxotrophies indicating the presence of complex network of interactions between microbial taxa within the community.

This dissertation studies the US housing market, banks' behavior under regulations and effects of bank capital constraint on the monetary transmission mechanism. It revolves around understanding the determination of the capital regulations on banks' optimal behavior, as well as quantifying the impact of these regulations on the effectiveness of the monetary policy. The first chapter, “The Impact of Local School Quality on Housing Price Volatility”, studies the effects of local school quality on housing-price booms and busts under the impact of exogenous credit-supply shocks, using school-district-level data in California between 2000 and 2012. The analysis shows that school quality, as an important amenity and utility dividend, reduces the impact of the exogenous shocks and anchors local housing values. The empirical work verifies that better schools make housing prices less volatile. The findings match the analysis of previous research in financial markets, in which there is a similarly negative association between share prices volatility and dividend yields. The second chapter, “How Do the Minimum Capital Requirements Affect Banking Competition and Profitability?”, examines the effect of the Minimum Capital Requirements (MCR) on banks' competition and profitability. The theoretical model shows that, in competitive market, banks trade off the costs and benefits of capital to maximize their profits. The MCR are thus likely to be an important factor on the bank's optimal choice and the target ratios increase with the MCR and decrease with banks' size. This paper also adopts the Industrial Organization (IO) approach to analyze the competitive effects of MCR on the oligopolistic market. Banks may collude to hold even higher capital ratios in the oligopolistic market since the capacity constraints caused by MCR reduce the competition. Using a sample of US banks from 2002 to 2015, the empirical works reveals that the relation between capital and profitability is nonlinea

The first and only exhaustive review of the theory, thermodynamic fundamentals, mechanisms, and design principles of dynamic covalent systems Dynamic Covalent Chemistry: Principles, Reactions, and Applications presents a comprehensive ...

In eukaryotes, nascent proteins that are destined for the secretory pathway enter the endoplasmic reticulum (ER) in unfolded states and generally leave only after they have reached their native conformation. Protein folding in the ER is challenging and often error-prone. To prevent accumulation of misfolded proteins, the ER uses the ER-associated protein degradation (ERAD) machinery to detect and commit these defective proteins for retrotranslocation to cytosol for degradation via the ubiquitin-proteasome system. Previously, our group and others discovered an ERAD pathway that requires the generation of a specific N-glycan structure on misfolded luminal N-glycoproteins to permit their degradation. This N-glycan degradation signal can potentially serve as a mark to flag the defective states of the attached protein, but whether the generation of this N-glycan degradation signal is directly connected to the folding state of the attached protein has remained unknown.My thesis research work is focused on characterization of Htm1p, the mannosidase that is responsible for generating this N-glycan signal in Saccharomyces cerevisiae. Utilizing an in vitro reconstitution system of Htm1p in complex with its interacting partner, Pdi1p, and glycoprotein substrates whose structures can be closely manipulated, I find that unlike other members of the same mannosidase family, Htm1p-Pdi1p is a glycoprotein-specific mannosidase that has little activity against free glycan. I find that Htm1p-Pdi1p targets intrinsically and artificially misfolded proteins but not their native counterparts. Most importantly, I find that Htm1p-Pdi1p differentiates detailed folding states of misfolded proteins and preferentially acts on partially folded proteins to globally unfolded species. I further find that by forming a tight complex with Pdi1p, Htm1p blocks the intrinsic oxidoreductase function of Pdi1p but keeping the chaperone activity, suggesting a potential mechanism of how the Htm1p-Pdi1p complex

BackgroundThe development of oral squamous cell carcinoma (OSCC) is a multistep process that involves in both genetic alterations and epigenetic modifications. Previous studies suggest SOX4 might function as an oncogene or a tumor suppressor in different types of cancers. However, whether SOX4 involves in promoting the progression of oral precancer to cancer is unknown.MethodsLiquid chromatography with tandem mass spectrometry (LC-MS/MS) was used to identify the proteins that may be differentially expressed between oral lichen planus (OLP) and OLP-associated OSCC (OLP-OSCC) formalin-fixed paraffin-embedded (FFPE) tissues. Immunohistochemistry (IHC) and Western blotting were performed to evaluate SOX4 expression between OLP and OLP-OSCC tissues and among oral cancer cell lines and normal human oral keratinocytes (NHOKs). SOX4 siRNA was used to knock down the expression of SOX4 in UM1 oral cancer cells. MTT, cell counting, migration and Matrigel invasion assays were utilized to examine the effect of SOX4 down-regulation on proliferation, migration and invasion capacity of UM1 cells.ResultsLC-MS/MS analysis showed that 88 proteins including SOX4 were only identified in OLP-OSCC FFPE tissues when compared to OLP FFPE tissues. IHC confirmed that SOX4 expression was significantly higher in OLP-OSCC than OLP and Western blot analysis indicated that SOX4 was over-expressed in UM1/UM2 cells when compared to NHOKs. Knockdown of SOX4 significantly inhibited the proliferation, migration and invasion of UM1 cells (P<0.01).ConclusionsOur study indicated that SOX4 is significantly upregulated in OLP-OSCC versus OLP tissues. In addition, down-regulation of SOX4 led to significantly reduced proliferation, migration and invasion capability of oral cancer cells. These findings suggest that SOX4 might be actively involved in the progression of OLP to OSCC.

This dissertation investigates predictability in strategic air traffic management with a focus on ground delay programs (GDPs). Through a survey of flight operators, we confirm the proposition that flight operators care about predictability. We then develop models that incorporate predictability into GDP cost optimization after failing in finding an existing model that can serve this purpose. This is accomplished by modifying traditional GDP delay cost functions so that they incorporate predictability, and determining the sensitivities of the optimal planned capacity recovery time and associated cost to the unpredictability premiums included in the cost functions. To do this, we develop two stochastic GDP models: a GDP no-revision, or static, model; and a GDP revision, or dynamic, model considering one GDP revision. GDP scope, which matters only in the revision model, is also considered. The optimization results from the case study show that the cost of unpredictability clearly matters, particularly in the more realistic case where GDP revision is allowed. Of the two unpredictability cost parameters, the one for unplanned delay has a stronger impact than the one for planned un-incurred delay. The insights from this analysis might eventually be used to develop a decision support tool that air traffic managers could use in determining what the planned end time should be for a GDP in a manner that reflects the importance of predictability to flight operators.

Microenvironments that modulate fate commitments of mesenchymal stromal cells (MSCs) are composed of chemical and physical cues, but the latter ones are much less investigated. Here we demonstrate that intermittent fluid shear stress (IFSS), a potent and physiologically relevant mechanical stimulus, regulates osteogenic differentiation of MSCs through Transient receptor potential melastatin 7 (TRPM7)-Osterix axis. Immunostaining showed the localization of TRPM7 near or at cell membrane upon IFSS, and calcium imaging analysis demonstrated the transient increase of cytosolic free calcium. Expressions of osteogenic marker genes including Osterix, but not Runx2, were upregulated after three-hour IFSS. Phosphorylation of p38 and Smad1/5 was promoted by IFSS as well. TRPM7 gene knockdown abolished the promotion of bone-related gene expressions and phosphorylation. We illustrate that TRPM7 is mechanosensitive to shear force of 1.2 Pa, which is much lower than 98 Pa pressure loading reported recently, and mediates distinct mechanotransduction pathways. Additionally, our results suggest the differential roles of TRPM7 in endochondral and intramembranous ossification. Together, this study elucidates the mechanotransduction in MSCs fate commitments and displays an efficient mechano-modulation for MSCs osteogenic differentiation. Such findings should be taken into consideration when designing relevant scaffolds and microfluidic devices for osteogenic induction in the future.

The main result of this dissertation shows that every orientable closed 3-manifold admits a nonzero degree map onto at most finitely many homeomorphically distinct non-geometric prime 3-manifolds. Furthermore, for any integer d > 0, every orientable closed 3-manifold admits a map of degree d onto only finitely many homeomorphically distinct 3-manifolds. This answers a question of Yongwu Rong. The finiteness of JSJ piece of the targets under nonzero degree maps was known earlier by the results of Soma and Boileau–Rubinstein–Wang, and a new proof is provided is this dissertation. We also prove analogous results for dominations rela-tive to boundary. As an application, we describe the degree set of dominations onto integral homology 3-spheres.

Researchers estimate that electronic health record systems record roughly 2-million ambulatory adverse drug events and that patients suffer from adverse drug events in roughly 30% of hospital stays. Some have used structured databases of patient medical records and health insurance claims recently-going beyond the current paradigm of using spontaneous reporting systems like AERS-to detect drug-safety signals. However, most efforts do not use the free-text from clinical notes in monitoring for drug-safety signals. We hypothesize that drug-disease co-occurrences, extracted from ontology-based annotations of the clinical notes, can be examined for statistical enrichment and used for drug safety surveillance. When analyzing such co-occurrences of drugs and diseases, one major challenge is to differentiate whether the disease in a drug-disease pair represents an indication or an adverse event. We demonstrate that it is possible to make this distinction by combining the frequency distribution of the drug, the disease, and the drug-disease pair as well as the temporal ordering of the drugs and diseases in each pair across more than one million patients.

Includes bibliographical references (leaves 189-204)., Includes abstract and appendices.

Spontaneous slip on frictional interfaces involves both short-lived inertially-driven events and long-term quasi-static sliding. An example of considerable practical importance is the response of faults in the Earth's crust to tectonic loading. The response combines earthquakes that cause destructive ground motions and aseismic slip. Numerical models are needed to study the physics and mechanics of such complex behavior. In part, the models can help understand the observed slip patterns and interpret them in terms of constitutive properties of rocks determined in the lab. This thesis contains two main contributions. The first one is the development and implementation of a 3D methodology for simulations of spontaneous long-term interface slip punctuated by rapid inertially driven ruptures. Our approach is the first one to combine long-term deformation histories and the resulting stress redistribution on faults with full inclusion of inertial effects during simulated earthquakes in the context of 3D models. It reproduces all stages of earthquake cycles, from accelerating slip before dynamic instability, to rapid inertially driven propagation of earthquake rupture, to post-seismic slip, and to interseismic creep, including aseismic transients. The second main contribution is the discovery of the potentially dominating effect of favorable heterogeneity on intersonic transition in earthquakes, in both 2D models of single dynamic ruptures and 3D models of long-term fault slip. Studies of intersonic ruptures are practically important as they have the potential to cause strong ground motion farther from the fault than subsonic ruptures. Our conclusion that rheological boundaries promote transition to intersonic speeds in 3D rupture models is completely unexpected, as the neighboring stably slipping regions inhibit fast, inertially driven slip. The result could not be established in earlier studies, as it requires the computational methodology developed here that c

Quantum mechanics has important consequences for machines that store and manipulate information. In particular, quantum computers might be more powerful than classical computers; examples of this include Shor's algorithm for factoring and discrete logarithms, and Grover's algorithm for black-box search. Because of these theoretical results, and the possibility that we may eventually succeed in building scalable quantum computers, it is interesting to study complexity classes based on quantum computation. QMA (Quantum Merlin-Arthur) is the quantum analogue of the class NP. There are a few QMA-complete problems, most of which are variants of the "Local Hamiltonian" problem introduced by Kitaev. In this dissertation we show some new QMA-complete problems which are very different from those known previously, and have applications in quantum chemistry. The first one is "Consistency of Local Density Matrices" : given a collection of density matrices describing different subsets of an n-qubit system (where each subset has constant size), decide whether these are consistent with some global state of all n qubits. This problem was first suggested by Aharonov. We show that it is QMA-complete, via an oracle reduction from Local Hamiltonian. Our reduction is based on algorithms for convex optimization with a membership oracle, due to Yudin and Nemirovskii. Next we show that two problems from quantum chemistry, "Fermionic Local Hamiltonian" and "N- representability," are QMA-complete. These problems involve systems of fermions, rather than qubits; they arise in calculating the ground state energies of molecular systems. N-representability is particularly interesting, as it is a key component in recently developed numerical methods using the contracted Schrodinger equation. Although these problems have been studied since the 1960's, it is only recently that the theory of quantum computation has provided the right tools to properly characterize their complexity. Finally, we study

Thus, this is not only an extremely valuable source of information for synthetic organic chemists, but also a ready reference for scientists working in related fields of arene chemistry, stereoselective synthesis, material science, and ...

The significant economic, social, and emotional costs of depression would bestow much value on a cost-effective nutritional therapy such as supplementation. Recently, a relationship between folate and depression has been observed in clinical studies and inferred from increased understanding of the role of folate in neural mechanisms involved in mood regulation. Current studies suggest that a subpopulation of depressed patients may benefit from treatment with folate supplementation. However, further studies are needed to replicate and extend these findings and to clarify the circumstances under which folate supplementation may effect a role in antidepressant therapy; only then can any routine screening criteria or treatment protocols be established.