Mechanisms of thrombosis under flow

Goel, Mukul Shri University of Pennsylvania 2003 해외박사(DDOD)

소속기관이 구독 중이 아닌 경우 오후 4시부터 익일 오전 9시까지 원문보기가 가능합니다.

We examined how neutrophils, platelets and erythrocytes interact with each other under coagulating flow conditions to stimulate and enhance thrombotic processes. Experiments were designed to decouple flow-regulated adhesion events from flow-regulated coagulation biochemistry. Individual surface adherent neutrophils were found to accelerate fibrin deposition by generating and capturing fibrin protofibrils in a CD18-dependent mechanism and generating thrombin and fibrin when the contact pathway is intact through elastase/cathepsin G-mediated pathways. At the same time, neutrophils promoted fibrin production by interacting with platelets and turning them into fully procoagulant structures via released elastase/cathepsin G, even when FXIIa was inhibited by corn trypsin inhibitor. As relative rates of thrombin generation for various coagulation scenarios were measured under static conditions to complement the videomicroscopy-imaged flow assays, purified cathepsin G was found to be a more potent activator of platelet-dependent coagulation than elastase. Platelet activation by cathepsin G was more critical than the role of cathepsin G in cleaving coagulation factors. Individual GPVI activated platelets supported prothrombinase activity in the absence of activated coagulation factors or external tissue factor from plasma through pathways mediated by VIIa and tissue factor. We demonstrated that normal red blood cells can perform active roles in thrombosis by adhering to activated neutrophils, activated platelets and surface-deposited fibrin (polymerized from plasma) at low wall shear rates below 100 s<super>−1 </super> through receptor-mediated adhesion. Adhesion of red cells to activated platelets was partly CD36 and GPIb dependent and sensitive to soluble fibrinogen. The adhesion of normal RBC to activated neutrophils was found to be mediated by Mac-1 and LW (ICAM-4) and was insensitive to physiological levels of fibrinogen. We also demonstrated that linkage of tPA or reteplase to RBC (via biotin-streptavidin crosslinking) preserves the fibrin specificity and the fibrinolytic activity of these plasminogen activators. This research provides fundamental insight relevant to deep vein thrombosis, biomaterial thrombosis and inflammation-coagulation crosstalk.

A unified framework for symbolic simulation and model checking

Goel, Amit Carnegie Mellon University 2004 해외박사(DDOD)

소속기관이 구독 중이 아닌 경우 오후 4시부터 익일 오전 9시까지 원문보기가 가능합니다.

The efficient representation and algorithmic manipulation of symbolic values by Binary Decision Diagrams (BDDs) and related data structures has made it possible to extend the capacity of several traditional analysis techniques. Symbolic simulation is a method for evaluating multiple behaviors of an executable model by using symbols to encode multiple inputs and states. Symbolic model checking uses symbolic techniques to formally verify that a model satisfies a given temporal logic property. This thesis develops the necessary framework for symbolic simulation based model checking. The motivations for such an approach are that symbolic simulation is applicable to a wider variety of models and is often more efficient than the commonly used transition relation approach. Most model checking algorithms involve image computation based fix-point computations for state-space exploration. Symbolic model checking thus involves the symbolic manipulation of state-spaces. This is typically done using characteristic functions but Boolean functional vectors are the natural set representation mechanism for symbolic simulation. Their use thus far has been limited because of a lack of the necessary set manipulation algorithms for model checking. We provide a new formulation for canonical Boolean functional vectors based on an ordered selection interpretation. This intuitive formulation enables us to develop the necessary set manipulation algorithms for model checking and to provide a powerful abstraction mechanism. We present examples to show the usefulness of our approach and show how our framework relates to existing methods and techniques.

Multiple surrogates and error modeling in optimization of liquid rocket propulsion components

Goel, Tushar University of Florida 2007 해외박사(DDOD)

소속기관이 구독 중이 아닌 경우 오후 4시부터 익일 오전 9시까지 원문보기가 가능합니다.

Design of space propulsion components is extremely complex, expensive, and involves harsh environments. Coupling of computational fluid dynamics (CFD) and surrogate modeling to optimize performance of space propulsion components is becoming popular due to reduction in computational expense. However, there are uncertainties in predictions using this approach, like empiricism in computational models and surrogate model errors. We develop methods to estimate and to reduce such uncertainties. We demonstrate the need to obtain experimental designs using multiple criteria by showing that using a single-criterion may lead to high errors. We propose using an ensemble of surrogates to reduce uncertainties in selecting the best surrogate and sampling strategy. We also develop an averaging technique for multiple surrogates that protects against poor surrogates and performed at par with best surrogate for many problems. We assess the accuracy of different error estimation models, including an error estimation model based on multiple surrogates, used to quantify prediction errors. While no single error model performs well for all problems, we show possible advantage of combining multiple error models. We apply these techniques to two problems relevant to space propulsion systems. First, we employ surrogate-based strategy to understand the role of empirical model parameters and uncertainties in material properties in a cryogenic cavitation model, and to calibrate the model. We also study the influence of thermal effects on predictions in cryogenic environment in detail. Second, we use surrogate models to improve the hydrodynamic performance of a diffuser by optimizing the shape of diffuser vanes. For both problems, we observed improvements using multiple surrogate models. While we have demonstrated the approach using space propulsion components, the proposed techniques can be applied to any large-scale problem.

Application of an active comparator-based benefit-risk assessment in evaluating clinical trial design features of a new chemical entity using a Bayesian decision-theoretic framework

Goel, Varun University of Minnesota 2010 해외박사(DDOD)

소속기관이 구독 중이 아닌 경우 오후 4시부터 익일 오전 9시까지 원문보기가 가능합니다.

During the drug development process, drug candidates are screened for their efficacy and toxicity. Dose selection is a crucial part of drug development and specifying the right dose imparts pharmacological activity while minimizing side effects. Evaluation of the benefit/risk ratio is typically done by examining the effect of a drug on efficacy and safety endpoints. However, this comparison can be difficult when there are multiple endpoints that are clinically and commercially relevant. A decision-based clinical utility is proposed and evaluated to aid in dose selection. A dose is viable if it has higher efficacy and lower toxicity than the values specified in multi-attribute decision criteria. PD 0200390 is a ligand of the alpha2delta subunit of the voltage-gated calcium channel being investigated for the treatment of primary insomnia and non-restorative sleep. Wake after sleep onset and number of awakenings are the measures of sleep consolidation while ease of awakening and morning behavior following wakefulness are the measures of residual effects. The objective of this research is to select a dose that maximizes the probability of a decision criterion characterized over safety and efficacy attributes. Data is obtained from two phase II double blind, randomized, placebo controlled crossover studies in subjects with primary insomnia. Dose response models are developed as hierarchical non-linear model using NONMEMRTM and WinBUGS RTM. A Sensitivity analysis is performed to test the robustness of the selected dose with varying decision attributes.

Gradient-, Ensemble-, and Adjoint-Free Data-Driven Parameter Estimation

Goel, Ankit ProQuest Dissertations & Theses University of Mich 2019 해외박사(DDOD)

소속기관이 구독 중이 아닌 경우 오후 4시부터 익일 오전 9시까지 원문보기가 가능합니다.

In many applications, models of physical systems have known structure but unknown parameters. By viewing the unknown parameters as constant states, nonlinear estimation methods such as the extended Kalman filter, unscented Kalman filter, and ensemble Kalman filter can be used to estimate the states of the augmented system, thereby providing estimates of the parameters along with the dynamic states. These methods tend to be computationally expensive due to the need for Jacobians, ensembles, or adjoints, especially when the models are high-dimensional. This dissertation presents retrospective cost parameter estimation (RCPE), which does not require gradients, ensembles, or adjoints. Rather, RCPE estimates unknown parameters from a single trajectory, and requires updating an adaptive integrator gain for each unknown parameter. RCPE is applicable to parameter estimation in linear and nonlinear models, where the parameterization may be either affine or nonaffine. The main contribution of this work is to show that the parameter estimates may be permuted in an arbitrary way, and thus a permutation is needed to correctly associate each parameter estimate with the corresponding unknown parameter. RCPE is illustrated through several numerical examples including the Burgers equation and the Global Ionosphere Thermosphere Model (GITM), where the goal is to estimate representational parameters such as eddy diffusion coefficient and thermal conductivity coefficients using measurements of atmospheric variables such as total electron content, density, temperatures etc.The next part of the dissertation focuses on forgetting in the context of recursive least squares (RLS) algorithm. It is a well-known fact that classical RLS with forgetting diverges in the cases where the excitation is not persistent. In this work, an information-driven directional forgetting technique is proposed, which constrains the forgetting to directions in which new information is available, thereby allowing RLS to operate without divergence during periods of loss of persistency. In the last part of this dissertation, retrospective cost adaptive control (RCAC) is extended to the problem of control allocation in overactuated systems. In particular, it is shown that the applied control input lies in the range of the target model used in RCAC, thereby providing a simple technique to constrain the control input to a desired subspace. Finally, RCAC is extended to asymptotically enforce output constraint by formulating the problem as a problem of following conflicting commands, and is used to prevent a scramjet combustor from unstarting using pressure measurements.

Viscoelastic measurements of fracturing fluids for proppant transport application

Goel, Naval The University of Oklahoma 2001 해외박사(DDOD)

소속기관이 구독 중이 아닌 경우 오후 4시부터 익일 오전 9시까지 원문보기가 가능합니다.

One of the primary functions of a fracturing fluid is to transport and distribute proppant through a fracture and to keep the particles suspended till reservoir closes on the fracture. The proppant when suspended and uniformly distributed in the fracture improves the productivity of the reservoir. Therefore, a question is frequently asked regarding the minimum fluid viscosity required for satisfactory proppant transport through a fracture. The knowledge of this viscosity is useful for evaluating fluids prior to their use in the stimulation treatment and for demonstrating the effectiveness of new fluid formulations for fracturing application. The present study addresses this very important question. The study is performed by characterizing crosslinked guar gels for their viscoelastic and suspension properties. The gels are then evaluated for their proppant transport capabilities in two slot models using a field-scale test facility. These characterizations are performed in fracturing slurries prepared at low as well as high sand concentrations and evaluated at ambient as well as elevated temperature conditions. These characterizations are performed for borate-crosslinked gels and then, validated with zirconate-crosslinked gel. The results show that the proppant transport capability of crosslinked gels correlates with the fluid's elasticity and not with its viscosity. Based on these results, a minimum elastic modulus criterion required for a satisfactory performance of crosslinked fluids in a fracturing treatment is proposed. The criterion proposed in this work is developed from the proppant transport behavior evaluated using a field-scale test facility. This criterion also provides a useful and simple method to evaluate fracturing fluids in a laboratory without the need for extensive fluid testing.

From Finite to Infinite: Scalable Automatic Verification of Hardware Designs and Distributed Protocols

Goel, Aman ProQuest Dissertations & Theses University of Mich 2021 해외박사(DDOD)

소속기관이 구독 중이 아닌 경우 오후 4시부터 익일 오전 9시까지 원문보기가 가능합니다.

As the world increasingly depends on complex systems to transfer messages, store our data, and control our finances, how can we tell whether the system is correct, secure, and reliable? Common practices continue to employ computation-intensive simulation-based verification and tedious manual verification. Formal verification using model checking provides an automatic way to identify functional errors in human-engineered designs. Our work presents a collection of scalable model checking techniques to automatically verify hardware designs and distributed protocols by incorporating often ignored structural information readily available at the design level. For hardware designs, we developed equality abstraction, a novel technique that abstracts away unimportant low-level specifics and automatically identifies crucial information using equality relations over source-code level objects, such as branch conditions, operations, etc. Our hardware verifier, called AVR, won the prestigious Hardware Model Checking Competition 2020, outperforming state-of-the-art verifiers with a wide margin, and showed large benefits on a variety of challenging industrial-strength designs and RISC-V cores. Recognizing the lack of automation in verifying distributed protocols, we developed IC3PO, a new verifier that significantly outperforms the state-of-the-art by taking advantage of three structural features in protocol specifications: a) the spatial regularity over replicas that can be permuted arbitrarily, b) the temporal regularity over ordered ranges, and c) the hierarchical protocol structure. IC3PO was able to prove the safety of the Paxos consensus protocol, presenting the first demonstration of an automatically-inferred inductive invariant for Lamport's original Paxos specification. Both AVR and IC3PO generate mathematical explanations, called certificates, that can be independently checked to guarantee design correctness. They can also generate counterexamples that help in identifying design bugs before deployment resulting in robustness against malicious attacks and reduction in down-times and loss of revenue.

Maturation and sex differences in stress sensitivity

Goel, Nirupa University of Pennsylvania 2009 해외박사(DDOD)

소속기관이 구독 중이 아닌 경우 오후 4시부터 익일 오전 9시까지 원문보기가 가능합니다.

Dysregulation of stress neurocircuitry has been implicated in the etiology of depressive and anxiety disorders, both of which are more prevalent in women than in men. Examination of physiological and behavioral stress responses and the mechanisms underlying elevated sensitivity may elucidate the neurobiology of affective disorders. The circuitry mediating these responses is highly dynamic, changing during periods of sexual differentiation of the brain and with exposure to gonadal hormones. To investigate how stress pathways contribute to affective disease vulnerability, we utilized a genetic model of heightened stress responsivity as well as examination of sex differences. We found that in male mice, stress pathways mature during puberty, leading to decreased stress sensitivity in adults as compared to juveniles. However, genetic dysregulation of the corticotropin-releasing factor system in males results in altered maturational processes and increased stress sensitivity as adults. We therefore hypothesized that the rise of testosterone during puberty plays a crucial role in maturation of stress pathways and in the development of sex differences. As adults, females exhibit greater hypothalamic-pituitary-adrenal (HPA) axis activity and greater passive stress-coping behaviors. We found that testosterone exposure during puberty in females decreases stress sensitivity and diminishes these sex differences. Examination of the mechanisms underlying sex differences in HPA stress response revealed that stimulation of the serotonin system has a greater impact on the female HPA axis. This response was supported by differences in serotonin-induced neural activation where females displayed lower fos protein in brain regions that inhibit the stress axis. Testosterone exposure in females and gonadectomy in males ameliorated sex differences in the serotonergic influence on the stress circuitry. Moreover, females exhibited heavier adrenal glands than males, indicative of greater corticosterone synthesis. Testosterone again masculinized this difference. In addition, we found sex differences in expression of stress-relevant genes indicating that females may have a decreased capacity for glucocorticoid- and GABA-mediated negative regulation of the HPA axis. Overall, this work demonstrates that testosterone exposure during developmental periods is a major factor in reducing stress responsivity and that sex differences in stress neurocircuitry may contribute to increased female vulnerability to affective disorders.

Delay constrained communication over fading channels: A queued-code approach

Goel, Satashu Carnegie Mellon University 2009 해외박사(DDOD)

소속기관이 구독 중이 아닌 경우 오후 4시부터 익일 오전 9시까지 원문보기가 가능합니다.

Wireless communications allow un-tethered access to information, voice and multimedia services. However, the performance of communication systems over wireless channels may be severely limited by various impairments, such as time dispersion, fading and inter-channel interference. This makes the design of communication systems for wireless channels very challenging, especially for applications that demand high data rates and stringent delay bounds. This thesis focuses on design issues related to channel fading. Delay constrained communication requires both, reliability of communication, which is ensured through the physical layer design, as well as guarantees on delay bound, which are provided by the link layer design. Traditionally, the communication system design is based on either the pure physical layer (channel coding) approach or the pure link layer (queuing) approach. The pure channel coding approach uses long codewords which span the entire allowable delay, to average over time-varying channel gains, and hence, guarantees low decoding error probability. However, this approach results in pessimistic performance guarantees, since it does not allow rate adaptation. On the other hand, the pure queuing approach allows rate adaptation, and hence, permits improved performance under a delay constraint. However, this approach results in overly optimistic performance guarantees, since it uses short codewords to allow rate adaptation across codewords, but ignores the decoding errors. This thesis presents a novel queued-code system design which combines ideas from channel coding and queuing approaches to overcome their individual limitations. The system is analyzed in the regime of large delay bounds by combining analysis techniques from information theory and large deviations theory. The result of this analysis shows that the optimal queued-code balances the requirements of the coding system and the queuing system, which is a satisfying result. An alternate problem formulation is considered next, where a function of delay metrics must be optimized, while guaranteeing a fixed probability of violation. This formulation models applications which have delay requirements in terms of delay statistics, e.g., mean, variance. A trade-off between mean and variance of delay is explored in this setting. Numerical results show that the queued-code can attain a significant reduction in delay jitter, compared to the fixed rate coding system, for a given mean delay constraint. A practical implementation of the queued-code is also presented. The practical codes are designed by adding rate adaptation and queuing to low density parity check (LDPC) codes. Implementations based on both block and convolutional LDPC codes are presented. Two rate adaptation schemes are considered---one based on puncturing and repetition of coded symbols, and the other based on adaptive modulation. Simulations results are presented, which show the advantage of the queued-code over fixed rate coding. Finally, the applicability of the queued-code in multiuser scenarios is investigated. In particular, cellular downlink scenario is considered, where the base station must communicate with multiple users, each requiring guarantees on delay, data rate and error rate. The problem of minimizing the error rate of the worst user is considered. Numerical results show that the queued-code can extract gains from both time diversity and multiuser diversity, while providing explicit guarantees on delay, data rate and error rate, to the users.

Algorithms for budgeted auctions and multi-agent covering problems

Goel, Gagan Georgia Institute of Technology 2009 해외박사(DDOD)

소속기관이 구독 중이 아닌 경우 오후 4시부터 익일 오전 9시까지 원문보기가 가능합니다.

In this thesis, we do an algorithmic study of optimization problems in budgeted auctions, and some well known covering problems in the multi-agent setting. We give new results for the design of approximation algorithms, online algorithms and hardness of approximation for these problems. Along the way we give new insights for many other related problems. Budgeted auctions. We study the following allocation problem which arises in budgeted auctions: Given a set of m indivisible items and n agents; agent i is willing to pay bij for item j and has an overall budget of Bi (i.e. the maximum total amount agent i is willing to pay). The goal is to allocate items to the agents so as to maximize the total revenue obtained. We give two approximation algorithms with 3/4-approximation factor, improving upon the previous best known factor of ≃ 0.632. We use linear programming based techniques, and our approximation ratio is optimal in the sense that it matches the integrality gap of the linear program used by us and by the other authors [24, 2, 3]. We also show hardness of approximation factor of 15/16 for the above problem, and use our techniques to improve the hardness results for other related allocation problems. We also study the above allocation problem in an online setting. Online version of the problem has motivation in Ad Auctions which are run by search engines such as Google, Microsoft Live, Yahoo!. Previously, the online version was mostly studied in the worst-case setting. But in applications such as Ad Auctions it is unlikely to see a worst-case sequence of items as input. Motivated by this, we study the online version of the problem in which the items arrive in a random order i.e. the set of items are adversarially chosen but the order in which they arrive is random. Our main result is an analysis to show that a natural greedy algorithm has a competitive ratio of 1 - 1/e in this model, which we also show to be tight. Lastly, we define a new bidding language for budgeted auctions---Decreasing valuation bids. We make a case for why this language is better both for the sellers and the buyers. Multi-agent covering problems. To motivate this class of problems, consider the network design problem of constructing a spanning tree of a graph, assuming that there are many agents willing to construct different parts of the tree. The cost of each agent for constructing a particular set of edges could be a complicated function. For instance, some agents might provide discounts depending on how many edges they construct. The algorithmic question that one would be interested in is: Can one find a spanning tree of minimum cost in polynomial time in these complex settings? Note that such an algorithm will have to find a spanning tree, and partition its edges among the agents. Above are the type of questions that we are trying to answer for various combinatorial problems. We look at the case when the agents' cost functions are submodular. A function f : 2X → R is said to be submodular if, for all S,T ⊆ X, f(S ∩ T) + f(S ∪ T) ≤ f(S) + f(T). Submodular functions form a rich class and capture the natural properties of economies of scale or the law of diminishing returns. Based on these considerations, we define the following general class of problems---We are given a set of elements X (|X| = n) and a collection C ⊆ 2X. Here the collection C is given via some combinatorial structure like a matroid or a graph property (for instance the set of all spanning trees in a graph G with edge set X). We are also given k agents, where each agent i specifies a non-decreasing submodular cost function fi : 2X → R+. The goal is to find a set S ∈ C and a partition S1,..., Sk of S such that sum i fi(Si) is minimized. Note that one can study various covering type problems in this setting by suitably defining the collection set C. We study the following fundamental problems in this setting--- Vertex Cover, Spanning Tree, Perfect Matching, Reverse Auctions. We look at both the single agent and the multi-agent case, and study the approximability of each of these problems. The approximation ratio (upper bound) and the hardness of approximation (lower bound) for each of these problems is presented in the table below.*. *Please refer to dissertation for diagram.