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      • Development of Drug delivery Systems for Combination Therapy Using GNRs Contained Nanoplatform

        SHUKLA NUTAN RAKESHKUMAR Convergence Science, Sahmyook university 2023 국내박사

        RANK : 247359

        Multimodal approaches combined with various nanomaterials and advanced techniques have been developed for synergistic cancer treatment. Among various therapies, conventional chemotherapy (CHT) is one of the direct and certain cancer treatments that compromise unintended effects due to non-specific action on both tumor and normal cells whereas, patient-friendly photothermal therapy (PTT) has the possibility to treat embedded tumors in vital regions with its minimal invasion, though it does not guarantee complete removal of cancers. On the other hand, the combination of CHT-PTT enables to the provision of a promising tool for direct cancer treatment with minimal side effects. In this regard, nanostructured materials such as gold nanorods (GNRs) with tuned size and surface characteristics are the key components and are designed to enhance heating capacity and deliver drugs actively or passively at the tumor site. In this review, we summarize the pioneering work done in the synergism of CHT and PTT and provide the current state of the art in the development of inorganic and organic nanocomposites for combinational therapy. Upon near-infrared (NIR) irradiation, combined treatment comprising of photothermal therapy (PTT) and chemotherapy (CHT) offers synergistic effects by inducing localized heat to intended tumor sites and simultaneously allowed delivering drugs thus minimizing undesired side-effects but enhances cytotoxic therapies. In this study, we developed a novel platform that enables simultaneously to respond light stimuli with localized heat and released drugs using drug contained gold nanorods (GNRs). Methotrexate (MTX), a model anticancer drug is attached through hydrolytic ester bonding to targeting molecular hyaluronic acid (HA) that is coated onto GNRs. Based on the rationale, HA provides a good scaffold for high biocompatibility to shield risky GNRs, targeting for a CD44 receptor, and easy chemical binding of drugs. Upon a single light irradiation, MTX-HA functionalized GNRs (MTX-HA @GNRs) provide localized heat to cancer areas for PTT and the elevated temperature accelerates hydrolytic cleavage of the ester bond onto GNRs in physiological condition for CHT, ultimately releasing MTX to cells. In contrast to previous combination therapies that do not concurrently offer heat and drugs upon light stimuli, our NIR triggered CHT with PTT provides clinically effective options with combinatorial treatment that possesses high efficacy resulted in in vitro tests. Nobel metals, especially gold based nanorods (GNRs) complexed with amphiphilic polymers, have gained attention in combination treatments consisting of photothermal therapy (PTT) and chemotherapy (CHT). Such nanano scscaffolds haveehave en recognized as excellent nanocarriers (NC) for the encapsulation of hydrophobic and hydrophilic molecules. GNRs provide synergistic effects by inducing localized cytotoxic heat and drug release in response to near-infrared irradiation (NIR). Because of this w,e concentrated on miniaturizing ofart nanoplatforms by agitating GNRs with pre-synthesized amphiphilic PP (PPEG) and PPFA (PPEG-Folic acid). These novel nanostructures, called PP-GNRs and PPFA-GNRs, enabled the substantial loading of hydrophobic substances such moas del drug (Nile red) and anticancer medications paclitaxel (PTX). The physical encapsulation preserved the PTX's action and exerted three distinct effects: first, passive targeting using enhanced permeability (EPR) and second, active targeting using FA receptor and third, regulated drug release by leveraging the plasmonic feature of GNRs in the presence of NIR. Contrarily, CHT-PTT outperforms individual thermo- or chemotherapies, and the findings imply that GNRs may be a potential nanocarrier for the delivery of hydrophobic medicines in various cancer microenvironments. Although persistent infection from chronic wound lowers the efficacy of single therapy; But combination therapy with prolonged drug release have shown promising effect, such as elimination of heavy bacterial film and multi/single drug resistance with minimal side effects. One such breakthrough is multilayered scaffold that are chemically and physiologically stable. To achieve this objective, we demonstrated construction of layer-by-layer (LBL) assembly aligned by alternate deposition of (PEI/PSS and PAA/PSS) based on electrostatic force. These films exhibited loading of IBU and gen which can be altered depending on different parameter such dipping time, pH and number of layers. Briefly, gen was encapsulated onto PPGNRs, as GNRs have good stability and their antibacterial properties can be enhanced by tuning surface upon adding chemical drugs. Such functionalized GNRs showed excellent photo thermal property which assisted controlled release of gen via deconstruction of thin layers, whereas burst release of IBU. Furthermore, complete disruption of bacterial colonies when combined with near infrared irradiation (NIR).The formed LBL endowed the great healing capability, controlled antibiotic release solve the problems of bacterial resistance due to synergistic effect. Taken together, the antibacterial, cytocompatibility, and stimuli responsive characteristics of this robust multilayer assembly can be promising multifunctional drug delivery system in different medical aliments.

      • Automatic boundary detection method between subcutaneous fat and visceral fat

        Shukla, Alok 서울대학교 대학원 2012 국내석사

        RANK : 247359

        Abstract Automatic boundary detection method between subcutaneous fat and visceral fat 내장지방과 복부지방의 자동 분할 기법 Shukla Alok Shankarlal School of Computer Science and Engineering Seoul National University As the prevalence of obesity continues to rise, accurate tools for quantifying abdominal body and organ fat are critically needed to assist researchers investigating therapeutic and preventive measures against obesity and its comorbidities. Fatty infiltration of the liver, pancreas, and skeletal muscles are indicators of diabetes, the metabolic syndrome, and obesity. In addition to organ fat, the distribution of abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) play critical roles in determining one’s metabolic profile and health risks. Rapid comprehensive human body fat quantification remains an unsolved problem and unmet need. Magnetic resonance imaging (MRI) is a promising modality to address such challenge. The manual delineation of subcutaneous and visceral fat tissue is labour intensive, time consuming, and subject to observer variability. An automatic segmentation method would eliminate observer variability and provide more consistent and fast results. In this thesis, we propose a fully automatic technique, using Live Wire algorithm to detect the boundary between subcutaneous adipose tissue and visceral adipose tissue. The abdomen boundary is segmented, and the visceral adipose tissue is separated from the subcutaneous adipose tissue by means of active contours; incorporating intensity information derived through the unsupervised classification. Keywords: Image segmentation, abdominal fat, Live Wire, Active contours 비만율이 점점 증가함에 따라 복부와 내장의 지방양을 정확히 측정하는 방법이 필요해 지고 있다. 복부와 내장 지방 측정은 비만과 그 합병증 예방에 관한 연구에 도움을 준다. 지방이 간, 췌장, 골격근에 붙어 있는 것은 당뇨, 신진대사장애, 비만의 증거이다. 복부지방과 내장지방은 환자의 건강과 신진 대사 상태를 나타내는 중요한 지표이다. 사람의 지방양을 빠르게 측정하는 것은 꼭 필요하지만 여전히 해결되지 못하고 있다. MRI가 이러한 문제를 해결해 줄 것이라 예상되고 있다. 수동으로 복부지방과 내장지방을 그리는 것은 효율적이지 못하고 시간도 많이 걸린다. 게다가 그리는 사람에 따라 다르게 표현될 가능성이 있다. 하지만 자동 분할 방식은 이러한 문제점을 해결하고 좀 더 빠르고 효율적으로 결과를 얻을 수 있다. 본 논문에서 라이브와이어 알고리즘(Live Wire algorithm)을 이용하여 복부지방과 내장지방 경계의 자동 분할 방식을 제안한다. 복부 영상에서 오츠 이진화 알고리즘(Otsu binary algorithm)을 이용하여 배경과 복부를 분할한다. 복부 내부를 활성 외곽선 모델을 이용하여 내장과 복부 지방 사이의 경계를 분할 한다. 기존의 수동으로 경계를 그려야 하는 문제를 해결하고 어떤 도움없이 자동으로 다양한 형태에 대하여 분할이 가능하다. 본 논문에서 제안한 방법의 장점은 사전 정보 없이 밝기값만으로 복잡하고 다양한 모양의 복부와 내장 지방 사이의 경계를 분할 가능하다는 점이다. Keywords: 영상 분할, 복부지방, Live wire, 활성 외곽선 모델

      • Synthetic and Medicinal Chemistry of Antitumor Natural Products

        Shukla, Vyom The Scripps Research Institute ProQuest Dissertati 2019 해외박사(DDOD)

        RANK : 247343

        This document summarizes the author’s work on the synthetic and medicinal chemistry of antitumor natural products. These natural products are sourced from a variety of classes and are united by their fascinating molecular architectures and compelling biological activities.The first chapter of this thesis serves as an introduction to the art and science of natural products total synthesis while focusing on syntheses accomplished by our group using the tandem Diels–Alder, 1,3-dipolar cycloaddition cascade of 1,3,4-oxadiazoles.The second two chapters focus on the development, extension, and application of the tandem Diels–Alder, 1,3-dipolar cycloaddition cascade of 1,3,4-oxadiazoles. This cascade transformation has been extensively studied by our group over the past decade. The first chapter documents work towards extending the scope of this cascade towards the synthesis of the schizozygane alkaloids while the second chapter focuses on the development of a novel tandem intramolecular Diels–Alder, intermolecular 1,3-dipolar cycloaddition cascade and its application to the synthesis of the Amaryllidaceae alkaloids.The final two chapters of this thesis represent work done by the author as part of a team of scientists. Chapter 4 discusses the medicinal chemistry of the duocarmycin class of natural products while chapter 5 focuses on the synthesis and biochemical investigations of analogues of the potent antitumor drug vinblastine.All in all, this thesis represent the concerted effort by the author towards the discovery of novel synthetic routes towards biologically active natural products and key analogues.

      • Optimization and Learning in Dynamic Environments: Models and Algorithms

        Shukla, Apurv Columbia University ProQuest Dissertations & These 2022 해외박사(DDOD)

        RANK : 247343

        This dissertation proposes new models and algorithms for optimization and learning in dynamic environments. We consider three problems: design of variance-aware optimization algorithms for the optimal power flow problem, robust streaming PCA and the contextual Pareto bandit problem. For the variance-aware optimal power flow problem, we consider the incorporation of stochastic loads and generation into the operation of power grids gives rise to an exposure to stochastic risk. This risk has been addressed in prior work through a variety of mechanisms, such as scenario generation or chance constraints, that can be incorporated into OPF computations. We introduce a variety of convex variants of OPF that explicitly address the interplay of (power flow) variance with cost minimization, and present numerical experiments that highlight our contributions. In Robust Streaming PCA, we consider streaming principal component analysis (PCA) when the stochastic data-generating model is subject to adversarial perturbations. While existing models assume a fixed stochastic data-generating model, we instead adopt a robust perspective where the data generating model constrains the amount of allowed adversarial perturbations, and establish fundamental limits on achievable performance of any algorithm to recover appropriate principal components under this model. Using a novel proof technique, we establish the rate-optimality for robust versions of the noisy power method, previously developed for the non-robust version of the problem. Our modeling and analysis framework provides a unique lens to study sequential stochastic optimization with a non-convex objective and sheds light on the fragility of using off-the-shelf PCA algorithms in an adversarial environment. Our claims are further corroborated on a suite of numerical experiments. The results are numerically verified for a range of parameter values governing the streaming PCA problem. In contextual Pareto bandits, we consider a continuum-armed contextual bandit problem under vectorial rewards. For this problem, we propose a tree-based policy that maintains separate partitions for action and covariate spaces. In the presence of vectorial rewards, we evaluate the performance of the proposed policy in terms of its Contextual Pareto regret. We establish an upper bound on the performance of the proposed policy for this static policy. Finally, the efficacy of the proposed policy is described on a suite of numerical experiments.

      • Stationary hemispherical electrode under submerged jet impingement and validation of measurement model concept for impedance spectroscopy

        Shukla, Pavan Kumar University of Florida 2004 해외박사(DDOD)

        RANK : 247343

        Interpretation of electrochemical impedance measurements requires an adequate understanding of electrode surface phenomena, current distribution, and stochastic error structure. Most importantly, nonuniform current distributions obfuscate impedance analysis using regression. Traditional electrode systems such as the rotating disk electrode have a nonuniform current distribution; therefore, use of the rotating disk electrode is not suitable for impedance studies at high current levels. In this work, a stationary hemispherical electrode under submerged jet impingement is suggested to be an alternative. Primary and secondary current distributions on stationary hemispherical electrode system are uniform, increasing the likelihood of uniform tertiary current distribution. Moreover, electrochemical processes can be monitored in situ on a stationary hemispherical electrode. In the present work, a hydrodynamic model was devised using the boundary layer theory and compared to the computational fluid dynamic model developed at Vrije Universiteit Brussel, Belgium. Both models predicted a separation of boundary layer at the stationary hemispherical electrode under submerged jet impingement. The hydrodynamic model results were used to obtain a solution of convective-diffusion at the mass-transfer limiting condition. Calculations for steady-state current and potential distribution below the mass-transfer limited current were performed to obtain the conditions for uniform current. Reduction of oxygen and ferricyanide were studied on both the disk and the hemispherical electrode under jet impingement. The objective was to understand the differences in impedance response of the disk and the hemispherical electrodes. Repeated impedances measurements were conducted on both electrode systems. The impedance analysis of ferricyanide reduction showed the evidence of boundary layer separation at the hemispherical electrode. A systematic study was undertaken to evaluate the measurement model approach for assessing the error structure of electrochemical impedance measurements. The remaining question was whether the error structure obtained with this model was a property of the measurement or depended on the arbitrary selection of a measurement model. Transfer function and Voigt-element based models were used to assess the error structure of impedance measurements. In spite of differences in the fitting errors and numbers of parameters needed for the regression, the values for the frequency-dependent stochastic errors were found to be independent of the measurement model used. These results confirm the measurement model approach for error analysis. The confidence intervals for the parameter estimates differed for the two models. The Voigt-element based model was found to provide the tightest confidence intervals and was more suited for evaluation of consistency with the Kramers-Kronig relations.

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