Dielectric Spectrometers with Planar Nanofluidic Channels

Disclosed is a method for fabricating nanofluidic channels having a height of from about 1 nm to about 10 nm. Generally, the method includes formation of doped silicon parallel strips in a silicon substrate, formation of a native oxide layer on the substrate, and etching of the native oxide layer at one of the strips to form a channel of a depth of between about 1 nm and about 10 nm. The method also includes bonding a second wafer to the surface, the second wafer including through etched windows to provide probe contacts to two of the parallel strips during use. These parallel strips provide high-frequency transmission lines in the device that can provide broadband dielectric spectroscopy measurement within the nanochannels

Prehydrated Electron and Its Role in Ionizing Radiation Induced DNA Damage and Molecular Mechanisms of Action of Halogenated Sensitizers for Radiotherapy of Cancer

Despite advances in technology and understanding of biological systems in the past two decades, modern drug discovery is still a lengthy, expensive, difficult and inefficient process with low rate of new therapeutic discovery. The search for new effective drugs remains a somewhat empirical process. There is compelling need for a more fundamental, mechanistic understanding of human cancers and anticancer drugs to design more appropriate drugs. Radiotherapy is still the major therapy of cancer. It uses high-energy ionizing radiation such as x-rays and charged particle beams to destroy cancer cells. DNA is well known to be the principal biological target of radiotherapy, but the molecular mechanism of ionizing radiation induced DNA damage was elusive. The conventional thought of the ∙OH radical as the major origin for ionizing radiation induced DNA damage is questionable. Although various strategies and types of compounds have been designed and developed as potential radiosensitizers to enhance the radiosensitizing efficiency of radiotherapy, none of them have been approved for clinical use. The general outcomes of clinical trials have been disappointing. This thesis presents an innovative molecular-mechanism-based drug discovery project to develop novel drugs for effective radiotherapy of cancer through the emerging femtomedicine approach. Its ultimate goal is to develop more effective radiosensitizers, based on our unique molecular understandings of ionizing radiation induced DNA damage and halopyrimidines as a family of potential radiosensitizers. Direct, real-time observation of molecular reactions is of significant importance in diverse fields from chemistry and biology, environmental sciences to medicine. Femtosecond time-resolved laser spectroscopy (fs-TRLS) is a very powerful, direct technique for real-time observation of molecular reactions. Its key strength lies in short duration laser flashes of a time scale at which reactions actually happen - femtoseconds (fs) (1fs = 1015 second). Since the late 1980s, its application to study chemical and biological systems led to the births of new subfields of science, called femtochemistry and femtobiology. Recently, femtomedicine has been proposed as a new transdisciplinary frontier to integrate ultrafast laser techniques with biomedical methods for advances in fundamental understandings and treatments of major human diseases. This the remarkable opportunity afforded through real-time observation of biochemical reactions at the molecular level. Femtomedicine holds the promise of advances in the radiotherapy of cancer. Several important findings were made in this thesis. First, our results of careful and high-quality fs-TRLS measurements have resolved the long existing controversies about the physical nature and lifetimes of a novel ultrashort-lived electron species (epre) generated in radiolysis of water. These results have not only resolved the large discrepancies existing in the literature but provided new insights into electron hydration dynamics in bulk water. Such information is important for quantitative understanding and modeling of the role of non-equilibrium epre in electron-driven reactions in diverse environmental and biological systems, from radiation chemistry and radiation biology to atmospheric ozone depletion. Second, our fs-TRLS results have unraveled how epre plays a crucial role in ionizing radiation induced DNA damage. We found that among DNA bases, only T and especially G are vulnerable to a dissociative electron transfer (DET) reaction with epre leading to bond breaks, while the electron can be stably trapped at C and especially A to form stable anions. The results not only challenge the conventional notion that damage to the genome by ionizing radiation is mainly induced by the oxidizing •OH radical, but provide a deeper fundamental understanding of the molecular mechanism of the DNA damage caused by a reductive agent (epre). Our findings have led to a new molecular mechanism of reductive DNA damage. Third, halopyrimidines, especially BrdU and IdU, have passed Phase I to II clinical trials as potential hypoxic radiosensitizers, but the outcome of Phase III clinical trials was disappointing. Our results of fs-TRLS studies have provided a new molecular mechanism of action of halopyrimidines (XdUs, X=F, Cl, Br and I) in liquid water under ionizing radiation. We found that it is the ultrashort-lived epre, rather than the long-lived ehyd, that is responsible for DET reactions of XdUs. This reaction leads to the formation of the reactive dU• radical, which then causes DNA strand breaks and cancer cell death. Our results have challenged a long accepted mechanism that long-lived ehyd would be responsible for the radical formation from halogenated molecules. Furthermore, we found that the DET reaction efficacy leading to the formation of the reactive dU• radical is in the order of FdU << CldU < BrdU < IdU. Thus, only BrdU and IdU could be explored as potential radiosensitizers, in agreement with the results of bioactivity tests and clinical trials. Fourth, our fs-TRLS studies have provided a molecular mechanism for the DNA sequence selectivity of BrdU and IdU in radiosensitization. We found the DET reactions of BrdU/ IdU with dAMP* and dGMP* formed by attachment of epre generated by radiolysis of water in aqueous BrdU-dAMP/dGMP and IdU-dAMP/dGMP complexes under ionizing radiation. This new mechanistic insight into the interaction of BrdU and IdU with DNA provides clues to improve the halogen familty as potential radiosensitizers and to develop more effective radiosensitizers for clinical applications. Fifth, based on our molecular mechanistic understandings of DNA damage induced by ionizing radiation and halopyrimidines as potential radiosensitizers, we develop more effective new radisensitizing drug candidates through the femtomedicine approach. We have performed a fs-TRLS study of the DET reaction of a candidate compound (RS-1) with epre, and found that the DET reaction of epre with RS-1 is much stronger than that of IdU (and certainly BrdU and CldU). Moreover, we have tested the radiosensitizing effect of RS-1 against human cervical cancer (HeLa) cells exposed to various doses of x-ray irradiation through DNA damage measurements by gel electrophoresis and cell viability/death assays by MTT. Our results have confirmed that RS-1 can largely enhance the radiosensitivity of treated human cervical cancer (HeLa) cells to x-ray (ionizing) radiation. It is clearly demonstrated that RS-1 has a much better radiosensitizing effect than IdU. Although these are just preliminary results, our results have shown promise of developing more effective radiosensitizers. In summary, our studies have demonstrated the potential of femtomedicine as an exciting new frontier to bring breakthroughs in understanding fundamental biological processes and to provide an efficient and economical strategy for development of new anticancer drugs.1 yea

REAL-TIME OBSERVATION OF MOLECULAR REACTION MECHANISM OF HALOPYRIMIDINES AS RADIO-/PHOTOSENSITIZING DRUGS USING TIME-RESOLVED FEMTOSECOND LASER SPECTROSCOPY

Replacement of thymidine in DNA by halopyrimidines, such as bromodeoxyuridine (BrdU) and iododeoxyuridine (IdU), has long been known to enhance DNA damage and cell death induced by ionizing/UV radiation, but the mechanism of action of halopyrimidines at the molecular level is poorly understood. We have applied advanced time-resolved femtosecond laser spectroscopy to this molecular system of biological, chemical and medical significance. We obtained the first real-time observations of the transition states of the ultrafast electron transfer (UET) reactions of halopyrimidines with the ultrashort-lived precursor to the hydrated electron, which is a general product in ionizing/UV radiation. Our results provide a mechanistic understanding of these photo-/radiosensitizing drugs at the molecular level. We found that the UET reaction of BrdU is completed within 0.2 picosecond (ps) after the electronic exciataion, leading to the formation of the transition state BrdU* with a lifetime of ~1.5 ps that then dissociates into Br and a high reactive radical dU•. We have also demonstrated that the reaction efficiency for the formation of the reactive radical dU• to cause DNA damage and cell death is in the order of IdU>>BrdU>CldU>>FdU. This is due to the availability of two precursor states of ~0.2 ps and ~ 0.54 ps lifetimes for dissociative electron attachment (DEA) to IdU, of one precursor state of ~0.2 ps lifetime for DEAs to BrdU and CldU, and no precursors for DEA to FdU. This explains why BrdU and IdU were found to be effective radio-/photosensitizers and indicates that IdU should be explored as the most effective radiosensitizer among halopyrimidines. Moreover, as a by-product of this project, these halopyrimidines have been employed as quantum-state-specific molecular probes to resolve a long-standing controversy about the nature and lifetimes of prehydrated electrons. These findings also have a broader significance as they indicated that nonequilibrium precursor electrons may play an important role in electron-initiated reactions in many biological, chemical and environmental systems. We have also demonstrated UET reactions of nucleotides with the precursor to the hydrated electrons. Our results indicate that among DNA bases, adenine is the most efficient electron trapper and an effective electron transfer promoter, while guanine is the most effective in dissociative electron attachment. These results not only primarily explain the sequence selectivity of duplex DNA containing BrdU/IdU, but imply that the DEA of guanine is an important mechanism for radiation-induced DNA damage in ionizing radiation and radiotherapy of cancer

The impact of credit default swaps on corporate capital structure and investment policies

Credit default swaps (CDSs) are credit derivatives whose primary purposes include hedging and the trading of credit risks. Unlike other derivatives, such as options or futures, CDSs materially alter lender-borrower relations and thus have real economic effects on the companies referenced by the CDSs. In this thesis, I explore the impact of CDS trading on the cost of capital, corporate capital structure, and corporate social responsibility. First, I use the universe of U.S. public firms to examine the impact of CDS trading on a firm’s cost of capital during the period 2001 – 2018. My results robustly show that the inception of CDSs causes a significant reduction in a firm’s weighted average cost of capital (WACC). Further analyses reveal that highly levered firms tend to reduce their debt weight, while firms with low leverage increase their usage of debt. Moreover, CDS referenced firms adjust their debt types by using more arm-length debts, while they simultaneously decrease the usage of revolving credits and term loans from banks. The alteration in capital financing choices may be ascribed to the improved information environment and reflects the fact that CDS trading increases debt renegotiation costs but simultaneously also reduces capital supply-side frictions. After confirming that CDS can impact firms’ financing decisions, I further investigate whether CDS trading can affect a company’s investment in corporate social and environmental activities. A longitudinal sample spanning from 2002 to 2017 across 11 countries and regions was constructed to evaluate the impact. I find that the inception of CDS trading causes a significant reduction in the metric of environmental emission reduction. In addition, the initiation of CDS trading weakly but negatively influences other aspects of CDS firms’ social and environmental performance. Further analysis reveals that investments in emission reduction activities have no relationship to shareholder value creation, whereas engaging in CSR activities related to, e.g., employee, community, or eco-product innovation, etc., increases shareholder wealth. Collectively, my findings reveal one of the downsides of CDSs arising from CDS-protected lenders who become less accommodating over post-CDS periods

The information content of Canadian implied volatility indexes

For predicting future volatility, empirical studies find mixed results regarding two issues: (1) whether model free implied volatility has more information content than Black-Scholes model-based implied volatility; (2) whether implied volatility outperforms historical volatilities. In this thesis, we address these two issues using the Canadian financial data. First, we examine the information content and forecasting power between VIXC - a model free implied volatility, and MVX - a model-based implied volatility. The GARCH in-sample test indicates that VIXC subsumes all information that is reflected in MVX. The out-of-sample examination indicates that VIXC is superior to MVX for predicting the next 1-, 5-, 10-, and 22-trading days' realized volatility. Second, we investigate the predictive power between VIXC and alternative volatility forecasts derived from historical index prices. We find that for time horizons lesser than 10-trading days, VIXC provides more accurate forecasts. However, for longer time horizons, the historical volatilities, particularly the random walk, provide better forecasts. We conclude that VIXC cannot incorporate all information contained in historical index prices for predicting future volatility

Vasculogenic mimicry contributes to lymph node metastasis of laryngeal squamous cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Survival of laryngeal squamous cell carcinoma (LSCC) patients has remained unchanged over recent years due to its uncontrolled recurrence and local lymph node metastasis. Vasculogenic mimicry (VM) is an alternative type of blood supplement related to more aggressive tumor biology and increased tumor-related mortality. This study aimed to investigate the unique role of VM in the progression of LSCC.</p> <p>Methods</p> <p>We reviewed clinical pathological data of 203 cases of LSCC both prospectively and retrospectively. VM and endothelium-dependent vessel (EDV) were detected by immunohistochemistry and double staining to compare their different clinical pathological significance in LSCC. Survival analyses were performed to assess their prognostic significance as well.</p> <p>Results</p> <p>Both VM and EDV existed in LSCC type of blood supply. VM is related to pTNM stage, lymph node metastasis and pathology grade. In contrust, EDV related to location, pTNM stage, T stage and distant metastasis. Univariate analysis showed VM, pTNM stage, T classification, nodal status, histopathological grade, tumor size, and radiotherapy to be related to overall survival (OS). While, VM, location, tumor size and radiotherapy were found to relate to disease free survival (DFS). Multivariate analysis indicated that VM, but not EDV, was an adverse predictor for both OS and DFS.</p> <p>Conclusions</p> <p>VM existed in LSCC. It contributed to the progression of LSCC by promoting lymph node metastasis. It is an independent predictors of a poor prognosis of LSCC.</p

Development and Control of Soybean Aphid, Aphis glycines, in Heilongjiang Province

Originating text in Chinese.Citation: Wang, Chunrong, Chen, Jiguang, Guo, Yuren, Gong, Xiangyu, Xu, Zhaofei, Lin, Chao. (1998). Development and Control of Soybean Aphid, Aphis glycines, in Heilongjiang Province. Soybean Bulletin, 6, 15

Microwave Dielectric Properties of On-Chip Liquid Films

A microwave characterization method for on-chip liquid film dielectric property measurement is developed. Microstrip-line based on-chip test structures are fabricated to characterize the microwave dielectric properties of various on-chip liquid films: DI water and binary mixtures of DI water with glucose and ethanol. The obtained microwave dielectric properties are presented in Cole-Cole diagrams, which show general frequency dependence similar to that of bulk liquids. Different concentration levels of glucose and ethanol show different microwave dielectric responses. Therefore, on-chip microwave dielectric spectroscopy provides a promising and inexpensive on-chip sensing mechanism for biomedical and chemical applications