Discovery of Novel Tubulin Inhibitors and Selective Survivin Inhibitors for Advanced Melanoma and Total Synthesis of Bioactive 20S-hydroxyvitamin D3

According to the statistics from American Cancer Society, the 5-year survival rate for patients with advanced melanoma is as low as 5%. Treatment of advanced melanoma, therefore, represents an unmet medical need. In this dissertation, I will show the effort to develop new generations of bioavailable tubulin inhibitors targeting the colchicine binding site and selective small-molecule survivin inhibitors for treating advanced melanoma. Extensive structure-activity relationship (SAR) studies of lead molecules ABI-231 and UC-112 have been performed. Chapter 1 will introduce the current situation of advanced or metastatic melanoma, its clinical drug treatments, as well as problems in current drug treatments. Microtubule dynamics and survivin will be discussed as promising therapeutic targets for developing anticancer drugs. 20S-hydroxyvitamin D3 (20S-OH-D3) will be introduced as a promising anti-inflammatory scaffold. Chapter 2 will disclose the SAR study of ABI-231, a previously reported potent tubulin inhibitor from our lab. In this chapter, a new synthetic method was developed to enable the synthesis of ABI-231 analogues modifying the indole moiety. The novel synthetic method involved the synthesis of a key diamine intermediate and imidazoline formation. From the new synthetic method, thirty ABI-231 analogues were synthesized and tested for activities. Among all analogues, 10ab with a 4-methyl-3-indole moiety and 10bb with a 4-indole moiety showed the most potent antiproliferative activities against a panel of melanoma cell lines. 10ab and 10bb had IC50s of 2.2 and 3.0 nM, respectively. The SAR result revealed that modification of the indole moiety in ABI-231 was beneficial to activity. In Chapter 3, we will describe our effort to develop the SAR study of ABI-231 focusing on modification of the 3,4,5-TMP moiety. This is selected since it is one of the most common moieties in current tubulin inhibitors targeting the colchicine binding site. To circumvent the use of potentially explosive azide reported in Chapter 2, an alternative was established to efficiently generate ABI-231 analogues. This new synthetic method involved Suzuki coupling and Grignard reactions to modify the 3,4,5-TMP moiety and to produce target compounds in gram-scale. Among the eight analogues synthesized, the one containing an unique 3-methoxybenzo[4,5]-dioxene moiety had the strongest antiproliferative activity against a panel of melanoma cell lines with an average IC50 of 1.9 nM. To our best knowledge, it represents the most successful instance of isosterically modifying the 3,4,5-TMP moiety in CA-4 derivatives. Chapter 4 will highlight our effort to synthesize reverse ABI (RABI) analogues for SAR study. In this chapter, a novel and concise synthetic route was established toaccess RABI scaffold. RABI scaffold was constructed through a Grignard reaction/Suzuki-Miyaura coupling reaction strategy. From this new synthetic method, twelve novel RABI analogues were synthesized. Compared to MX-RABI (the previously reported most potent RABI), several new RABI analogues showed significantly improved cytotoxicities. In particular, analogue 15i with a 4-indazole moiety showed the most potent antiproliferative activity against a panel of melanoma cell lines and had an average IC50 of 0.8 nM. This is the first sub-nM anti-tubulin compound in the related scaffolds. Chapter 5 will reveal our latest SAR study of UC-112, a previously reported selective survivin inhibitor. Fourteen UC-112 analogues modifying the benzyloxy moiety of UC-112 were synthesized. Their corresponding SAR result demonstrated that indole moiety was the most favorable (analogue 12a). Subsequent structural optimization of 12a by introducing either mono-substituent or di-substituent to the indole moiety led to the synthesis of another twenty-four new UC-112 analogues. Several substituted indole analogues showed equipotency to that of UC-112 and MX-106. Importantly, new indole analogues exhibited significant abilities to overcome multidrug-resistance mediated by Pgp overexpression. Chapter 6 is characterized by the establishment of a total synthetic method of 20SOH-D3 which showed comparable antiproliferative activity to 1,25α-dihydroxyvitamin D3 without hypercalcemic toxic effect upto a concentration of 60 μg/kg in vivo. The total synthesis of 20S-OH-D3 involved parallel generation of key intermediates from ergocalciferol. The vitamin D3 core structure was constructed through Wittig-Horner coupling reaction. Deprotection of SEM and TBS was achieved in one step. 20S-OH-D3 was furnished in sixteen steps with an overall yield of 0.4%

BiFeO3-Based Nanoceramics Prepared by Spark Plasma Sintering

AbstractBiFeO3-based nanopowders were prepared via a sol-gel method, in which the gel (with metal-nitrate, maleic acid and water used as raw materials) was sintered at 650°C for 2 hours. The aggregation of nanopowders was destroyed by high energy ball milling for 12 hours. BiFeO3-based nanoceramics were prepared by spark plasma sintering method. XRD results indicate that there are two phases, ZrO2 and BiFeO3, in the ceramics. The results of SEM observation show that the ceramic grain size is about 50nm in diameter. These phenomena and the changes of sintering parameters indicate that ZrO2 phase exits in the grain boundaries and inhabits the growth of BiFeO3 grains. The dielectric constant of nanoceramics, about 70, is stable between 102 Hz and106 Hz

Rapid, simple, and sensitive detection of the ompB gene of spotted fever group rickettsiae by loop-mediated isothermal amplification

BACKGROUND: Spotted fever caused spotted fever group rickettsiae (SFGR) is prevalent throughout China. In this study, we describe a rapid, simple, and sensitive loop-mediated isothermal amplification (LAMP) assay targeting the ompB gene of spotted fever group rickettsiae ideal for application in China. The LAMP assay has the potential to detect spotted fever group rickettsiae early in infection and could therefore serve as an alternative to existing methods. METHODS: A set of universal primers which are specific 7 common species of spotted fever group rickettsiae in China were designed using PrimerExplorer V4 software based on conserved sequences of ompB gene. The sensitivity, specificity and reproducibility of the LAMP were evaluated. The LAMP assay for detecting SFGR was compared with conventional PCR assays for sensitivity and specificity in early phase blood samples obtained from 11 infected human subjects. RESULTS: The sensitivity of the LAMP assay was five copies per reaction (25 μL total volume), and the assay did not detect false-positive amplification across 42 strains of 27 members of the order Rickettsiales and 17 common clinical pathogens. The LAMP assay was negative to typhus group rickettsiae including R. prowazekii and R. typhi for no available conserved sequences of ompB was obtained for designing primers. To evaluate the clinical applicability of the LAMP assay, a total of 11 clinical samples, 10 samples confirmed serologically (3 cases), ecologically (1 case), by real-time polymerase chain reaction (PCR; 2 cases), ecologically and by real-time PCR (1 case), and serologically and by real-time PCR (3 cases) were analyzed by the ompB LAMP assay. Data were validated using a previously established nested PCR protocol and real-time PCR. A positive LAMP result was obtained for 8 of the 10 confirmed cases (sensitivity, 73%; specificity, 100%), while none of these samples were positive by nested PCR (sensitivity, 0%; specificity, 100%). CONCLUSIONS: The LAMP assay described here is the most reliable among the three methods tested and would be an ideal choice for development as a rapid and cost-effective means of detecting SFGR in China

A multi-stable memristor and its application in a neural network

© 2020 IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other uses, in any current or future media, including reprinting/republishing this material for advertising or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other works.Nowadays, there is a lot of study on memristorbased systems with multistability. However, there is no study on memristor with multistability. This brief constructs a mathematical memristor model with multistability. The origin of the multi-stable dynamics is revealed using standard nonlinear theory as well as circuit and system theory. Moreover, the multi-stable memristor is applied to simulate a synaptic connection in a Hopfield neural network. The memristive neural network successfully generates infinitely many coexisting chaotic attractors unobserved in previous Hopfield-type neural networks. The results are also confirmed in analog circuits based on commercially available electronic elements.Peer reviewe

Investigation of temperature stress tolerance in Arabidopsis STTM165/166 using electrophysiology and RNA-Seq

Plant electrical signals have been shown to be generated in response to various environmental stresses, but the relationship between these signals and stress tolerance is not well understood. In this study, we used the Arabidopsis STTM165/166 mutant, which exhibits enhanced temperature tolerance, to examine this relationship. Surface recording techniques were utilized to compare the generation ratio and duration characteristics of electrical signals in the STTM165/166 mutant and wild type (WT). Patch-clamp recording was employed to assess ion channel currents, specifically those of calcium ions. The current intensity of the mutant was found to be lower than that of the WT. As calcium ions are involved in the generation of plant electrical signals, we hypothesized that the reduced calcium channel activity in the mutant increased its electrical signal threshold. RNA-Seq analysis revealed differential expression of AHA genes in the STTM165/166 mutant, which may contribute to the prolonged depolarization phenotype. Gene Ontology enrichment of differentially expressed genes (DEGs) identified associations between these DEGs and various stresses, including temperature, salt, and those related to the jasmonic acid and abscisic acid pathways. These findings provide experimental evidence for the use of plant electrical signals in characterizing stress tolerance and explore potential ion mechanisms through patch-clamp recording and DEG Gene Ontology analysis. They also emphasize the need for further research on the relationship between plant electrical signals and stress tolerance.Comment: 20 pages, 5 figure

A Multi-Value 3D Crossbar Array Nonvolatile Memory Based on Pure Memristors

© 2022, The Author(s), under exclusive licence to EDP Sciences, Springer-Verlag GmbH Germany, part of Springer Nature. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1140/epjs/s11734-022-00576-9How to improve the storage density and solve the sneak path current problem has become the key to the design of nonvolatile memristive memory. In this paper, a high storage density and high reading/writing speed 3D crossbar array non-volatile memory based on pure memristors is proposed. The main works are as follows: (1) an extensible memristive cluster is proposed, (2) a memristive switch is designed, and (3) a 3D crossbar array non-volatile memory is constructed. The memory cell of the 3D crossbar array non-volatile memory is constructed by pure memristors and can be extended by adding memristor in a memristive cluster or adding memristive clusters in a memory cell to realize multi-value storage. The memristive switch can effectively reduce the sneak path current effect. The pure memristive memory cell solves the conflict between the storage density and sneak path current effect and greatly improves the storage density of memory cells. Furthermore, the 3D cross-array structure allows different memory cells on the same layer or different layers to be read and written in parallel, which greatly improves the speed of reading and writing. Simulations with PSpice verifies that the proposed memristive cluster can realize stable multi-value storage, has higher storage density, faster reading and writing speed, fewer input ports and output ports, better stability, and lower power consumption. Moreover, the structure proposed in this paper can also be used in the circuit design of the neuromorphic network, logic circuit, and other memristive circuits.Peer reviewe

Effects of land use, topography, climate and socio-economic factors on geographical variation pattern of inland surface water quality in China

The deterioration of water quality has become a primary environmental concern worldwide. Understanding the status of water quality and identifying the influencing factors are important for water resources management. However, reported analyses have mostly been conducted in small and focused areas. It is still unclear if factors driving spatial variation in water quality would be different in extended spatial scales. In this paper, we analyzed spatial pattern of inland surface water quality in China using a dataset with four water quality parameters (i.e., pH, DO, NH4+-N and CODMn) and the water quality level. We tested the effects of anthropogenic (i.e., land use and socio-economic) and natural (i.e., climatic and topographic) factors on spatial variation in water quality. The study concluded that the overall inland surface water quality in China was at level III (fair). Water quality level was strongly correlated with CODMn and NH4+-N concentration. In contrast to reported studies that suggested land use patterns were the determinants of inland surface water quality, this study revealed that both anthropogenic and natural factors played important roles in explaining spatial variation of inland surface water quality in China. Among the tested explanatory variables, mean elevation within watershed appeared as the best predictor for pH, while annual precipitation and mean air temperature were the most important explanatory variables for CODMn and DO, respectively. NH4+-N concentration and water quality level were most strongly correlated with the percent of forest cover in watershed. Compared to studies at smaller spatial scales, this study found different influencing factors of surface water quality, suggesting that factors may play different roles at different spatial scales of consideration. Therefore management policies and measures in water quality control must be established and implemented accordingly. Since currently adopted parameters for monitoring of inland surface water quality in China are largely influenced by natural variables, additional physicochemical and biological indicators are needed for a robust assessment of human impacts on water quality

A Triple-Memristor Hopfield Neural Network With Space Multi-Structure Attractors And Space Initial-Offset Behaviors

© 2023 IEEE. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1109/TCAD.2023.3287760Memristors have recently demonstrated great promise in constructing memristive neural networks with complex dynamics. This paper proposes a memristive Hopfield neural network with three memristive coupling synaptic weights. The complex dynamical behaviors of the triple-memristor Hopfield neural network (TM-HNN), which have never been observed in previous Hopfield-type neural networks, include space multi-structure chaotic attractors and space initial-offset coexisting behaviors. Bifurcation diagrams, Lyapunov exponents, phase portraits, Poincaré maps, and basins of attraction are used to reveal and examine the specific dynamics. Theoretical analysis and numerical simulation show that the number of space multi-structure attractors can be adjusted by changing the control parameters of the memristors, and the position of space coexisting attractors can be changed by switching the initial states of the memristors. Extreme multistability emerges as a result of the TM-HNN’s unique dynamical behaviors, making it more suitable for applications based on chaos. Moreover, a digital hardware platform is developed and the space multi-structure attractors as well as the space coexisting attractors are experimentally demonstrated. Finally, we design a pseudo-random number generator to explore the potential application of the proposed TM-HNN.Peer reviewe