844 research outputs found
In Defence of "the Lesser Cousin of History": An Interview with Rohan Wilson
No full textFew branches of postcolonial literature are as contested \ud
as the historical fiction of settler societies. This interview with the Australian historical novelist Rohan Wilson, author of The Roving Party (2011) and To Name Those Lost (2014), explores the intersections between truth, accuracy, and existential authenticity in his fictional accounts of nineteenth-century Tasmania. Wilson offers \ud
a nuanced yet robust defence of fiction’s role in narrating colonial history. He explains his intentions in writing two linked yet distinctive novels of the frontier—one that focuses on the “Black War” of the 1820s and 1830s, and another that explores how racial violence is refracted by capitalism in subsequent decades
I am Rohan Bopanna as told to Preethi Mathani
No full textTo feel a sense of pride and self confidence, to be able
to represent India at the Davis Cup, to hear the pride
in my parents’ voice, to experience a sense of personal contentment and to have the ability to give back to the people and sport that have formed an integral component of my being-these are priceless for me, Rohan Bopanna, a professional tennis player
Shape optimization of channels for incompressible flows
No full textNázev práce: Optimalizace tvaru kanálu v úlohách nestlačitelného proudění Autor: Zuzana Záhorová Katedra: Katedra numerické matematiky Vedoucí diplomové práce: Doc. Dr. Ing. Eduard Rohan e-mail vedoucího: [email protected] Abstrakt: V předložené práci studujeme problém tvarové optimalizace pro úlohy vnitřního proudění ve 3D. Uvažováno je laminární, nestlačitelné, stacionární proudění popsané Navier- Stokesovými rovnicemi. Jsou popsány stabilizace Navier-Stokesových rovnic potřebné pro řešení úloh s nízkou viskozitou. Předloženy jsou teoretické poznatky týkající se problému tvarové optimalizace včetně důkazu existence řešení. Je popsána adjungovaná metoda pro řešení optimalizační úlohy. Odvozena je analytická analýza citlivosti. Představujeme postupy využité při výpočtech a numerický software pro řešení optimalizačních úloh. Jsou prezentovány výsledky pro stabilizované i nestabilizované řešení Navier-Stokesových rovnic. Představíme výsledky zahrnující lineární omezení geometrie oblasti. Klíčová slova: Nestlačitelné Navier-Stokesovy rovnice, SUPG/PSPG stabilizace, Adjun- govaná metoda, Analýza citlivosti Title: Shape optimization of channels for incompressible flows Author: Zuzana Záhorová Department:..
Data and Code for "Universal Constraints on Protein Evolution in the Long-Term Evolution Experiment with Escherichia coli"
No full textinput data files are located in the data/ directory.
source code is located in the src/ directory.
code and data for the LTEE 60,000 generation metagenomics dataset are located in the LTEE-metagenomic-repo/ directory.
results from running the source code are located in the results/ directory.
for all inquiries: contact the author at rohan dot maddamsetti at duke dot ed
Design, synthesis and screening of a drug discovery library based on an Eremophila-derived serrulatane scaffold
No full textZhang, Chen, Lum, Kah Yean, Taki, Aya C., Gasser, Robin B., Byrne, Joseph J., Wang, Tao, Blaskovich, Mark A.T., Register, Emery T., Montaner, Luis J., Tietjen, Ian, Davis, Rohan A. (2021): Design, synthesis and screening of a drug discovery library based on an Eremophila-derived serrulatane scaffold. Phytochemistry (112887) 190: 1-10, DOI: 10.1016/j.phytochem.2021.112887, URL: http://dx.doi.org/10.1016/j.phytochem.2021.11288
Use of Natural Product Scaffolds in the Generation of Screening Libraries for Drug Discovery
No full textNatural products (NPs) have been a major source of chemical and structural diversity that has been a driving force for drug discovery over the past century. NPs have displayed a significant and vast range of biological activities, providing therapeutic agents in the areas of oncology, inflammation, infectious diseases, hypercholesteremia and tissue rejection in organ transplantation, to name a few. Many drugs on the market are of NP origin, either as unmodified or modified NPs. In 2016, it was reported that approximately 50% of new chemical entities approved between 1981 and 2014 were of NP origin, as unaltered NPs, NP derivatives or synthetic drugs that were inspired by NP pharmacophores. NPs also represent a repository of lead molecules that have played important roles in various drug development programs. Notable example includes pleuromutilin, a fungal metabolite which was a lead compound for the development of the antibiotics tiamulin, valnemulin, retapamulin, and BC-3781. Another remarkable example is the semi-synthetically derived antifungal drugs caspofungin, anidulafungin, and micafungin, which were all developed based on the NP lead compounds echinocandin B and pneumocandin B.
While chemists have used motifs derived from natural sources as starting points for the synthesis of bioactive compounds, the semi-synthetic approach is gradually gaining popularity as targeted scaffolds become easier to obtain. Many research groups are now utilising isolated NPs as scaffolds for the generation of semi-synthetic analogue libraries rather than pursuing the total synthesis of a bioactive NP, since this has the advantages of saving both cost and time. Also, the use of NP scaffolds for drug discovery has the tendency of increasing the probability of finding new and unique lead compounds for different diseases. Thus, including molecules with a NP template or NP-like template into screening libraries will increase hit rates, and hopefully translate into more, and better quality leads or drugs.
Owing to the success of NPs in drug discovery programs, the main aim of this PhD project was to identify unique NP scaffolds with suitable physicochemical parameters and use them for the generation of chemically diverse libraries, evaluate these libraries against a range of biological targets and if possible delineate structure-activity relationships (SARs). The scaffolds chosen for this project were prioritised based on factors such as abundant quantities, low molecular weight, availability of chemical handles for medicinal chemistry studies, and if possible the presence of stereogenic centres, which confers unique 3D shape on the molecule. Using these selection criteria, the plant NP valerenic acid was used in the generation of a novel screening library that consisted of 11 amide analogues. This library was semi-synthetically obtained using parallel solution-phase synthesis followed by C18 HPLC purifications. The chemical structures of all semi-synthetic analogues were elucidated following analysis of the spectroscopic and spectrometric data (NMR and MS). Two of the analogues afforded crystalline products and their structures were confirmed by single X-ray crystallographic analysis. All analogues together with the NP scaffold were evaluated for their ability to inhibit the release of IL-8 and TNF-α. Six analogues showed moderate activity in the IL-8 assay with IC50 values of 2.8–8.3 μM, while none of the tested compounds showed any significant effect on inhibiting TNF-α release.
The second NP scaffold project was based on the naturally occurring hormone found in plants and fungi, gibberellic acid. Treatment of this NP scaffold with a variety of primary amines afforded a total of 12 drug-like secondary amides. The structures of all the analogues were elucidated by NMR and MS analysis. Slow evaporation of a solution of one of the analogues in MeOH resulted in crystals suitable for X-ray diffraction, whose structure was confirmed by single X-ray crystallography. All compounds were evaluated in vitro for cytotoxicity and deregulation of lipid metabolism in LNCaP prostate cancer cells. While no cytotoxic activity was identified at the concentrations tested, five analogues were able to substantially reduce cellular uptake of free cholesterol in prostate cancer cells when compared with the parent compound, which suggests a novel role of gibberellic acid derivatives in deregulating cholesterol metabolism.
For the third PhD project, the plant alkaloid papaverine was subjected to some recently developed late stage functionalisation chemistry. Initially, with the hope of expanding and applying C-H late stage funcationalisation chemistry (through the use of sulfinate reagents) to the NP field, a search of the in-house Davis compound library led to the identification of eight abundant NPs (3-chloro-4-hydroxyphenylacetic acid, boldine, 2′,6′-dihydroxy-4′-methoxy-3′,5′-dimethyl chalcone, xanthurenic acid, the 4-methylumbelliferone, norharmane, papaverine hydrochloride, and DL-kavain. These prioritised compounds had been synthesised, isolated or purchased and were available in quantities, that would allow for preliminary sulfinate reactivity and eventual optimisation studies. Preliminary reactions on these eight NPs with zinc trifluoromethanesulfinate identified papaverine hydrochloride as the most promising NP scaffold for this type of late stage functionalisation chemistry. Reaction of papaverine hydrochloride with 12 other sulfinate reagents showed that this chemistry is more favourable with smaller sized sulfinates, compared to the larger molecular weight and bulkier reagents. The chemical structures of the seven analogues generated were confirmed by detailed analyses of both the 1D/2D NMR and MS data analysis. A library of seven analogues was generated and will be randomly screened in a variety of bioassays in the near future.
Finally, the marine natural products, thiaplakortones A and B were used for the generation of several halogenated analogues. This was achieved by reacting the marine NP scaffolds with N-bromosuccinimide and N-iodosuccinimide. The regio-isomer of thiaplakortone B, which was present in abundant quantities due to previous synthetic work that was performed in the Davis labs, was likewise used as a scaffold to generate additional analogues. This resulted in the generation of 16 semi-synthetic compounds. Late stage innate one-pot C-H functionalisation reactions using sulfinate reagents resulted in the synthesis of ten additional analogues. The structure of all analogues was determined following 1D/2D NMR and LRESIMS data analysis. These thiaplakortone-based semi-synthetic compounds are currently undergoing in vitro anti-malarial screening.
Altogether, this thesis entitled “Use of Natural Product Scaffolds in the Generation of Screening Libraries for Drug Discovery” describes the generation of novel compound libraries using four different NP scaffolds. The chemical structures of all the semi-synthesised compounds were elucidated following interpretation of extensive NMR and MS data. The libraries generated were screened in a variety of bioassays (e.g. anti-inflammatory, anti-cancer, anti- lipogenesis) with some of the analogues showing moderate to high activities when compared with the parent molecule. All compounds isolated or semi-synthesised during this PhD project will be deposited into the Davis Open-Access Compound Library, which is located at Compounds Australia (Griffith University). Compounds Australia will make these unique libraries available for biological evaluations by both local and international researchers. This Open Access deposition means that these novel compounds will be a lasting legacy of this PhD project where they may potentially impact pharma and chemical biology research in the future.Thesis (PhD Doctorate)Doctor of Philosophy (PhD)School of Environment and ScScience, Environment, Engineering and TechnologyFull Tex
KŌDA ROHAN\nTsuyu Dandan and Nineteenth Century English Literature
No full textpdfKōda Rohan recorded explanatory notes for Tsuyu Dandan (1889) as follows. "One: The ineptitude of the writing aside, to say that my literary devices are quite something and that Edward George Bulwer Lytton and William Makepeace Thackeray are really nothing is a big lie, for in fact I indulge in mere magic tricks. The discerning reader will quickly penetrate them."
Here with the coyness of a neophyte author, a self-assertive attitude which emphasizes the use of as a narrative technique can be seen. This study will deal with four questions.
① What function did Kōda Rohan think that narrative technique had in Edo popular fiction? I will first investigate the topology of , clarifying this technique which overflows the boundaries of , , in connection with Lytton and Thackeray. Naturally, this will result in ③ an investigation as to whether or not Lytton and Thackeray were borrowed from Tsubouchi Shōyō's Shōsetsu shinzui, Tō sei shosei katagi, or translations. If so,④ the question of why it was not George Eliot or Charles Dickens naturally arises. Through questions ② to④ I would like to clarify the relationship between Koda Rohan and nineteenth century English literature and to capture anew the stratifications of Rohan's literature.conference pape
Detection and Characterisation of Compounds Inhibiting Stress Granule Formation in Cancer Cells
No full textCancer is one of the leading causes of death worldwide and despite significant improvements to treatment and prevention, cancer cases remain on the rise. Chemotherapy is used to treat patients with cancer, however these do not only kill the cancer cells but also kill normal, healthy cells in the patient. Furthermore, cancer cells have the capacity to become resistant to chemotherapeutic treatment. Therefore, new treatments need to be developed to overcome this problem. One avenue that is being researched is the use of natural products as chemotherapeutic drugs. Over 60% of anticancer drugs used today are either natural products, or their synthetic derivatives and new research is being performed to screen plant and animal secondary metabolites to discover new compounds with anti-cancer therapeutic potential. The research reported in this thesis uses two compounds purified from natural products to explore a novel approach for cancer treatment.
Stress granules (SGs) are messenger ribonucleoprotein particles that are produced in the cytoplasm of the cell in response to stress. Stress granules have been linked to the inhibition of apoptosis and development of multiple drug resistance and it has been suggested that cancer cells can hijack stress granules and use their biological activities to enhance cancer cell survival. In a study by Fournier et al the inhibition of stress granules in bortezomib resistant cancer cells allowed these cells to become sensitive to bortezomib treatment and resulted in an increase in cell death from 15% to 75% (Fournier et al., 2010). This suggests that the inhibition of stress granule formation may restore chemo-sensitivity to the cancer cells, however, the full effect has not been explored beyond the cell based experiments described by Fournier et al.
This research project was based on the research by Fournier et al, suggesting that SG inhibition can increase the efficacy of bortezomib. The aims of this project were to discover natural products that inhibited SG formation and use these natural products in combination with the chemotherapeutics bortezomib and sorafenib to increase their efficacies.
Chapter 3 describes the optimisation and characterisation of SG formation in HEK293, MCF7, T47D, Vero, HeLa, MDAMB231 and MCF7MDR cells for the development of a SG inhibition assay. Chapter 4 describes the screening of 36 compounds from the Davis Open Access Compound Library from which 2 compounds, RAD112 and psammaplysin F were discovered; having activity inhibiting SG formation in the in vitro SG inhibition assay. In chapter 5, the mechanism of action of RAD112 and psammaplysin F were explored. RAD112 belongs to the chalcone class and this class of compound is known for the disruption of microtubules. A microtubule assay was performed analysing the effect of RAD112 against a known microtubule inhibitor, nocodazole and it was confirmed that RAD112 was disrupting microtubules. Psammaplysin F did not cause the disruption of microtubules, therefore, the most common pathway of SG formation, phosphorylation of eIF2α (p-eIF2α) was analysed. It was discovered that psammaplysin F was reducing the amount of p-eIF2α in HEK293, MCF7, Vero and MCF7MDR cells. The mechanism of action studies of both compounds show promising results that warrant further evaluation.
Combinational therapies have many advantages over single chemotherapy regimes in breast cancer as it has been shown that it can increase the patients disease free survival rate and reduce the risk of reoccurrence. In chapter 6 RAD112 and psammaplysin F were used in combination with bortezomib or sorafenib and the interaction between RAD112 with bortezomib or sorafenib and psammaplysin F with bortezomib or sorafenib was determined by cell viability assays and analysed using Compusyn software. The increase in efficacy of bortezomib or sorafenib when combined with RAD112 and psammaplysin F was also examined in the in vitro combinational assay. All combinations of the compounds with the drugs resulted in a synergistic interaction in most cell lines. However, psammaplysin F and sorafenib had the strongest synergistic interaction in MCF7MDR cells, with a combination index (CI) value of <0.4. The IC50 of sorafenib was decreased 4 fold in MCF7MDR cells and 7 fold in MCF7 cells when combined with psammaplysin F. The efficacy of bortezomib and sorafenib was increased after treatment with RAD112 and psammaplysin F suggesting that psammaplysin F and bortezomib have the potential to be used in combination with known chemotherapeutics to restore drug efficacy.
Altogether, this thesis has identified two compounds that inhibit SG formation, RAD112 and psammaplysin F. The mechanism of action studies has revealed two different mechanisms of action for SG inhibition, microtubule inhibition and inhibition of p-eIF2α for RAD112 and psammaplysin F respectively. Combinational studies has resulted in synergistic interactions between RAD112 and bortezomib or sorafenib and psammaplysin F and bortezomib and sorafenib and increased efficacy of bortezomib and sorafenib. These findings show promise as a new strategy in the battle against cancer and further studies involving the complete mechanism of action of these compounds have to be carried out before they can move onto pre-clinical evaluation.Thesis (PhD Doctorate)Doctor of Philosophy (PhD)School of Environment and ScScience, Environment, Engineering and TechnologyFull Tex
'Nicely Boiled and Scraped': Medicine, Radicalism, and the "Useful Body" in a Lloyd Penny Blood
No full textThe publisher Edward Lloyd (1815-1890) helped shape Victorian popular culture in waysthat have left a legacy that lasts right up to today. He was a major pioneer of both popular fiction and journalism but has never received extended scholarly investigation until now. Lloydshaped the modern popular press: Lloyd’s Weekly Newspaper became the first paper to sell over a million copies. Along with publishing songs and broadsides, Lloyd dominated the fiction market in the early Victorian period issuing Gothic stories such as Varney the Vampire (1845-7) and other ’penny dreadfuls’, which became bestsellers. Lloyd’s publications introduced the enduring figure of Sweeney Todd whilst his authors penned plagiarisms of Dickens’s novels, such as Oliver Twiss (1838-9). Many readers in the early Victorian period may have been as likely to have encountered the author of Pickwick in a Lloyd-published plagiarism as in the pages of the original author. This book makes us rethink the early reception of Dickens. In this interdisciplinary collection, leading scholars explore the world of Edward Lloyd and his stable of writers, such as Thomas Peckett Prest and James Malcolm Rymer. The Lloyd brand shaped popular taste in the age of Dickens and the Chartists. Edward Lloyd and his World fills a major gap in the histories of popular fiction and journalism, whilst developing links with Victorian politics, theatre and music
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