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Pages
- Title
- Lives and Voyages of Drake Cavendish and Dampier.
- Creator
-
PALMM (Project)
- Identifier
- DP0004058
- Format
- E-book
- PURL
- http://purl.flvc.org/ucf/fd/DP0004058
- Title
- DETERMINATION OF SELECTIVITY AND POTENTIAL FOR DRUG RESISTANCE OF NOVEL ANTIMALARIAL COMPOUNDS FROM NATURE-INSPIRED SYNTHETIC LIBRARIES.
- Creator
-
Keasler, Eric, Keasler, Eric, University of Central Florida
- Abstract / Description
-
As malaria, caused by Plasmodium spp., continues to afflict millions of people worldwide, there is a dire need for the discovery of novel, inexpensive antimalarial drugs. Although there are effective drugs on the market, the consistent development of drug resistant species has decreased their efficacy, further emphasizing that novel therapeutic measures are urgently needed. Natural products provide the most diverse reservoir for the discovery of unique chemical scaffolds with the potential to...
Show moreAs malaria, caused by Plasmodium spp., continues to afflict millions of people worldwide, there is a dire need for the discovery of novel, inexpensive antimalarial drugs. Although there are effective drugs on the market, the consistent development of drug resistant species has decreased their efficacy, further emphasizing that novel therapeutic measures are urgently needed. Natural products provide the most diverse reservoir for the discovery of unique chemical scaffolds with the potential to effectively combat malarial infections, but, due to their complex structures, they often pose extreme challenges to medicinal chemists during pharmacokinetic optimization. In our laboratory we have performed unbiased, cell-based assays of numerous synthetic compounds from chemical libraries enriched with nature-like elements. This screening has led to the discovery of many original chemical scaffolds with promising antimalarial properties. In an attempt to further characterize these scaffolds, the most promising compounds were assayed in order to determine their cytotoxic effects on mammalian cells. In addition, the development of a drug resistant parasite line of Plasmodium falciparum to the most promising compound was done in order to determine the relative probability for parasite resistance development.
Show less - Date Issued
- 2012
- Identifier
- CFH0004223, ucf:44900
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFH0004223
- Title
- 3-AMINO-2-PIPERIDINEQUINOLINE A NOVEL NATURAL PRODUCT-INSPIRED SYNTHETIC COMPOUND WITH ANTIMALARIAL ACTIVITY.
- Creator
-
Valor, Cristhian, Chakrabarti, Debopam, University of Central Florida
- Abstract / Description
-
Malaria afflicts about 500 million people worldwide thus causing significant global economic toll. The drugs available to treat the disease are rapidly losing their efficacy because of widespread prevalence of drug resistant parasites. Thus there is an urgent need to discover novel malaria therapeutics. This research is focused on to study the properties of a novel natural-like synthetic scaffold and analyze its selectivity, and cellular mechanism of action in Plasmodium falciparum. We have...
Show moreMalaria afflicts about 500 million people worldwide thus causing significant global economic toll. The drugs available to treat the disease are rapidly losing their efficacy because of widespread prevalence of drug resistant parasites. Thus there is an urgent need to discover novel malaria therapeutics. This research is focused on to study the properties of a novel natural-like synthetic scaffold and analyze its selectivity, and cellular mechanism of action in Plasmodium falciparum. We have identified a novel compound, 3-amino-2-piperidinequinoline (APQ), which we termed UCF401. APQ demonstrated IC50 at submicromolar concentrations against Plasmodium falciparum using the SYBR Green-I fluorescence assay measuring cellular proliferation. This compound also demonstrated low cytotoxicity against the NIH3T3 and HEPG2 cells using MTS assays, showing an IC50 of 174 uM and 125 uM respectively, suggesting of excellent selectivity. We evaluated the compliance of APQ with Lipinski's parameters and determined the in vitro physicochemical profiles of the compound. Our results show that APQ is a Lipinski parameter compliant and has good physicochemical properties. The cellular mechanism of action of APQ was characterized through the assessment of the effects of the compound at different stages of the parasite's intraerythrocytic life cycle. This assay was done by treating a synchronized cell line with the compound at 5X the IC50 value and then imaging the cells at 12-hour intervals. We found that APQ arrests parasite development at the trophozoite stage. In addition we determined that APQ is parasitocidal after a 96 h exposure. These results demonstrate that APQ can be considered as a validated hit and/or early lead.
Show less - Date Issued
- 2014
- Identifier
- CFH0004593, ucf:45233
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFH0004593
- Title
- Discovery and characterization of novel antimicrobials against Mycobacterium tuberculosis.
- Creator
-
Rodrigues Felix, Carolina, Rohde, Kyle, Jewett, Mollie, Self, William, Phanstiel, Otto, University of Central Florida
- Abstract / Description
-
Tuberculosis disease is currently a global health emergency, causing the most deaths worldwide due a single infectious agent. Eradication of TB is hampered by lack of an effective vaccine and poor treatment options. During infection, host-derived cues such as hypoxia and starvation induce Mycobacterium tuberculosis to halt replication and become dormant, which leads to tolerance to front-line antibiotics used in the TB treatment. This dormant phenotype causes delayed clearance of M....
Show moreTuberculosis disease is currently a global health emergency, causing the most deaths worldwide due a single infectious agent. Eradication of TB is hampered by lack of an effective vaccine and poor treatment options. During infection, host-derived cues such as hypoxia and starvation induce Mycobacterium tuberculosis to halt replication and become dormant, which leads to tolerance to front-line antibiotics used in the TB treatment. This dormant phenotype causes delayed clearance of M. tuberculosis, therefore a long treatment time is required for stable cure without relapse. Poor patient compliance increases the emergence of drug resistant strains, posing yet another challenge for the eradication of TB. There is dire need for novel compounds targeting not only drug-resistant, but also dormant bacteria so as to effectively eliminate drug-resistant strains and also shorten treatment time. This requires compounds with novel modes of action and novel drug screening approaches which focus on dormant M. tuberculosis. In the current work a method was optimized which induces the dormant phenotype of M. tuberculosis in vitro allowing large scale screening of compounds against these tolerant bacteria. The high chemical diversity of marine natural products was explored to increase the chances of finding novel compounds with novel mechanisms of action. Additionally, gold-complexed scaffolds were examined for their putative ability to inhibit topoisomerase 1, which is a highly conserved and essential protein of mycobacteria, not currently targeted in classical treatment regimens. Several marine natural products were identified with selective bactericidal activity against dormant bacteria, emphasizing the powerful tool that was developed for drug screening. Moreover, the gold-complexes were also bactericidal against not only replicating and dormant bacilli, but also mycobacteria resistant to front-line TB drugs. Compounds characterized in this study represent a promising starting point for the development of novel TB therapeutics and discovery of new conditionally essential pathways of dormant bacteria.
Show less - Date Issued
- 2017
- Identifier
- CFE0007294, ucf:52172
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0007294
- Title
- IDENTIFICATION OF NOVEL ANTIMALARIALS FROM MARINE NATURAL PRODUCTS FOR LEAD DISCOVERY.
- Creator
-
Alvarado, Stephenie, Chakrabarti, Debopam, University of Central Florida
- Abstract / Description
-
An estimated 500 million cases of malaria occur each year. The increasing prevalence of drug resistant strains of Plasmodium in most malaria endemic areas has significantly reduced the efficacy of current antimalarial drugs for prophylaxis and treatment of this disease. Therefore, discovery of new, inexpensive, and effective drugs are urgently needed to combat this disease. Marine biodiversity is an enormous source of novel chemical entities and has been barely investigated for antimalarial...
Show moreAn estimated 500 million cases of malaria occur each year. The increasing prevalence of drug resistant strains of Plasmodium in most malaria endemic areas has significantly reduced the efficacy of current antimalarial drugs for prophylaxis and treatment of this disease. Therefore, discovery of new, inexpensive, and effective drugs are urgently needed to combat this disease. Marine biodiversity is an enormous source of novel chemical entities and has been barely investigated for antimalarial drug discovery. In an effort to discover novel therapeutics for malaria, we studied the antimalarial activities of a unique marine-derived peak fraction library provided by Harbor Branch Oceanographic Institute (HBOI). Within this unique library, we have screened 2,830 marine natural product (MNP) peak fractions through a medium throughput screening effort utilizing the SYBR Green-I fluorescence based assay, and have identified 253 fractions that exhibit antimalarial activity. From those inhibiting fractions we have identified twenty species of marine organisms that inhibit Plasmodium falciparum growth, from which thirty-five fractions were selected for further study. Among those thirty-five, eighty-three percent were also found to inhibit the chloroquine resistant strain of P. falciparum, Dd2. The most potent inhibitors were then screened for their cytotoxic properties using the MTT cell viability assay. Among the samples that exhibited potent inhibition of P. falciparum growth were fractions derived from a sponge of the genus Spongosorites sp.. This genus of sponge has been reported to contain the nortopsentin and topsentin class of bis-indole imidazole alkaloids. Nortopsentin A inhibited the parasite growth at the trophozoite stage with an IC50 value of 1.6 µM. This is the first report of antimalarial activity for this class of compound.
Show less - Date Issued
- 2010
- Identifier
- CFE0003472, ucf:48932
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0003472
- Title
- Discovery and characterization of antimalarial compounds with novel cellular mechanisms of action.
- Creator
-
Roberts, Bracken, Chakrabarti, Debopam, Jewett, Travis, Self, William, University of Central Florida
- Abstract / Description
-
Malaria kills over 500,000 people each year and over a third of the global population is at risk of infection. Though the human race has been fighting the malaria war for over 4,000 years and we have made great strides in eliminating malaria from many countries, we are treading on the edge of what could be another malaria epidemic primarily due to widespread drug resistance. There are documented cases of resistance for every known antimalarial in use today, including Artemisinins. It is...
Show moreMalaria kills over 500,000 people each year and over a third of the global population is at risk of infection. Though the human race has been fighting the malaria war for over 4,000 years and we have made great strides in eliminating malaria from many countries, we are treading on the edge of what could be another malaria epidemic primarily due to widespread drug resistance. There are documented cases of resistance for every known antimalarial in use today, including Artemisinins. It is critical that we open a new window of discovery in development of next generation antimalarials that circumvent current resistance paradigms. These compounds must attack new targets, have different speeds of action, and ideally possess powerful transmission blocking potential if they are to be successful antimalarial candidates. Screening endeavors historically focused on either synthetic or natural product libraries. Recent efforts have focused on combining privilege elements of natural products into synthetically tractable compounds to create hybrid libraries. To discover novel antimalarial pharmacophores, we have screened natural products derived from marine biodiversity as well as natural product-inspired synthetic libraries. Our phenotypic screening of 3,164 marine natural products from the Harbor Branch Oceanographic Institute, 56 high density combinatorial natural product based libraries from the Torrey Pines Institute for Molecular Studies, alkaloid, terpene, and macrocyclic libraries from Memorial Sloan Kettering Cancer Center, and 594 natural productinspired compounds from Asinex have identified several new selective antiplasmodial hit chemotypes. iv In this study, we have focused on compounds that exhibit cellular actions differing from current antimalarials. Two of the scaffolds, UCF 201 and 501, a spirocyclic chromane and a nitroquinoline, respectively, act early in the development cycle and block invasion. The alkaloid derived compound M03 blocks egress. UCF 501 cures malaria in the rodent model and significantly inhibits stage V gametocytogenesis. Given that discovery of transmission blocking agents are a priority in the malaria elimination strategies, this result is significant. This work is of high impact as it addresses a critical need in the field- next generation antimalarial scaffolds for malaria therapy and elimination campaign.
Show less - Date Issued
- 2017
- Identifier
- CFE0006785, ucf:51815
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0006785
- Title
- HURRICANE SHOES AND OTHER STORIES.
- Creator
-
Smeltzer, Kristie, Lamazares, Ivonne, University of Central Florida
- Abstract / Description
-
Hurricane Shoes and Other Stories is a collection of short stories that center on evolving and devolving relationships. The characters in these stories form tentative bonds with people in their lives while other relationships slip away. In "Hurricane Shoes," Katrina attempts to reinvent herself by ending an affair. Katrina's pregnancy and her mother's cancer pull the two women closer. "Da's Violets" is about Cheryl's changing relationship with her father. Just as he moves on from the wife who...
Show moreHurricane Shoes and Other Stories is a collection of short stories that center on evolving and devolving relationships. The characters in these stories form tentative bonds with people in their lives while other relationships slip away. In "Hurricane Shoes," Katrina attempts to reinvent herself by ending an affair. Katrina's pregnancy and her mother's cancer pull the two women closer. "Da's Violets" is about Cheryl's changing relationship with her father. Just as he moves on from the wife who left him for her podiatrist, the wife returns with hopes to reconcile. These stories catch characters in moments when they must make difficult choices and endure the uncertainties and ambiguities of relationships. In "Lady Luck," Laurel is a cocaine addict and alcoholic on the verge of finalizing a divorce. She propositions a young man named River to exchange sex for money. River turns the table, and offers Laurel a deal where she'll have all the money and drugs she wants, as long as she helps him transport cocaine. "Bridges" is a coming of age story in which Linda and Kristin have a close call with a train, and Linda matures as she realizes love has limits. The catalyst for changing relationships is sometimes an exchange between characters. In "Special Son," Mark's father is dying of cancer. The father asks his son to take special care of his mother, and Mark needs his father to finally acknowledge Mark's sexuality. In "Swim or Sink," Doreen befriends her campground neighbor, Michael McBride. McBride has been living at the campground since he left his cheating wife, and he offers Doreen insight when she discovers her husband's infidelity. Together the stories function as a mosaic--each very different, but a complement to the others in forming a larger portrayal of relationships.
Show less - Date Issued
- 2005
- Identifier
- CFE0000746, ucf:46573
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0000746
- Title
- ANTON CHEKHOV:THE CHARACTERIZATION AND INTERPRETATIONOF A HISTORICAL FIGURE FOR THE STAGE.
- Creator
-
gALLANT, Alan, Seay, Donald, University of Central Florida
- Abstract / Description
-
ABSTRACT This thesis will explore the execution of the monograph role of "Anton Chekhov" in the original one-act play, An Evening with Anton Chekhov. The play script, rehearsal and public performances of the piece are all self- generated by the candidate, with the proper assistance of the thesis committee. This written thesis serves as the completion of the thesis project, and includes analysis of several key areas of the development of the script and thesis role. This document includes the...
Show moreABSTRACT This thesis will explore the execution of the monograph role of "Anton Chekhov" in the original one-act play, An Evening with Anton Chekhov. The play script, rehearsal and public performances of the piece are all self- generated by the candidate, with the proper assistance of the thesis committee. This written thesis serves as the completion of the thesis project, and includes analysis of several key areas of the development of the script and thesis role. This document includes the original script with endnotes and a structural analysis. Social and historical background of the character, Anton Chekhov, a real person, is presented. This background includes the history as it pertains to Anton Chekhov and the national mindset in pre-revolutionary Russia. This background is integral in not only the development of the character, but also of the script which supports the character. Much of what is contained in the script is from correspondences, anecdotes, and written material from and about Anton Chekhov. These materials will be used as interpretive tools in the development of the character, and includes clues to physical appearance and personality. The character analysis contained herein is, in part, a reflection of these historical and environmental concerns. In addition, external and internal portrayal and the means used to achieve them are discussed. These means include physical and vocal techniques for the stage in conjunction with the use of emotional recall, behaving "as if," and being emotionally and energetically present for the acting partner. Since this is a "one man show," the acting partner will take the form of the audience as other or confidante. This phenomenon, and its effect on the performance, is included in the written thesis. The acting approach in execution of the monograph will also be reflected in a journal, which will contain a record of the successes, challenges, choices and adjustments made in the rehearsal/performance process. Included among these will be the various adjustments made in order to achieve a higher level of spontaneity in movement and transition, and how this semi-improvisational approach aided in adjusting to each unique audience in performance. Analysis will be provided by members of the committee. Dr. Julia Listengarten and Mark Brotherton will submit performance analysis, while the committee chair, Dr. Donald Seay will also provide rehearsal reports. Script work on An Evening with Anton Chekhov will begin in October of 2005, with rehearsals commencing on February 6, 2006. Two performances will be given at the Black Box theatre on the campus of UCF on Monday, February 27, and Tuesday February 28, 2006.
Show less - Date Issued
- 2006
- Identifier
- CFE0000961, ucf:46722
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0000961
- Title
- Waiving Miranda.
- Creator
-
Voyles, Vance, Bartkevicius, Jocelyn, Roney, Lisa, Rushin, Patrick, University of Central Florida
- Abstract / Description
-
Waiving Miranda is a nonfiction collection that explores my career in law enforcement with a special emphasis on how the day-to-day association with others can lure a person into self-observation. The essays include my experiences as a road-patrol deputy, sex-crimes detective, and homicide detective in one of the largest county law enforcement agencies in the nation. Instead of the TV version of law enforcement(-)anecdotes of police chases and shoot outs(-)this thesis examines people on both...
Show moreWaiving Miranda is a nonfiction collection that explores my career in law enforcement with a special emphasis on how the day-to-day association with others can lure a person into self-observation. The essays include my experiences as a road-patrol deputy, sex-crimes detective, and homicide detective in one of the largest county law enforcement agencies in the nation. Instead of the TV version of law enforcement(-)anecdotes of police chases and shoot outs(-)this thesis examines people on both sides of the yellow crimes scene tape as they face their own mortality and the gruesome truth of people's unabashed cruelty towards one another.These essays wrestle with such issues as the following: confronting my own perceived inadequacies while encountering the expectations of those whose ideas of police work come from shows such as SWAT, Law and Order, and NYPD Blue; balancing career and parenting in the aftermath of divorce and a loss of purpose; pursuing a career in law enforcement with the idea of serving the community; discovering that policing in real life is a direct contradiction to the celluloid heroes I grew up watching on television; staging an internal war and ultimately resolving to move past resentment and move forward with a new purpose.Unlike most true crime dramas, this collection does not promise a happily ever after. Instead, it's a detailed account of the men and women in the law enforcement community today, and how, as much as they guard the public against criminals at large, so must they guard themselves against the emotional toll that this knowledge carries with it.
Show less - Date Issued
- 2011
- Identifier
- CFE0004490, ucf:49277
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0004490
- Title
- Recueil de pièces sur la Floride, inédit.
- Creator
-
PALMM (Project), Ternaux-Compans, Henri , 1807-1864
- Abstract / Description
-
A collection by various authors of 16th century documents relating to Florida, most previously unpublished.
- Identifier
- DP0007113
- Format
- E-book
- PURL
- http://purl.flvc.org/ucf/fd/DP0007113
- Title
- BISTRO GIRLS.
- Creator
-
Blakeslee, Vanessa, Rushin, Pat, University of Central Florida
- Abstract / Description
-
"Bistro Girls" is an interconnected collection of short stories focusing on characters whose lives intertwine in the affluent Floridian town of Bellamy Park. In "Bistro Girls of Bellamy Park," a senior at a privileged college struggles to confront an old friend who has slipped into addiction. In "Bobby Blues," two women's stifling situations with live-in boyfriends give way to a small hope as Valerie casts aside her illusions and leaves to find a new apartment, temporarily freeing herself...
Show more"Bistro Girls" is an interconnected collection of short stories focusing on characters whose lives intertwine in the affluent Floridian town of Bellamy Park. In "Bistro Girls of Bellamy Park," a senior at a privileged college struggles to confront an old friend who has slipped into addiction. In "Bobby Blues," two women's stifling situations with live-in boyfriends give way to a small hope as Valerie casts aside her illusions and leaves to find a new apartment, temporarily freeing herself from the pattern of relying on a man. In these stories people wrestle with flawed concepts of personal identity that create outward limitations in their interactions with those they care about most. In "Disconnect," an eccentric millionaire struggles with spirituality and a romance spoiled by his inability to find satisfaction. In "The Coffee Shop," the emotionally removed Don leaves Valerie in the inevitable position to find contentment through self-reliance. Through trial and error, the obstacles of insecurity and disillusionment can at times be overcome. In "Scout's Honor," a young woman marries under the spell of fateful disillusionment, with tragic results. An annulment is the catalyst for her maturity, yet the road before her promises to be a long, painful one. As the characters come closer to acceptance of the imperfections and possibilities in themselves and the world around them, there is almost always some hope, no matter how difficult the means to get there.
Show less - Date Issued
- 2005
- Identifier
- CFE0000745, ucf:46576
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0000745
- Title
- Recueil de pièces sur la Floride, inédit.
- Creator
-
Ternaux-Compans, Henri, PALMM (Project)
- Abstract / Description
-
A collection by various authors of 16th century documents relating to Florida, most previously unpublished.
- Date Issued
- 1841
- Identifier
- AAC3713QF00001/25/200703/12/200713403BnamI D0QF, FHP C CF 2007-01-25, FCLA url 20070308xOCLC, 85834841, CF00001733, 2701055, ucf:20254
- Format
- E-book
- PURL
- http://purl.flvc.org/fcla/tc/fhp/CF00001733.jpg
- Title
- Autonomous Discovery and Maintenance of Mobile Frees-Space-Optical Links.
- Creator
-
Khan, Mahmudur, Yuksel, Murat, Pourmohammadi Fallah, Yaser, Ewetz, Rickard, Turgut, Damla, Nam, Boo Hyun, University of Central Florida
- Abstract / Description
-
Free-Space-Optical (FSO) communication has the potential to play a significant role in future generation wireless networks. It is advantageous in terms of improved spectrum utilization, higher data transfer rate, and lower probability of interception from unwanted sources. FSO communication can provide optical-level wireless communication speeds and can also help solve the wireless capacity problem experienced by the traditional RF-based technologies. Despite these advantages, communications...
Show moreFree-Space-Optical (FSO) communication has the potential to play a significant role in future generation wireless networks. It is advantageous in terms of improved spectrum utilization, higher data transfer rate, and lower probability of interception from unwanted sources. FSO communication can provide optical-level wireless communication speeds and can also help solve the wireless capacity problem experienced by the traditional RF-based technologies. Despite these advantages, communications using FSO transceivers require establishment and maintenance of line-of-sight (LOS). We consider autonomous mobile nodes (Unmanned Ground Vehicles or Unmanned Aerial Vehicles), each with one FSO transceiver mounted on a movable head capable of scanning in the horizontal and vertical planes. We propose novel schemes that deal with the problems of automatic discovery, establishment, and maintenance of LOS alignment between these nodes with mechanical steering of the directional FSO transceivers in 2-D and 3-D scenarios. We perform extensive simulations to show the effectiveness of the proposed methods for both neighbor discovery and LOS maintenance. We also present a prototype implementation of such mobile nodes with FSO transceivers. The potency of the neighbor discovery and LOS alignment protocols is evaluated by analyzing the results obtained from both simulations and experiments conducted using the prototype. The results show that, by using such mechanically steerable directional transceivers and the proposed methods, it is possible to establish optical wireless links within practical discovery times and maintain the links in a mobile setting with minimal disruption.
Show less - Date Issued
- 2018
- Identifier
- CFE0007575, ucf:52573
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0007575
- Title
- Multi-target high-throughput screening assays for antimicrobial drug discovery.
- Creator
-
Grube, Christopher, Roy, Herve, Chakrabarti, Debopam, Moore, Sean, Koculi, Eda, University of Central Florida
- Abstract / Description
-
The rise of antibiotic resistant microbes (bacteria, fungi, and parasites), combined with the current void of new drugs entering the clinical setting, has created an urgent need for the discovery of new antimicrobials. High-throughput screening (HTS) assays represent a fast and cost-efficient method for identifying new therapeutic compounds and have been the longstanding gold standard for drug discovery. The focus of this dissertation is on the development and implementation of novel...
Show moreThe rise of antibiotic resistant microbes (bacteria, fungi, and parasites), combined with the current void of new drugs entering the clinical setting, has created an urgent need for the discovery of new antimicrobials. High-throughput screening (HTS) assays represent a fast and cost-efficient method for identifying new therapeutic compounds and have been the longstanding gold standard for drug discovery. The focus of this dissertation is on the development and implementation of novel methodologies to increase the throughput of target-based HTS by designing assays that allow multiple drug targets to be probed simultaneously. During my graduate studies, I developed three distinct HTS assays. In each of these assays, drug targets were incorporated into synthetic pathways obeying various reaction topologies (e.g., cyclical, parallel, or linear). Each of these reaction topologies conferred specific advantages and limitations to the individual assays. The first assay reconstitutes the bacterial tRNA-dependent pathway for lipid aminoacylation. This two-step pathway combines a tRNA aminoacylation step catalyzed by an aminoacyl-tRNA synthetase (aaRS), and a transferase step, which transfers the amino acid born by the tRNA onto membrane lipids. aaRSs are essential enzymes in all domains of life and represent longstanding drug targets in pathogenic species. The transferase reaction in the pathway is also an appealing drug target since it impacts the cellular permeability of antibiotics. Inhibitors of this reaction could dramatically increase the efficacy of existing therapeutics. The second assay I developed also targets aaRSs, but utilizes a parallel topology that permits the probing of the synthetic and editing activities of up to four aaRSs simultaneously. The third assay utilizes a linear topology that reconstitutes the entire purine salvage pathway from Plasmodium falciparum. Because parasites are unable to synthesize purines de novo, this pathway represents an appealing target for novel antimalarials. Pilot screens using this assay revealed inhibitors for multiple enzymes in the pathway, validating the design of the system. This body of work aims to shift the current paradigm of single-target systems that have historically dominated the HTS field, toward multi-target designs that can be used to more efficiently screen compound libraries against essential pathways in pathogenic microbes.
Show less - Date Issued
- 2019
- Identifier
- CFE0007642, ucf:52469
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0007642
- Title
- Techniques for automated parameter estimation in computational models of probabilistic systems.
- Creator
-
Hussain, Faraz, Jha, Sumit, Leavens, Gary, Turgut, Damla, Uddin, Nizam, University of Central Florida
- Abstract / Description
-
The main contribution of this dissertation is the design of two new algorithms for automatically synthesizing values of numerical parameters of computational models of complexstochastic systems such that the resultant model meets user-specified behavioral specifications.These algorithms are designed to operate on probabilistic systems (-) systems that, in general,behave differently under identical conditions. The algorithms work using an approach thatcombines formal verification and...
Show moreThe main contribution of this dissertation is the design of two new algorithms for automatically synthesizing values of numerical parameters of computational models of complexstochastic systems such that the resultant model meets user-specified behavioral specifications.These algorithms are designed to operate on probabilistic systems (-) systems that, in general,behave differently under identical conditions. The algorithms work using an approach thatcombines formal verification and mathematical optimization to explore a model's parameterspace.The problem of determining whether a model instantiated with a given set of parametervalues satisfies the desired specification is first defined using formal verification terminology,and then reformulated in terms of statistical hypothesis testing. Parameter space explorationinvolves determining the outcome of the hypothesis testing query for each parameter pointand is guided using simulated annealing. The first algorithm uses the sequential probabilityratio test (SPRT) to solve the hypothesis testing problems, whereas the second algorithmuses an approach based on Bayesian statistical model checking (BSMC).The SPRT-based parameter synthesis algorithm was used to validate that a given model ofglucose-insulin metabolism has the capability of representing diabetic behavior by synthesizingvalues of three parameters that ensure that the glucose-insulin subsystem spends at least 20minutes in a diabetic scenario. The BSMC-based algorithm was used to discover the valuesof parameters in a physiological model of the acute inflammatory response that guarantee aset of desired clinical outcomes.These two applications demonstrate how our algorithms use formal verification, statisticalhypothesis testing and mathematical optimization to automatically synthesize parameters ofcomplex probabilistic models in order to meet user-specified behavioral properties
Show less - Date Issued
- 2016
- Identifier
- CFE0006117, ucf:51200
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0006117
- Title
- DEVELOPMENT OF A FLUORESCENT DRUG SCREENING PLATFORM FOR INHIBITORS OF MYCOBACTERIUM TUBERCULOSIS PROTEIN-PROTEIN INTERACTIONS.
- Creator
-
Versfeld, Zina, Rohde, Kyle, University of Central Florida
- Abstract / Description
-
Tuberculosis (TB) is a respiratory disease caused by Mycobacterium tuberculosis (Mtb) that kills around 1.3 million people annually. Multi-drug resistant TB (MDR-TB) strains are increasingly encountered, in part resulting from shortcomings of current TB drug regimens that last between six to nine months. Patients may stop taking the antibiotics during their allotted regimen, leading to drug resistant TB strains. Novel drug screening platforms are therefore necessary to find drugs effective...
Show moreTuberculosis (TB) is a respiratory disease caused by Mycobacterium tuberculosis (Mtb) that kills around 1.3 million people annually. Multi-drug resistant TB (MDR-TB) strains are increasingly encountered, in part resulting from shortcomings of current TB drug regimens that last between six to nine months. Patients may stop taking the antibiotics during their allotted regimen, leading to drug resistant TB strains. Novel drug screening platforms are therefore necessary to find drugs effective against MDR-TB. In order to discover compounds that target under-exploited pathways that may be essential only in vivo, the proposed screening platform will use a novel approach to drug discovery by blocking essential protein-protein interactions (PPI). In Mtb, PPI can be monitored by mycobacterial protein fragment complementation (M-PFC). This project will re-engineer the M-PFC assay to include the red fluorescent mCherry reporter for increased efficiency and sensitivity in high-throughput screening applications. To optimize the mCherry assay, we have developed fluorescent M-PFC reporter strains to monitor distinct PPI required for Mtb virulence: homodimerization of the dormancy regulator DosR. A drug screen will then identify novel compounds that inhibit this essential PPI. The screen will involve positional-scanning combinatorial synthetic libraries, which are made up of chemical compounds with varying side chains. This work will develop novel tools for TB drug discovery that could identify new treatments for the emerging world threat of MDR-TB.
Show less - Date Issued
- 2015
- Identifier
- CFH0004785, ucf:45369
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFH0004785
- Title
- CHARACTERIZATION OF NOVEL ANTIMALARIALS FROM COMPOUNDS INSPIRED BY NATURAL PRODUCTS USING PRINCIPAL COMPONENT ANALYSIS (PCA).
- Creator
-
Balde, Zarina Marie G, Chakrabarti, Debopam, University of Central Florida
- Abstract / Description
-
Malaria is caused by a protozoan parasite, Plasmodium falciparum, which is responsible for over 500,000 deaths per year worldwide. Although malaria medicines are working well in many parts of the world, antimalarial drug resistance has emerged as one of the greatest challenges facing malaria control today. Since the malaria parasites are once again developing widespread resistance to antimalarial drugs, this can cause the spread of malaria to new areas and the re-emergence of malaria in areas...
Show moreMalaria is caused by a protozoan parasite, Plasmodium falciparum, which is responsible for over 500,000 deaths per year worldwide. Although malaria medicines are working well in many parts of the world, antimalarial drug resistance has emerged as one of the greatest challenges facing malaria control today. Since the malaria parasites are once again developing widespread resistance to antimalarial drugs, this can cause the spread of malaria to new areas and the re-emergence of malaria in areas where it had already been eradicated. Therefore, the discovery and characterization of novel antimalarials is extremely urgent. A previous drug screen in Dr. Chakrabarti's lab identified several natural products (NPs) with antiplasmodial activities. The focus of this study is to characterize the hit compounds using Principal Component Analysis (PCA) to determine structural uniqueness compared to known antimalarial drugs. This study will compare multiple libraries of different compounds, such as known drugs, kinase inhibitors, macrocycles, and top antimalarial hits discovered in our lab. Prioritizing the hit compounds by their chemical uniqueness will lessen the probability of future drug resistance. This is an important step in drug discovery as this will allow us to increase the interpretability of the datasets by creating new uncorrelated variables that will successively maximize variance. Characterization of the Natural Product inspired compounds will enable us to discover potent, selective, and novel antiplasmodial scaffolds that are unique in the 3-dimensional chemical space and will provide critical information that will serve as advanced starting points for the antimalarial drug discovery pipeline.
Show less - Date Issued
- 2018
- Identifier
- CFH2000405, ucf:45893
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFH2000405
- Title
- IDENTIFICATION OF POTENTIAL LEAD ANTIMALARIAL COMPOUNDS FROM MARINE MICROBIAL EXTRACTS.
- Creator
-
Carbonell, Abigail, Chakrabarti, Debopam, University of Central Florida
- Abstract / Description
-
Malaria, caused by the parasite Plasmodium falciparum, has a long history as a global health threat. The vector-borne disease causes millions of deaths yearly, especially in developing countries with tropical climates that facilitate transmission. Compounding the problem is the emergence of drug-resistant strains due to overuse of outdated treatments. New compounds with antiplasmodial activity are needed to be developed as effective drugs against malaria. The hypothesis for this project is...
Show moreMalaria, caused by the parasite Plasmodium falciparum, has a long history as a global health threat. The vector-borne disease causes millions of deaths yearly, especially in developing countries with tropical climates that facilitate transmission. Compounding the problem is the emergence of drug-resistant strains due to overuse of outdated treatments. New compounds with antiplasmodial activity are needed to be developed as effective drugs against malaria. The hypothesis for this project is that marine microorganisms have a high likelihood of yielding novel antiplasmodial chemotypes because of their high diversity, which has not yet been explored for antimalarial development. In this project, microbes harvested and fermented by the Harbor Branch Oceanographic Institute in Fort Pierce, Florida were explored as sources for antiplasmodial natural products. Using a SYBR Green I fluorescence-based assay, 1,000 microbial extracts were screened for inhibition of the multidrug-resistant Plasmodium falciparum strain Dd2. Dose-response analysis was performed on 46 fractions from isolates whose extracts demonstrated [greater-than or equal to] 70% inhibition of Dd2 at 1 [micro]g/mL. To evaluate cytotoxicity, the MTS cell viability assay was used to calculate IC50 of extracts from active isolates in NIH/3T3 embryonic mouse fibroblasts. Several extracts demonstrated low IC50 in Dd2 and high IC50 in 3T3, suggesting that they contain potential lead antimalarial compounds. Extracts with high selectivity indices (potent plasmodial inhibition with low mammalian toxicity) have been prioritized for dereplication, with the goal of identifying novel active components that can be developed as antimalarial drugs.
Show less - Date Issued
- 2013
- Identifier
- CFH0004332, ucf:45035
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFH0004332
- Title
- Florida, its history and its romance: the oldest settlement in the United States, associated with the most romantic events of American history, under the Spanish, French, English, and American flags, 1497-1904.
- Creator
-
Fairbanks, George R. (George Rainsford), PALMM (Project)
- Abstract / Description
-
History of Florida from the expedition of Ponce de Leon in 1513 through the first years of the twentieth century.
- Date Issued
- 1904
- Identifier
- AAA6243QF00004/30/200301/26/200419584BfamIa D0QF, ONICF145- 9, FHP C CF 2003-04-30, FCLA url 20040122xOCLC, 54085728, CF00001619, 2571313, ucf:13925
- Format
- E-book
- PURL
- http://purl.flvc.org/fcla/tc/fhp/CF00001619.jpg
- Title
- Histoire de la conquête de la Floride, ou, Relation de ce qui s'est passé dans la découverte de ce païs par Ferdinand de Soto: Seconde partie.
- Creator
-
Vega, Garcilaso de la, Richelet, Pierre, PALMM (Project)
- Abstract / Description
-
Describes Hernando de Soto's march of conquest in Florida and other parts of southeastern North America.
- Date Issued
- 1709
- Identifier
- AAA3453QF00001/16/200208/04/200516032BfamI D0QF, BN2433 - 3244, 2167482c, FHP C CF 2002-01-16, FCLA url 20020610xOCLC, 50187090, CF00001576_0002_000, 2434468, ucf:21237
- Format
- E-book
- PURL
- http://purl.flvc.org/fcla/dl/CF00001576.jpg
