Biochemistry, Biophysics, and Structural Biology Commons^™

Nanoparticle Conjugated Photosensitizer For Targeted Photodynamic Inactivation Of Cancer Cells, Symone D. Crowder

Honors College Theses

Photodynamic therapy (PDT) is considered to be a potential replacement for traditional methods of chemotherapy. It includes the administration of photosensitizing agents (PS), which generate reactive oxygen species (ROS) upon excitation at a specific wavelength. With new outlooks and techniques, cancer research is advancing each day. It has allowed the progress of several theranostic drug delivery systems (DDS) exploring the area of nanomedicine.2 In the present work, a Rhodamine derivative, Rhodamine 6G (R6G) was used as the PS. In general, rhodamine compounds undergo cytotoxic reactions on photoexcitation by electron transfer reactions with folic acid within cells, making them a favorable …

Synthesis Of Trifluoromethyl Ketones By (Diethylamino) Sulfur Trifluoride (Dast)-Mediated Nucleophilic Trifluoromethylation Of Benzoic Acids, Michael A. Vescio

Honors College Theses

Within the past few decades, the presence of fluorine containing

organic molecules has increased significantly. Many of the

current industrial production methods are not cost-effective,

practical, or inherently safe. This work describes a new methodology

for the synthesis of trifluoromethyl ketones. Our new method involves

the use of benzoic acid and trifluoromethyl trimethylsilane (TMSCF₃) as starting

materials along with diethylamino sulfur trifluoride (DAST) as a reagent

to obtain moderate to good yields of expected products in a short

reaction times.

The Use Of Silica Nanoparticles For Controlled Drug Delivery Of Nicotine, Jennifer C. Iwenofu

Honors College Theses

Drug molecules can be administered in different ways to the human body. Nanotechnology stands out over other alternatives by delivering drugs to specific locations and reducing reactivity time. In this research, the hydrogen bond between silica nanoparticles and the drug molecule, nicotine, were studied to controllably deliver nicotine by varying pH values.

Analysis Of The Light Responsive Azobenzene Peptide Nucleic Acid Duplexes, Kat Nguyen

Honors College Theses

Peptide nucleic acids (PNAs) are oligonucleotide analogues in which the sugar-phosphate backbone has been replaced by a pseudopeptide skeleton. Since PNAs use the natural nucleobases (Adenine, Thymine, Cytosine, Uracil, and Guanine) found in either DNA and/or RNA, they are able to hybridize according to Watson-Crick base-pairing to form duplexes. PNA is a promising therapeutic agent because they can function as antigene or antisense chemical agents. To further enhance their utility, we aim to incorporate a photoswitchable moiety using azobenzene. Here, we report the results of the synthesis and purification of a photoswitchable 11 mer PNA along with initial characterization efforts.

Physiological And Biochemical Thermal Stress Conditions Of The Ribbed Mussel, Geukensia Demissa, From Exposed And Less Exposed Areas In The Intertidal Salt Marsh On Tybee Island, Georgia., Jody E. Erber

Honors College Theses

Geukensia demissa, the ribbed mussel, is a keystone species of Georgia’s coastline that is at risk of experiencing detrimental thermal stress due to climate change. G. demissa interacts positively with a species of salt marsh cordgrass, Spartina alterniflora. Mussels form aggregates beneath salt marsh cordgrass stems where they are shaded and less exposed to sun rays. However, some mussels end up in areas which lack cordgrass and are directly exposed to sun rays. Body temperatures of mussels from exposed areas were found to be higher than mussels from less exposed areas. Thermal stress levels of mussels can be …

Structural And Functional Characterization Of Two Poly(Aspartic Acid) Hydrolases, Amanda Jansch

Electronic Theses and Dissertations

Due to the accumulation of polymers in the environment, biodegradable alternatives should be used in place of commonly used polymers like poly(carboxylates). Poly(carboxylates) are water-soluble polymers (WSPs) that make up a variety of consumer products, such as detergents, descaling agents, and superabsorbent materials commonly found in diapers and feminine hygiene products. While the visible accumulation of these products may not be obvious, it is necessary to reduce the amount entering the environment. Poly(aspartic acid) (PAA) is an alternative WSP that is biodegradable through the action of three different enzymes, PahZ1_KT-1, PahZ2_KT-1, and PahZ1_KP-2. Originally …

Development Of Novel Pyridazine Derivatives And Drug Delivery Systems Against Dengue, Janae A. Culmer

Electronic Theses and Dissertations

The lack of approved vaccines, medications and treatment regimens has significantly contributed to the rapid spread of mosquito-borne viruses such as Dengue and Zika virus. The complex immunopathology of these viruses presents limitations for the development and implementation of a definitive, safe and effective approach to combat infections.Previous research has demonstrated that vector control strategies such as the elimination of larval habitats, larviciding with insecticides, the use of biological agents and the application of adulticides have been unsuccessful in the reduction of viral transmission leading to the need for the continued development of antivirals. This research proposes an approach for …

Biomimetic Synthesis Of Palladium Nanoparticles For Catalytic Application, Emily A. Groover

Electronic Theses and Dissertations

The synthesis of palladium nanoparticles (Pd NPs) using materials-directed peptides is a novel, nontoxic approach which exerts a high level of control over the particle size and shape. This biomimetic technique is environmentally benign, featuring nonhazardous ligands and ambient conditions. Nanoparticles are extremely reactive catalysts, boasting a large surface-to-volume ratio when compared to their bulk counterparts. The rational design of these nanoparticles using peptides has been very successful in aqueous environments, but no research has been done to apply it in organic systems. As such, the biomimetic synthesis of Pd NPs in an organic system is here investigated, with ethanol …

Investigating The Toxicology Of Intramuscular Injected Cnt-Ab In Mice Followed By Microwave Hyperthermia., Conner Clark

Honors College Theses

The advent of carbon nanotubes (CNTs) has led to a wide range of research in various fields including cancer therapy for targeting specific localized and site-specific treatment. Carbon nanotubes bound to tumor specific antibodies (Ab) offers specific treatment for cancer cells without affecting surrounding tissue. This treatment makes use of infrared absorptive properties of nanotubes to incinerate both the nanotube and its associated tumor in vivo. We seek to affirm the initial results of CNT in cancer therapy by investigating the toxicological effect in mice injected with CNT-Ab followed by microwave hypothermia. After 1-week post-injection, mice were sacrificed followed …

Synthesized Tripodal Amine As Potential Anti-Cancer Therapeutic, Abigail G. Mcnamee

Honors College Theses

Cancer remains a prevalent disease today. This disease may manifest itself in many different ways and affect a variety of tissues with everything from the brain to the blood. With this wide diversity of cancer types, treatment can be complicated since there is not a “one size fits all” treatment for the disease. Surgery, radiation, and chemotherapy are all options that must be weighed with their benefits and side effects. Ultimately though, there are not enough effective treatment options available for every type of cancer. This leaves many with the grim prognosis of never being cured. With this clear need …

Determination Of Optimal Mild Organic Solvents Of Pdnps For Carbon-Carbon Coupling Reactions, Trina Biswas

Honors College Theses

The synthesis of nanoparticles is an increasingly popular field of interest. The application of nanoparticles is especially popular in the field of nanocatalysts. Metal nanoparticles (NPs) are favorable for catalysis because of the large surface area to volume ratio, which allows them to catalyze a variety of reactions using lesser amounts of active material. As the field of nanoparticle research expands, efforts are being made to create more sustainable approaches to the synthesis of these particles. This research sought to translate the benefits of peptide-based synthesis to organic solvents and use less toxic organic solvents for carbon-carbon coupling reactions, like …

Wetland Biogeochemical Responses To Predicted Climate Change Scenarios, Angela R. Shaffer

Electronic Theses and Dissertations

Wetlands are one of the world's largest known carbon sinks while comprising only a small amount of the Earth's surface. However, the amount of carbon sequestered by wetlands is shrinking as droughts and human disturbance increases. Carbon in wetlands is stored through the contrast of decomposition and sedimentation of organic matter and absorption of CO₂ from the atmosphere by soil microbes. Understanding how changing hydrological regimes and increased wildfires will affect wetland soil and microbial processes is important in the face of predicted climate change for future wetland conservation practices. Specifically, I seek to understand the response of southeastern …

Small Molecule Disruption Of Ros-Regulating Pathways In Human Carcinoma, Rebecca E. Mccall

Electronic Theses and Dissertations

Gold (I) coordinated N-heterocyclic carbenes containing appended redox cycling moieties were designed and analyzed for their ability to target the antioxidant network via multiple mechanisms in various human cancer cell models. Complexes containing either ferrocene or naphthoquinone redox cycling moieties were screened for inhibition of cell growth, inhibition of thioredoxin reductase (TrxR), and accentuation of exogenous ROS. The cell death pathway employed was determined by flow cytometry via detection of Annexin-V FITC. Furthermore, differential gene expression between treated cells and untreated cells revealed the induction of endoplasmic reticulum stress and unfolded protein response pathways.

Longitudinal Transcriptomic Dysregulation In The Peripheral Blood Of Transgenic Huntington’S Disease Monkeys, Jannet Kocerha, Yuhong Liu, David Willoughby, Kumaravel Chidamparam, Joseph Benito, Kate Nelson, Yan Xu, Tim Chi, Heidi Engelhardt, Sean Moran, Shang-Hsun Yang, Shi-Hua Li, Xiao-Jiang Li, Katherine Larkin, Adam Neumann, Heather Banta, Jinjing Yang, Anthony W. S. Chan

Jannet Kocerha

Background: Huntington’s Disease (HD) is a progressive neurodegenerative disorder caused by an expansion in the polyglutamine (polyQ) region of the Huntingtin (HTT) gene. The clinical features of HD are characterized by cognitive, psychological, and motor deficits. Molecular instability, a core component in neurological disease progression, can be comprehensively evaluated through longitudinal transcriptomic profiling. Development of animal models amenable to longitudinal examination enables distinct disease-associated mechanisms to be identified.

Results: Here we report the first longitudinal study of transgenic monkeys with genomic integration of various lengths of the human HTT gene and a range of polyQ repeats. With this unique group …

Advances In Profiling Of Noncoding Rnas In Neurological Disease, Murray J. Cairns, Jannet Kocerha

Jannet Kocerha

No abstract provided.

Expression Of Fused In Sarcoma Mutations In Mice Recapitulates The Neuropathology Of Fus Proteinopathies And Provides Insight Into Disease Pathogenesis, Christophe Verbeeck, Mariely Dejesus-Hernandez, Carolina Ceballos-Diaz, Jannet Kocerha, Todd Golde, Pritam Das, Rosa Rademakers, Dennis W. Dickson, Thomas Kukar

Jannet Kocerha

Background: Mutations in the gene encoding the RNA-binding protein fused in sarcoma (FUS) can cause familial and sporadic amyotrophic lateral sclerosis (ALS) and rarely frontotemproal dementia (FTD). FUS accumulates in neuronal cytoplasmic inclusions (NCIs) in ALS patients with FUS mutations. FUS is also a major pathologic marker for a group of less common forms of frontotemporal lobar degeneration (FTLD), which includes atypical FTLD with ubiquitinated inclusions (aFTLD-U), neuronal intermediate filament inclusion disease (NIFID) and basophilic inclusion body disease (BIBD). These diseases are now called FUS proteinopathies, because they share this disease marker. It is unknown how FUS mutations cause disease …

Patterns Of Chemosensory Behavior In A Closed Population Of Wild African Elephants (Loxodonta Africana), Russell W. Blogg

Electronic Theses and Dissertations

Chemosensory behaviors are used by many mammalian species to assess chemical signals in the environment. These chemical signals may contain important information about reproductive state, identity, status, or location of conspecifics. Elephants are a long-lived species and males reproduce at a much later age than females, which provides a protracted developmental period for males. This study examined chemosensory behaviors in a population of African elephants living in Addo Elephant National Park, South Africa and demonstrated that patterns emerge as elephants develop and approach sexual maturity. Older pubescent males (15-19 year olds) performed more chemosensory behaviors than younger pubescent males (10-14 …

The Path To Microrna Therapeutics In Psychiatric And Neurodegenerative Disorders, Anthony W. S. Chan, Jannet Kocerha

Jannet Kocerha

The microRNA (miRNA) class of non-coding RNAs exhibit a diverse range of regulatory roles in neuronal functions that are conserved from lower vertebrates to primates. Disruption of miRNA expression has compellingly been linked to pathogenesis in neuropsychiatric and neurodegenerative disorders, such as schizophrenia, Alzheimer’s disease, and autism. The list of transcript targets governed by a single miRNA provide a molecular paradigm applicable for therapeutic intervention. Indeed, reports have shown that specific manipulation of a miRNA in cell or animal models can significantly alter phenotypes linked with neurological disease. Here, we review how a diverse range of biological systems, including Drosophila, …

Altered Microrna Expression In Frontotemporal Lobar Degeneration With Tdp-43 Pathology Caused By Progranulin Mutations, Jannet Kocerha, Naomi Kouri, Matt Baker, Nicole Finch, Mariely Dejesus-Hernandez, John Gonzalez, Kumaravel Chidamparam, Keith A. Josephs, Bradley F. Boeve, Neill R. Graff-Radford, Julia Crook, Dennis W. Dickson, Rosa Rademakers

Jannet Kocerha

Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disorder that can be triggered through genetic or sporadic mechanisms. MicroRNAs (miRNAs) have become a major therapeutic focus as their pervasive expression and powerful regulatory roles in disease pathogenesis become increasingly apparent. Here we examine the role of miRNAs in FTLD patients with TAR DNA-binding protein 43 pathology (FTLD-TDP) caused by genetic mutations in the progranulin (PGRN) gene.

Results

Using miRNA array profiling, we identified the 20 miRNAs that showed greatest evidence (unadjusted P < 0.05) of dysregulation in frontal cortex of eight FTLD-TDP patients carrying PGRN mutations when compared to 32 FTLD-TDP patients with no apparent genetic abnormalities. Quantitative real-time PCR (qRT-PCR) analyses provided technical validation of the differential expression for 9 of the 20 miRNAs in frontal cortex. Additional qRT-PCR analyses showed that 5 out of 9 miRNAs (miR-922, miR-516a-3p, miR-571, miR-548b-5p, and miR-548c-5p) were also significantly dysregulated (unadjusted P < 0.05) in cerebellar tissue samples of PGRN mutation carriers, consistent with a systemic reduction in PGRN levels. We developed a list of gene targets for the 5 candidate miRNAs and found 18 genes dysregulated in a reported FTLD mRNA study to exhibit anti-correlated miRNA-mRNA patterns in affected cortex and cerebellar tissue. Among the targets is brain-specific angiogenesis inhibitor 3, which was recently identified as an important player in synapse biology.

Conclusions

Our study suggests that miRNAs may contribute to the pathogenesis of FTLD-TDP caused by PGRN mutations and …

Rnai Screen Indicates Widespread Biological Function For Human Natural Antisense Transcripts, Mohammad A. Faghihi, Jannet Kocerha, F. Modarresi, P. G. Engstrom, A. M. Chalk, S. P. Brothers, E. Koesema, G. St. Laurent, Claes Wahlestedt

Jannet Kocerha

Natural antisense transcripts represent a class of regulatory RNA molecules, which are characterized by their complementary sequence to another RNA transcript. Extensive sequencing efforts suggest that natural antisense transcripts are prevalent throughout the mammalian genome; however, their biological significance has not been well defined. We performed a loss-of-function RNA interference (RNAi) screen, which targeted 797 evolutionary conserved antisense transcripts, and found evidence for a regulatory role for a number of natural antisense transcripts. Specifically, we found that natural antisense transcripts for CCPG1 and RAPGEF3 may functionally disrupt signaling pathways and corresponding biological phenotypes, such as cell viability, either independently or …

Striatal Microrna Controls Cocaine Intake Through Creb Signalling, Jonathan A. Hollander, Heh-In Im, Antonio L. Amelio, Jannet Kocerha, Purva Bali, Qun Lu, David Willoughby, Claes Wahlestedt, Michael D. Conkright, Paul J. Kenny

Jannet Kocerha

Cocaine addiction is characterized by a gradual loss of control over drug use, but the molecular mechanisms regulating vulnerability to this process remain unclear. Here we report that microRNA-212 (miR-212) is upregulated in the dorsal striatum of rats with a history of extended access to cocaine. Striatal miR-212 decreases responsiveness to the motivational properties of cocaine by markedly amplifying the stimulatory effects of the drug on cAMP response element binding protein (CREB) signalling. This action occurs through miR-212-enhanced Raf1 activity, resulting in adenylyl cyclase sensitization and increased expression of the essential CREB co-activator TORC (transducer of regulated CREB; also known …

De Novo Truncating Fus Gene Mutation As A Cause Of Sporadic Amyotrophic Lateral Sclerosis, Mariely Dejesus-Hernandez, Jannet Kocerha, Nicole Finch, Richard Crook, Matt Baker, Pamela Desaro, Amelia Johnston, Nicola Rutherford, Aleksandra Wojtas

Jannet Kocerha

Mutations in the gene encoding fused in sarcoma (FUS) were recently identified as a novel cause of amyotrophic lateral sclerosis (ALS), emphasizing the genetic heterogeneity of ALS. We sequenced the genes encoding superoxide dismutase (SOD1), TAR DNA-binding protein 43 (TARDBP) and FUS in 99 sporadic and 17 familial ALS patients ascertained at Mayo Clinic. We identified two novel mutations in FUS in two out of 99 (2.0%) sporadic ALS patients and established the de novo occurrence of one FUS mutation. In familial patients, we identified three (17.6%) SOD1 mutations, while FUS and TARDBP mutations were excluded. The de novo FUS …