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Do 5-HT7R Antagonists have Anti-Cocaine Effects?

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Substance abuse costs the United States over $740 billion annually in healthcare, law enforcement, rehabilitation, and decreased work productivity costs. While there are certain clinical treatments for nicotine, opioid,

Substance abuse costs the United States over $740 billion annually in healthcare, law enforcement, rehabilitation, and decreased work productivity costs. While there are certain clinical treatments for nicotine, opioid, and alcohol addiction, there is yet an equivalent treatment for psychostimulant addiction. The 5-HT7 receptor (5-HT7R) is one of the more recently discovered members of the serotonin receptor family. The involvement of 5-HT7Rs in thermoregulation, memory, and circadian rhythms, suggests that the receptor also plays a role in mood regulation, making it a potential target in the treatment of psychiatric disorders. Given’ the distribution of the 5-HT7Rs in the brain and its known cellular functions, the receptor has also been implicated in addiction processes. Most studies to date have mainly focused on psychiatric conditions like depression, having yet to explore the role of 5-HT7Rs in psycho-stimulant behaviors. In our study, the effects of SB 269970(SB), a selective antagonist for 5-HT7Rs, were tested on 8-OH-DPAT induced hypothermia, cocaine-induced locomotion, and fos expression in the nucleus accumbens. We found that SB effectively reversed 8-OH-DPAT induced hypothermia, indicating the drug is indeed binding to the 5-HT7R. However, while cocaine did increase locomotor activity and fos expression in the nucleus accumbens in rats, SB had no effect on either measure. These results suggest that 5-HT7Rs may work through pathways other than motor and should be explored through additional behavioral tests. Other brain regions should also be studied for fos expression to see if there is a region-specific effect of 5-HT7Rs and fos expression. The efficacy of SB to 5-HT7Rs and results of past studies on the drug suggests its potential as a pharmacological treatment for psychostimulant disorders.

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  • 2019-05

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Assessing Light Use Efficiencies (LUEs) Of Benthic Reef Communities For Spectral Modeling Applications

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Coral reefs are diverse marine ecosystems, where reef building corals provide both the structure of the habitat as well as the primary production through their symbiotic algae, and alongside algae

Coral reefs are diverse marine ecosystems, where reef building corals provide both the structure of the habitat as well as the primary production through their symbiotic algae, and alongside algae living on the reef itself, are the basis of the food web of the reef. In this way, coral reefs are the ocean's "forests" and are estimated to support 25% of all marine species. However, due to the large size of a coral reef, the relative inaccessibility and the reliance on in situ surveying methods, our current understanding of reefs is spatially limited. Understanding coral reefs from a more spatially complete perspective will offer insight into the ecological factors that contribute to coral reef vitality. This has become a priority in recent years due to the rapid decline of coral reefs caused by mass bleaching. Despite this urgency, being able to assess the entirety of a coral reef is physically difficult and this obstacle has not yet been overcome. However, similar difficulties have been addressed in terrestrial ecosystems by using remote sensing methods, which apply hyperspectral imaging to assess large areas of primary producers at high spatial resolutions. Adapting this method of remote spectral sensing to assess coral reefs has been suggested, but in order to quantify primary production via hyper spectral imaging, light-use efficiencies (LUEs) of coral reef communities need to be known. LUEs are estimations of the rate of carbon fixation compared to incident absorbed light. Here, I experimentally determine LUEs and report on several parameters related to LUE, namely net productivity, respiration, and light absorbance for the main primary producers in coral reefs surrounding Bermuda, which consist of algae and coral communities. The derived LUE values fall within typical ranges for LUEs of terrestrial ecosystems, with LUE values for coral averaging 0.022 ± 0.002 mol O2 mol photons-1 day-1 at a water flow rate of 17.5 ± 2 cm s^(-1) and 0.049 ± 0.011 mol O2 mol photons-1 day-1 at a flow rate of 32 ± 4 cm s^(-1) LUE values for algae averaged 0.0335 ± 0.0048 mol O2 mol photons-1 day-1 at a flow rate of 17.5 ± 2 cm s^(-1). These values allow insight into coral reef productivity and opens the door for future remote sensing applications.

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  • 2019-05

Dynamic Characteristics of Parent-Child Interactions: Mediating Role in Relation Between Parental Catastrophizing and Child Chronic Pain

Description

Child chronic pain is both common and consequential and identification of malleable risk factors is a critical step towards developing effective interventions. Existing evidence points to the possibility that parent

Child chronic pain is both common and consequential and identification of malleable risk factors is a critical step towards developing effective interventions. Existing evidence points to the possibility that parent behavior may play a significant role in the development of children’s chronic pain through modeling of pain-related behaviors. An important parental trait that predicts parent behavior in pain contexts is parental pain catastrophizing, which has been linked to child pain outcomes as well as to increased facial pain behavior in both parents and their children during pain induction. Existing research has examined facial pain behavior in aggregate, summarizing facial expressions over the course of an entire dyadic interaction, which does not allow for evaluation of the dynamic interplay between a parent and child. The current study aimed to test the hypothesis that higher parental catastrophizing would predict decreased flexibility in emotional dynamics between parent and child (reflected in facial affect during a parent-child interaction that occurs within the context of child pain-induction), which would in turn predict fewer child chronic pain symptoms. The approach used dynamic systems analysis of facial behaviors during the parent-child interaction during the child’s performance of a pain inducing cold pressor task to assess dyadic emotional flexibility. Nine-year old children from a larger sample of twins (N = 30) were video recorded during a cold-water pain task while their parents observed them. Videos of the children and their parent from these interactions were analyzed using facial action unit software (AffDex), into positive, neutral, and negative facial emotional expressions. Synchronized parent and child coded facial data were then analyzed for flexibility using GridWare (version 1.1). Parents completed the Pain Catastrophizing Scale (PCS) to assess parental trait pain catastrophizing and the Body Pain Location/Frequency scale to assess child chronic pain symptoms during the prior three months. Contrary to prediction, parental catastrophizing was related to higher levels of flexibility, and flexibility was unrelated to child chronic pain. Exploratory analyses indicated that children with higher levels of effortful control had more emotionally flexible interactions with their parent during the cold pressor, and emotionally flexible interactions predicting lower levels of children’s negative emotional responses to the acute pain task. suggesting some promising avenues for future research.

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  • 2019-05

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The Effects of Sex Chromosome Complement Aware Read Mapping on Variant Calling in Hepatocellular Carcinoma

Description

Hepatocellular carcinoma (HCC) is a type of liver cancer common in Sub-Saharan Africa and South East Asian countries. Each year more than 700,000 new cases and more than 600,000 deaths

Hepatocellular carcinoma (HCC) is a type of liver cancer common in Sub-Saharan Africa and South East Asian countries. Each year more than 700,000 new cases and more than 600,000 deaths are recorded worldwide due to HCC. According to the American Cancer Society HCC is ranked the 5th most common cancer worldwide with a male:female susceptibility ratio ranging between 2:1 and 8:1. HCC risk factors include lifestyle behaviors, such as persistent alcohol abuse and smoking, prolonged exposure to aflatoxins, chronic viral hepatitis infections, inherited metabolic diseases and non-alcoholic fatty liver diseases. To understand the genetic effects underlying sex-bias in HCC, it is necessary to include the sex chromosomes in genomics analyses. X and Y chromosomes are often discluded in genomics studies because of the technical and analytical challenges: sequence homology. The purpose of this thesis is to analyze the effects of sex chromosome complement aware read mapping to germline variant calling. 10 male and 10 female tumor adjacent samples from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA LIHC) cohort were processed using sex-aware and default reference and the concordance of the two approaches was examined. We detected a higher disconcordance of 0.69% on variants called on the X chromosome and a disconcordance of 0.51% on variants called on the Y chromosomes for the reference and alternative alleles respectively compared to autosomes. Variants called on the REF/ALT genotypes had a disconcordances of 1.00%, 1.05%, 1.35% and 12.34% for the autosomes, chromosome 7, the X, and the Y chromosome, respectively. At the end of the project we concluded that the generated datasets showed the effect of sex-aware read mapping on variant calling. Though the data did not show the sites that can be called as variants in one dataset but not in the other, rather the concordance looked at sites that were called as variants in both data sets.

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  • 2019-05

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Production and functional testing of a recombinant fusion protein immunotherapy for glioblastoma

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Fusion protein immunotherapies such as the bispecific T cell engager (BiTE) have displayed promising potential as cancer treatments capable of engaging the immune system against tumor cells. It has been

Fusion protein immunotherapies such as the bispecific T cell engager (BiTE) have displayed promising potential as cancer treatments capable of engaging the immune system against tumor cells. It has been shown that chlorotoxin, a 36-amino peptide found in the venom of the deathstalker scorpion (Leiurus quinquestriatus), binds specifically to glioblastoma (GBM) cells without binding healthy tissue, making it an ideal GBM cell binding moiety for a BiTE-like molecule. However, chlorotoxin’s four disulfide bonds pose a folding challenge outside of its natural context and impede production of the recombinant protein in various expression systems, including those relying on bacteria and plants. To overcome this difficulty, we have engineered a truncated chlorotoxin variant (Cltx∆15) that contains just two of the original eight cystine residues, thereby capable of forming only a single disulfide bond while maintaining its ability to bind GBM cells. We further created a BiTE (ACDClx∆15) which tethers Cltx∆15 to a single chain ⍺-CD3 antibody in order to bring T cells into contact with GBM cells. The gene for ACDClx∆15 was cloned into a pET-11a vector for expression in Escherichia coli and isolated from inclusion bodies before purification via affinity chromatography. Immunoblot analyses confirmed that ACDClx∆15 can be expressed in E. coli and purified with high yield and purity; moreover, flow cytometry indicated that ACDClx∆15 is capable of binding GBM cells. These data warrant further investigation into the ability of ACDClx∆15 to activate T cells against GBM cells.

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  • 2019-05

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Protecting amphibians from a deadly Chytrid Fungus using a novel technology

Description

Infectious disease in wild animals has historically been a challenge that is difficult to overcome, primarily because isolating a disease outbreak to prevent further transmission in these types of populations

Infectious disease in wild animals has historically been a challenge that is difficult to overcome, primarily because isolating a disease outbreak to prevent further transmission in these types of populations is nearly impossible. Wild animals are free to roam, and humans often have limited means of tracking infection in populations. Vaccines and treatments can be formulated but are often somewhat impractical for wild populations because it is not feasible to vaccinate or treat every member in a susceptible community. One such pathogen, Batrochochytrium dendrobatidis (Bd) is infecting amphibian populations around the world to the point where many species are already extinct. Even though finding an effective preventative for the fungal pathogen may not mean that I am able to reach every member in a population, it may mean the difference between extinction and eventual release back into the wild for threatened populations.
In this study I hoped to create an attenuated version of Batrochochytrium dendrobatidis, by using a novel laser technology: SEPHODIS. This laser technology disrupts hydrogen bonds between proteins in the lumen of the cell while simultaneously preserving the membrane and associated proteins on the outside of the cell. This process ultimately affects the pathogenicity of the target but leaves identity markers intact so that the host immune system may recognize the pathogen and create antibodies against it. The laser was ultimately effective at killing Bd fungal cells, and I did observe a significant change in the appearance of the cells. However, samples obtained after exposure to the laser were contaminated and more research is needed to determine if SEPHODIS could be a feasible method for vaccine production.

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  • 2019-05

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Codon Optimization of Human TRAIL Gene for Maximal Expression in a Self-Destructing Salmonella Strain for Efficient Colorectal Cancer Treatment

Description

Colorectal cancer is the third most common type of cancer that affects both men and women and the second leading cause of death in cancer related deaths[1, 2]. The most

Colorectal cancer is the third most common type of cancer that affects both men and women and the second leading cause of death in cancer related deaths[1, 2]. The most common form of treatment is chemotherapy followed by radiation, which is insufficient to cure stage four cancers[3]. Salmonella enteric has long been shown to have inherent tumor targeting properties and have been able to penetrate and exist in all aspects of the tumor environment, something that chemotherapy is unable to achieve. This lab has developed a genetically modified Salmonella typhimurium (GMS) which is able to deliver DNA vaccines or synthesized proteins directly to tumor sites. These GMS strains have been used to deliver human TNF-related apoptosis inducing ligand (TRAIL) protein directly to tumor sites, but expression level was limited. It is the hope of the experiment that codon optimization of TRAIL to S. typhimurium preferred codons will lead to increased TRAIL expression in the GMS. For preliminary studies, BALB/c mice were subcutaneously challenged with CT-26 murine colorectal cancer cells and treated with an intra-tumor injection with either PBS, strain GMS + PCMV FasL (P2), or strain GMS + Pmus FasL). APC/CDX2 mutant mice were also induced to develop human colon polyps and treated with either PBS, strain GMS + vector (P1), P2, or P3. The BALB/c mouse showed statistically significant levels of decreased tumor size in groups treated with P2 or P3. The APC/CDX2 mouse study showed statistically significant levels of decreased colon polyp numbers in groups treated with P3, as expected, but was not significantly significant for groups treated with P1 and P2. In addition, TRAIL was codon optimized for robust synthesis in Salmonella. The construct will be characterized and evaluated in vitro and in vivo. Hopefully, the therapeutic effect of codon optimized TRAIL will be maximal while almost completely minimizing any unintended side effects.

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  • 2019-05

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Development of fungicide resistance in the amphibian chytrid fungus Batrachochytrium dendrobatidis

Description

Amphibians around the world are suffering the effects of the chytrid fungus, Batrachochytrium dendrobatidis (Bd). Whenever amphibians are housed in captivity, they must go through a decontamination protocol to ensure

Amphibians around the world are suffering the effects of the chytrid fungus, Batrachochytrium dendrobatidis (Bd). Whenever amphibians are housed in captivity, they must go through a decontamination protocol to ensure they are not infected with diseases such as Bd. Itraconazole is the most commonly used fungicide used in these protocols. This study set out to determine if Bd could develop resistance or tolerance to itraconazole. Two 24 well plates were prepared with different concentrations of itraconazole with Bd zoospores added. Plate 1 had concentrations similar to what animals are currently being treated with in decontamination protocols. Plate 2 had concentrations at and below the published minimum inhibitory concentration values (MIC). Plate 1 displayed the ability of itraconazole to kill Bd sporangia with higher concentrations and Plate 2 showed that even under published MIC values, Bd still struggled to complete its reproductive cycle. I find the evolution of a resistant/tolerant strain of Bd unlikely given the efficacy of this drug, the sensitivity of Bd to itraconazole, and the lack of evidence of the completion of Bd’s reproductive cycle under the conditions used in this study.

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  • 2019-05

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Cancer Type Specific FrAmeShifT (FAST) Vaccine

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In this study, we demonstrate the effectiveness of a cancer type specific FrAmeShifT (FAST) vaccine. A murine breast cancer (mBC) FAST vaccine and a murine pancreatic cancer (mPC) FAST vaccine

In this study, we demonstrate the effectiveness of a cancer type specific FrAmeShifT (FAST) vaccine. A murine breast cancer (mBC) FAST vaccine and a murine pancreatic cancer (mPC) FAST vaccine were tested in the 4T1 breast cancer syngeneic mouse model. The mBC FAST vaccine, both with and without check point inhibitors (CPI), significantly slowed tumor growth, reduced pulmonary metastasis and increased the cell-mediated immune response. In terms of tumor volumes, the mPC FAST vaccine was comparable to the untreated controls. However, a significant difference in tumor volume did emerge when the mPC vaccine was used with CPI. The collective data indicated that the immune checkpoint blockade therapy was only beneficial with suboptimal neoantigens. More importantly, the FAST vaccine, though requiring notably less resources, performed similarly to the personalized version of the frameshift breast cancer vaccine in the same mouse model. Furthermore, because the frameshift peptide (FSP) array provided a strong rationale for a focused vaccine, the FAST vaccine can theoretically be expanded and translated to any human cancer type. Overall, the FAST vaccine is a promising treatment that would provide the most benefit to patients while eliminating most of the challenges associated with current personal cancer vaccines.

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  • 2019-05

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The Contribution of Lithuanian Deportees’ Memoirs to Lithuanian National Identity

Description

Between 1941 and 1953, thousands of Lithuanians were deported by the Soviet Union as far from their homeland as the northern reaches of Siberia. While many perished as they contended

Between 1941 and 1953, thousands of Lithuanians were deported by the Soviet Union as far from their homeland as the northern reaches of Siberia. While many perished as they contended with hunger, thirst, illness, harsh weather, ill-suited clothing, and poor housing, several survived, returned, and recounted their experiences. Returned adult deportees often recall solidarity among Lithuanians, interactions with locals and authorities, and efforts to maintain agency and continue cultural traditions. Children remember going to school, relying on their parents, and returning to Lithuania. Deportees and others involved in recording their memoirs wrote them in Lithuanian or translated them into English for different purposes and with different intended audiences. The ways in which deportees describe their experiences and what they omit from their stories have shaped Lithuania’s national identity when it reemerged as the Soviet Union fell following Stalin’s death in 1953 and Lithuania redeclared its independence in 1990. The years in which memoirs were published also likely influence their contents. Despite the horrors of deportation, returnees describe positive aspects of the experience. Many deportees portray themselves as struggling for survival, but not as helpless victims. Relatively rare mention of conflict among Lithuanian deportees and identification of non-Lithuanian deportees’ ethnicities suggest the importance of Lithuanians striving together for a common goal: survival and return to Lithuania. The creation of museums focused on deportation, incorporation of memoirs in school curricula, observation of a Day of Mourning and Hope, and portrayal of deportations in works of literature and film demonstrate their lasting impact and significance.

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  • 2019-05