SYNTHESIS OF NOVEL SELECTIVE-SEROTONIN
As the number of people who have fallen victim to depression increases annually, the search for a drug that exhibits both complete efficacy and minimal side effects is of utmost importance. Since the late 1980s, selective-serotonin reuptake inhibitors (SSRIs) have dominated treatment of depression, increasing the concentration of serotonin within serotonergic synapses by inhibiting its reuptake by the serotonin transporter (SERT). However, despite their undeniable effectiveness, SSRIs are accompanied by a myriad of side effects, the most distressing being sexual dysfunction. Thus, the object of this study is to synthesize a bi-functional SSRI that can perform two functions: inhibit SERT while preventing sexual dysfunction. It was previously decided that fluoxetine (ProzacŇ), a popular SSRI, and cyproheptadine (Periactinâ), used to treat SSRI-induced sexual dysfunction, could be coupled because of their remarkable efficacy in their respective functions. Cyproheptadine hydrochloride sesquihydrate 1 was treated with sodium methoxide and ethyl chloroformate to form compound 2. Potassium hydroxide was added to 2 to form demethyl cyproheptadine 3, with 97% yield. Key intermediates 7 (94% yield) and 8 (93% yield) have been successfully produced for the eventual synthesis of target molecules 9 and 10. Future in vitro and in vivo biological evaluation of target molecules 5, 6, 9, and 10 is needed before conclusions can be made about the efficacy of the bi-functional SSRIs. Nonetheless, the successful synthesis of these novel SSRIs retains full potential to revolutionize the impending treatment of depression.
BIOMECHANICAL ANALYSIS OF MANUAL
Biomechanical engineers strive to accurately model the human body in order to analyze the effects of certain activities on the musculoskeletal system. Visualizing the human body with a computer model, biomechanicians are trying to determine the precise causes of low back pain (LBP) derived from manual material handling. Three dimensional motion capture systems attempt to accurately translate human motion into a computer model using precise cinematography. By determining practical locations for multiple cameras, we were able to establish a testing environment in which the test subjects' movements could be easily detected. Camera positioning was crucial for recording human motion because accurate results require that each point on the body be monitored by at least two cameras. We also attempted to produce effective markers which could be recognized by the video software. To minimize the ratio of size to brightness, we designed light emitting diode (LED) circuits which could pinpoint the joints of interest on the human body. While the test subjects performed various lifting tasks, the three dimensional tracking system allowed the computer software to generate accurate models. Observing trends in lifting kinematics helps in understanding the mechanics of the human body by demonstrating how forces affect skeletal dynamics. From such data, engineers can develop more ergonomic and safer lifting methods. Ultimately, this research will minimize spending on occupational injury compensation by contributing to industrial guidelines regarding manual material handling.
TISSUE MODIFICATION USING PHOTOACTIVATABLE
4-Alkylamino 1,8 naphthalimide derivatives have been previously shown to photochemically oxidize amino acid residues on tissue surfaces. The photo-oxidized surface contains reactive functional groups which can provide adhesion to tissue tears by catalyzing a physical bond formation via protein crosslinking. Such adhesion can be used to expedite healing of meniscal tears due to the avascular nature and slow healing process of human menisci. This experiment sought to synthesize five naphthalimide compounds with different C4 substituents to photo-oxidize a bovine pericardial tissue surface as a model for human menisci and use a chemiluminescent assay to determine the optimum conditions for tissue modification. The assay was formed by biotinylating the oxidized tissue surface with Biotin Hydrazide and utilizing the affinity of the protein Avidin for biotin to attach Avidin Horseradish Peroxidase, which oxidizes and excites the chemiluminescent molecule luminol. The intensity of the luminescent signal of the decaying bonded luminol demonstrated the level of successful tissue modification and thus the potential strength of a protein crosslinking bond. However, the 5% concentration of Trifluoroacetic acid necessary to dissolve the naphthalimide in solution was too potent to be realistically biocompatible with the bovine pericardium. This same type of tissue oxidation has potential in other aspects of surface modification, including encapsulation of pancreatic Islets of Langerhans for transplantation or creation of biocompatible naphthalimide-ended dendrimers, with a variety of useful transportation and bonding applications.
ACUTE AND CHRONIC EFFECTS OF AN EMERGING CONTAMINANT TO DAPHNIA MAGNA: A CASE STUDY WITH VENLAFAXINE
Over the next several decades, the burgeoning human population of Texas will be increasingly confronted with pressure for increased water resources. Although an increasing number of ambient water quality criteria have been developed for many priority pollutants such as agrochemicals and heavy metals, none have been outlined for emerging contaminants such as pharmaceuticals and personal care products (PPCPs), which are released from wastewater treatment plant effluents. Releasing wastewater effluents to rapidly urbanizing semi-arid and arid watersheds can result in effluent-dominated bodies of water, representing worst-case scenarios for analyzing aquatic response to emerging contaminants. Unlike many conventional pollutants, these therapeutic compounds are intrinsically designed to elicit biological responses. Venlafaxine, a widely distributed serotonin-norephephrine reuptake inhibitor, has been detected in effluent and surface water, but the effects on aquatic organisms are poorly understood. My objective was to assess venlafaxine toxicity to the model aquatic invertebrate Daphnia magna. Acute and chronic toxicity tests were performed according to standard US Environmental Protection Agency protocols to evaluate aquatic hazard. Dose-dependent acute and chronic responses in D. magna were observed with increasing concentrations of venlafaxine. An acute LC50 value was calculated at 9.783 mg/L. A no observable adverse effect level and a lowest observable adverse effect level for D. magna were calculated at 30 μg/L and 100 μg/L, respectively, in the chronic experiment. Although acute and chronic selective adverse effects were observed at levels above actual environmental concentrations (250 ng/L), sublethal effects such as behavior in other organisms (e.g., fish) should be explored in future studies.
FUNCTION OF SPASTIN IN DROSOPHILA PHOTORECEPTOR MORPHOGENESIS
The fruit fly, Drosophila melanogaster, is an extremely useful tool for scientists today because of its genetic similarity to humans. Although it is much less biologically complex than us, we share many of the same genes and proteins, allowing us to use Drosophila as a model to understand the genetic basis for human conditions and diseases. One of the shared genes, spastin, is present in photoreceptor cells in Drosophila eyes and is believed to regulate the formation of tubulin-based structures. Our purpose in this project was to better understand spastin's precise role in the development of the photoreceptors. To do this we compared the eyes of a wild-type Drosophila to those of one whose spastin gene had been completely deleted (a 100% mutation). This process involved dissection and isolation of the eyes of wild-type Drosophila larvae and pupae and mutant pupae, immunofluorescent staining of the eyes, and image analysis using fluorescent and confocal microscopy. In the images from the confocal microscope, we saw some clear differences between the wild-type and mutant eyes. The eyes lacking spastin showed a breakdown in the regular hexagonal pattern present in wild-type eyes and an increase in stabilized acetubulin in the mutant regions. These findings imply that spastin is a gene that regulates photoreceptor cell structure and the presence of a network of stabilized microtubules. Scientists can use this information to predict possible genetic causes for disorders in human eyes and hopefully even develop cures.
THE EFFECT OF DUAL-SIZED DUST PARTICLES ON COULOMB CRYSTAL FORMATION IN COMPLEX PLASMAS: A SECOND ORDER ANALYSIS
While complex (dusty) plasma physics experimentation has been used in the past to better understand the literal behavior of dust in plasma systems, like those used silicon wafer etching; dusty plasma research has developed a relatively new facet: solid-state physics exploration. Such research is possible due to the self-aligning qualities of the dust particles into a Coulomb crystal lattice, thus behaving like a macroscopic model of the microscopic lattice structures in solids. However, such research had only been conducted using either one or a random distribution of particle sizes; both of which are not truly representative of real crystal structures. These studies examine the effect of changes in the electrical power, pressure, and dc bias on the plasma, while second order analysis factors in particle size as a new variable. Thus, experimentation was performed using two sizes of melamine formaldehyde dust: 6.48 and 8.86 microns in diameter, in varying ratios. The different particle sizes interfered significantly with crystal formation, and tended to cause deviation from theoretical projections of dust behavior. However, we encountered problems with controlling the ratios of the different sized particles, and possible design ideas for new methods of dust dispersal into the reference cell are being considered. As such, the data and observations collected point to the need for more dual-sized particle experimentation, in order to better understand the dusty plasma representation of solid-state physics.
BINDING PROPERTIES OF SOME NOVEL TUBULIN POLYMERIZATION INHIBITORS
A tumor's reliance on a constant blood supply for nutrients and oxygen makes its vasculature an effective target for anti-tumor drugs. The treatments operating on this principle are vascular disrupting agents (VDAs). Some VDAs bind to tubulin, inhibiting blood flow in tumor vasculature by disrupting the dynamic instability of microtubules, an essential component of eukaryotic cell cytoskeletons. Tubulin inhibition has been widely researched for potential anti-cancer capabilities, leading to the synthesis of novel low-molecular-weight VDAs. In this study, compounds were tested for anti-tumor potential through analysis of their binding with tubulin. The thermodynamics of binding of the inhibitor (3,4-Dihydroxy-5-methoxy-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone (1) were found through isothermal titration calorimetry (ITC). We determined that the ITC for this compound could not be accomplished in the presence of dimethyl sulfoxide (DMSO) or without the dialyzation and removal of tubulin oligomers. The results exhibit an exothermic binding reaction with a ∆H° value of -73.35 ± 11.1 kJ/mol, binding to 0.47 ± 0.042 sites with a binding constant of 5.3E105 ± 3.5 E105, still to be confirmed through triplicate ITC results. The compounds 3-Methoxy-6-(1,2,3-trimethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylmethyl)-benzene-1,2-diol (2) and 9-Hydroxy-2,3,4,8-tetramethoxy-5,6-dihydro-benzo(a)fluoren-11-one (3) were tested for tubulin inhibiting properties by calculation of IC50 values based on a series of absorbance assays. The IC50 values obtained for (2), 6.8 μM and 8.125 μM, show that it has fairly potent anti-tubulin capabilities, while (3) was shown to not inhibit tubulin polymerization. Further research and in vivo testing could yield effective and rapidly acting anti-tumor agents.