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The mechanisms responsible for increased thrombosis in T2DM and MS are not well understood. Thrombosis requires the involvement of platelets, small anuclear cells in circulation that, when activated, can form blood clots.
Additionally, patients with T2DM and MS have an altered metabolic milieu, which can result in altered cell metabolism.
Therefore, we hypothesize that increased metabolic flux in platelets will lead to increased platelet activation induced by agonists. In order to better understand the contribution of platelet dysfunction to increased thrombosis in T2DM and MS, we used a murine model of diet-induced obesity (DIO). We fed mice a high fat diet of 45% fat (HFD) and a control normal fat diet of 10% fat (NFD) for 12 weeks. We monitored weight and performed glucose tolerance and insulin tolerance tests to verify the obese model. Platelets from these mice displayed similar counts, circulating half life, and mean platelet volume. However, HFD mice displayed increased sensitivity towards convulxin, a GPVI receptor agonist, when monitored by flow cytometry. Four out of 10 HFD mice displayed no tail rebleeding following tail lesion, whereas all NFD fed mice rebleed. Together these data indicate that in the murine model of DIO, platelet activation is increased. These studies could lead to therapies that could prevent thrombosis complications in T2DM and MS patients.
ENHANCING THE CHEMOSENSITIVITY OF ENDOMETRIAL AND OVARIAN CANCER CELL LINES TO
PACLITAXEL USING AN ADENOSINE A1 RECEPTOR AGONISTCarolina Garcia1, Russell Broaddus2, Su-Su Xie2, Jessica Bowser2.
University of Puerto Rico at Mayagüez, Mayagüez, PR, 2The University of Texas, MD Anderson Cancer Center, 1 Houston, TX.
Endometrial cancer and ovarian cancer are the most common and most deadly gynecological malignancies in the United States, respectively. Despite the advancement of single-agent and combined-agent chemotherapy regimens for these cancers, most tumors eventually develop resistance toward these agents. Therefore, strategies to enhance the sensitivity of tumor cells to common chemotherapies are needed. Adenosine is a small molecule known for its tissue-protective role in numerous tissues and organ systems. Recently, our lab has shown that adenosine’s activation of the adenosine A1 receptor (ADORA1) is protective of the integrity of epithelial cells in the endometrium. Studies in breast and colon cancer have shown that cancer cells are more sensitive to chemotherapy agents when they exhibit more epithelial-like features. Thus, we hypothesized that the treatment of cancer cells in combination with
AFTER A COMPLETE SPINAL CORD TRANSECTION TRANSPLANTED OLFACTORY ENSHEATING CELLS
(OECS) SURVIVE AND INTEGRATE INTO THE INJURY SITEDanielle Perez, Rana Khankan, Patricia Phelps.
University of California, Los Angeles, Los Angeles, CA.
Spinal cord injuries cause a loss of axonal connections across the injury site, which result in the loss of sensory and motor functions. Transplantation of OECs facilitates axon regeneration, neuronal preservation, and functional recovery in rats 8 months after a complete spinal cord transection (spinal rat), yet the interaction of OECs within the injury site is unknown. Following enhanced green fluorescent protein (eGFP)-labeled OEC or control eGFP-fibroblast (FB) transplants in spinal rats, we evaluate the cell survival and migration within the host injury site 1 to 4 weeks postinjury. We hypothesize that OECs will migrate into and integrate within the injury site, preserve neurons, and decrease the size of the lesion. Preliminary data shows no difference in lesion size between spinal rats transplanted with OECs versus FBs. One week post-transplantation both OECs and FBs survived and migrated into the lesion core in all spinal rats. Two weeks post-transection, 67% of OEC-transplanted and 33% of FB-transplanted spinal rats had visible cells, but no cells were found in the lesion core. After 4 weeks, 67% of the OEC-transplanted spinal rats had surviving cells and 33% of them had OEC migration into the lesion core. No FB-transplanted rats contained any transplanted cells at 4 weeks. There were no significant differences in neuronal preservation between rats transplanted with OECs or FBs, but in OEC-treated rats, neurons were found in the lesion core. To date, our findings suggest that OECs survive longer and migrate better than FBs within an injury site following a complete spinal cord transection.
EFFECTS OF HYPOCRETIN ANTAGONIST INTERACTION WITH ISOFLURANE ANESTHESIA ON LOCOMOTOR
BEHAVIOR IN MICEArthur Castaneda, Kayla Bower, Rebeccah Ryden, Kimberly D’Anna-Hernandez.
California State University San Marcos, San Marcos, CA.
Hypocretin (HCRT), a hypothalamic neuropeptide, is involved in arousal and wakefulness. HCRT acts in the lateral preoptic area of the hypothalamus, an area that opposes wakefulness by regulating sleep-promoting behavior via inhibitory GABAergic connections. Isoflurane anesthesia has been shown to enhance the effects of sleeppromoting systems through GABAergic pathways. Though much research has been done on the effects of HCRT on wakefulness, the interaction effects of HCRT and anesthesia are relatively underrepresented. Early work suggests that an HCRT/anesthesia interaction with mice will alter the ability to regain posture on foot-paws. In this study we examine recovery from an HCRT-receptor 1 antagonist and the interaction effects with isoflurane anesthesia by measuring gross locomotor movement over a 20 minute time period in an open-field apparatus. The HCRT antagonist will prevent the action of HCRT at the receptor, likely inhibiting typical levels of arousal and wakefulness.
We hypothesize that mice given an HCRT antagonist while under isoflurane anesthesia will exhibit significantly less locomotor movement on an open-field test than saline injected mice while under anesthesia. The results of this study may expose a confounding variable of drug interaction that has been overlooked in earlier HCRT research.
INTERLEUKIN-10 ADMINISTRATION TO DYSTROPHIC MICE MODULATES MUSCLE INFLAMMATION AND
INCREASES MUSCLE DIFFERENTIATIONIvan Flores, Chiara Rinaldi, James Tidball.
University of California, Los Angeles, Los Angeles, CA.
Duchenne muscular dystrophy (DMD) is a fatal disease characterized by muscle necrosis, inflammation, and variability in muscle fiber size. Pro-inflammatory M1 macrophages increase muscle damage by releasing cytolytic free radicals. Subsequently, anti-inflammatory M2 macrophages promote muscle regeneration. Recent findings show
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that interleukin-10 (IL-10) can shift muscle macrophages to an M2 phenotype, a change that coincides with muscle differentiation. Ablation of IL-10 from mdx mice increased muscle damage and weakness suggesting that increased delivery of IL-10 to dystrophic muscle will decrease pathology. We tested that possibility by injecting mdx mice with IL-10 and then assaying pathology. Our findings show M1 macrophages decrease, reflected by reduction in inducible nitric oxide synthase, while M2 macrophages increase, indicated by elevated arginase expression. Additionally, elevated levels of muscle regulatory factor-4 (MRF4) in treated muscles indicate an increase in muscle differentiation.
Muscle cell expression of MRF4 is elevated when they are co-cultured with IL-10 stimulated macrophages.
Collectively, these findings indicate that IL-10 can promote muscle differentiation through a macrophage mediated process. Further investigation will test whether IL-10 also has a direct effect on muscles. Establishing a relationship between muscle differentiation and IL-10 levels may lead to the development of therapeutic strategies for attenuating the pathology of DMD in human patients.
BPA SLOWS DOWN MEDIAL AND LATERAL GIANT FIBER CONDUCTION VELOCITY AND DISRUPTS
REGENERATION IN LUMBRICULUS VARIEGATUSAraik Sinanyan, Bruce A. O’Gara.
Humboldt State University, Arcata, CA.
Bisphenol A (BPA) is a carbon-based synthetic compound used to make certain plastics that are common in consumer goods. Recent studies have shown BPA exhibits hormone-like properties, which has raised concern for its possible hazards. The ability of Bisphenol A to disrupt both neurological function and regeneration were examined in the freshwater oligochaete worm, Lumbriculus variegatus. Worms can avoid predator attacks via a rapid shortening response mediated by the medial and lateral giant nerve fibers. Lumbriculus also possesses an extraordinary ability to regenerate lost body parts such as might occur after a partially successful predator attack. Noninvasive electrophysiological testing showed that immersion in water containing 10 μM BPA led to time- and concentrationdependent reductions in the conduction velocities of the medial and lateral giant nerve fibers. Exposure to 10 μM BPA, measured in 24 hour increments, produced significant reductions in giant fiber conduction velocities (n = 8).
To monitor regeneration, worms were cut into 3 equal parts and then exposed to BPA concentrations of 10 μM, 25 μM, and 50 μM (n = 8 worms per concentration). The regenerating ends were photographed and measured for growth using ImageJ. BPA exposure is expected to produce concentration-dependent reductions in the amount of regeneration present from cut surfaces. BPA induces conduction velocity reduction that could reduce the ability of the worm to escape predators, while its effects on regeneration would disrupt the ability of the animal to repair predatorinduced damage.
UPPER THERMAL LIMITS OF INSECTS ARE NOT THE RESULT OF INSUFFICIENT OXYGEN DELIVERYRoberto De Los Santos III, Marshall McCue.
St. Mary’s University, San Antonio, TX.
Most natural environments experience fluctuating temperatures that acutely affect an organism’s physiology and ultimately a species’ biogeographic distribution. Here we examine whether oxygen delivery to tissues becomes limiting as body temperature increases and eventually causes death at upper lethal temperatures. Because of the limited direct experimental evidence supporting this possibility in terrestrial arthropods, we explored the effect of ambient oxygen availability on the thermotolerance of insects representing six species: Acheta domesticus, Hippodamia convergens, Gromphadorhina portentosa, Pogonomyrmex occidentalis, Tenebrio molitor, and Zophobus morio; four taxonomic orders: Blattodea, Coleoptera, Hymenoptera, and Orthoptera; and multiple life stages: adults vs. larvae or nymphs. The survival curves of insects exposed to 45 °C or 50 °C under normoxic conditions (21% O2) were compared with those measured under altered oxygen levels 0%, 10%, 35%, and 95% O2. Kaplan-Meier log-rank analyses followed by Holm-Sidak pairwise comparisons revealed that anoxia sharply diminished survival times in all groups studied. Thermotolerance under moderate hyperoxia (35% O2) or moderate hypoxia (10% O2) was the same as or lower than that under normoxia. Half of the experimental treatments involving extreme hyperoxia (95% O2) caused reduced thermotolerance, and thermotolerance differed with developmental stage. Adult G. portentosa exhibited much higher thermotolerance than their first-instar nymphs, but responses from larval and adult Z. morio were equivocal. We conclude that some factors separate from oxygen delivery are responsible for the death of insects at upper lethal temperatures.
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Biological Sciences FRI-611
IMPACT OF ENDOCRINE-DISRUPTING COMPOUNDS ON SEX DIFFERENTIATION IN A TELEOST FISHEric Kessler, Kristy Forsgren.
California State University, Fullerton, Fullerton, CA.
Chemical contaminants enter the coastal marine ecosystem through a variety of sources including wastewater effluent, agricultural runoff, and urban runoff. Endocrine disrupting compounds (EDCs) interfere with the natural hormones of the endocrine system of organisms by altering their synthesis, secretion, transport, binding action, or a combination of these effects. While the potential for aquatic contamination is evident, an unanswered question is what effects EDC exposure has on embryonic development during sexual differentiation in marine organisms. Given the importance of endogenous sex hormones during reproductive development, our overall goal is to determine if two common contaminants found in the marine ecosystem have the potential to impact sex differentiation during embryonic development in teleost fishes. We hypothesize that zebrafish (Danio rerio) embryos exposed to environmentally relevant concentrations of an estrogenic insecticide, carbaryl, and an androgenic herbicide, diuron, will alter the phenotypic sex of fish. Zebrafish embryos will be exposed to carbaryl or diuron and will be compared to a positive control of estradiol or testosterone, respectively, and a negative control (no EDC exposure). Genotypic sex will be determined by measuring gene expression of doublesex/mab-3 related transcription factor 1 in males and forkhead transcription factor L2 in females. Observable phenotypic sex will be compared to genotypic sex to determine if EDCs altered gonadal tissue. Given the increased use of anthropogenic products that may contain EDCs such as insecticides, herbicides, pharmaceuticals, personal care products, and manufactured goods, a more comprehensive understanding of their impact on wildlife is imperative for improving risk assessment in coming years.
SEX CHROMOSOME EFFECTS ON OBESITY AND FEEDING RHYTHMSJessy Martinez, Xuqi Chen, Maureen Ruiz-Sundstrom, Arthur Arnold.
University of California, Los Angeles, Los Angeles, CA.