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2014-2015

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  • Thumbnail for Bacterial Quorum Sensing and its Responses to Increasing Signal Movement and Turnover by Stochastic Modeling
    Bacterial Quorum Sensing and its Responses to Increasing Signal Movement and Turnover by Stochastic Modeling by Nicholl, Leigh

    Quorum sensing is how bacteria communicate in response to cell density through the uptake and release of small signaling molecules called autoinducers. Through this form of signaling, bacteria dictate biofilm formation, motility, and pathogenesis, among many other cellular responses. Gram-negative bacteria employ N-acyl homoserine lactone molecules as their signaling molecule of choice, which then initiate a signaling cascade to turn on specific promoters. Previous research looking at bacterial behavior in the bistable regime has been largely from a deterministic point of view. Our two-cell model instead takes a stochastic approach, incorporating random noise into the system. Three models were observed: one with only one positive feedback loop, one with two feedback loops and no dimerization of the transcription factor, and one all-encompassing model with both feedback loops and dimerization. Two parameter values were varied in computer-run time trials: signal movement between the two cells and autoinducer turnover, or how quickly molecules were being replaced in the extracellular environment. As signal movement increased, the cells were more likely to enter the on state, and to enter it together. As autoinducer turnover increased, the cells were less likely to enter the on state and also less likely to turn on together. These results point to the potential to suppress QS by decreasing signal movement and increasing the affinity of the autoinducer to return to its parent cell, which could hold importance for research in the field of pathogenesis and microbial food spoilage. Future research will focus on acquiring accurate parameter rates, examining the role of negative feedback loops, and suppressing QS through inhibition of dimerization and blocking the second amplifying feedback loop from being initiated.

  • Thumbnail for Obstructive Sleep Apnea Augments Idiopathic Pulmonary Fibrosis via Chronic Intermittent Hypoxia
    Obstructive Sleep Apnea Augments Idiopathic Pulmonary Fibrosis via Chronic Intermittent Hypoxia by Braun, Felix Michael

    Obstructive sleep apnea (OSA) and idiopathic pulmonary fibrosis (IPF) are serious diseases with growing relevance in modern medicine. OSA affects around 300 individuals per 100,000 in the U.S. and IPF affects between 43-63 individuals per 100,000. Recent evidence has shown a strong and thus far unexplored correlation between IPF and OSA. Of patients diagnosed with IPF, 77-88% had OSA, and treatment of OSA in individuals suffering from both IPF and OSA decreases mortality rates. We hypothesized that increased oxidative stress from chronic intermittent hypoxia (CIH), a common complication of OSA, underlies this correlation and amplifies IPF. To test this, we chemically induced IPF in rats by instilling their lungs with bleomycin and subjected them to a regimen of repeating episodes of hypoxia to mimic CIH. After termination, we measured lipid peroxidation of lung tissue to determine levels of oxidative stress. Our results were inconclusive in determining whether oxidative stress from CIH was directly responsible for exacerbation of IPF. However, trends in our data indicated that lipid peroxidation may increase with CIH treatment, as lipid peroxidation was elevated in rats with both chemically-induced IPF and CIH. Furthermore, qualitative and quantitative data showed a possible anatomical shift of fibrosis within the lung itself as a result of CIH treatment. Performing the experiment with a longer period of CIH is recommended as this would better imitate the condition experienced by patients and would likely result in significant differences of lipid peroxidation between treatment groups.

  • Thumbnail for RNA-Binding Protein CPB-3 Required for Dendrite Morphogenesis in  Caenorhabditis elegans Sensory Neurons
    RNA-Binding Protein CPB-3 Required for Dendrite Morphogenesis in Caenorhabditis elegans Sensory Neurons by Wolf, Margaret Alice Hilbert

    Dendrites establish proper neural networks, allowing normal brain functions such as social networking, learning, and memory. Thus, it is no surprise that dendritic defects are associated with many neurological disorders. Accordingly, understanding the molecular mechanisms behind dendrite formation and maintenance is an important research goal. Recent investigations of dendrite morphogenesis have highlighted the importance of gene regulation at the post-transcriptional level. The CPEB class of RNA-binding proteins mediates many post-transcriptional mechanisms, and homologs of this protein have previously been identified as important in synaptic plasticity and dendrite morphogenesis. Here, we identify the Caenorhabditis elegans CPEB homolog CPB-3 as necessary for typical dendritic branching in the PVD multidendritic sensory neuron. This study also points to a previously undescribed function of a CPEB; loss of CPB-3 causes gene expression profile changes in touch neurons. Thus, we believe that CPB-3 is a very strong candidate for regulating the transport and translation of target mRNAs within dendrites. Furthermore, the CPB-3 homolog CPEB1 is expressed in the human brain suggesting that this RNA-binding protein is a candidate regulator of dendrite development in humans.

  • Thumbnail for Stochastic Modeling of the Quorum Sensing Network in Agrobacterium tumefaciens
    Stochastic Modeling of the Quorum Sensing Network in Agrobacterium tumefaciens by Davis, Brendan

    Stochastic Modeling of the Quorum Sensing Network in Agrobacterium tumefaciens Brendan Davis*, Leigh Nicholl, David Brown, and Phoebe Lostroh, Departments of Mathematics and Biology For years, prokaryotes were thought to be simple, single cell organisms without communicate or interact. We now know bacteria, such as Agrobacterium tumefaciens, use small, autoinducing molecules to sense population densities. This “quorum sensing” (QS) model works on a positive feedback loop and signals the bacteria to insert a tumor inducing (Ti) plasmid into the nucleus of a plant cell by horizontal gene transfer. Here, we used a stochastic model to mathematically evaluate the quorum sensing system. We found under certain conditions the model acted as a “bistable switch”, turning the system “on” and “off” at random. When a second cell was introduced to the model it increased the probability of the system turning “on”. We also found that by manipulating various variables we could alter the frequency of the QS network turning “on”. With this research, we are able to better understand the coordination involved in the infection of host plants by Agrobacterium tumefaciens. Thus, we can predict possible treatments for the progression of tumors in plants that are infected by crown gall disease. This type of model has implications to many other mathematical models in which this “bistable” phenomenon may be observed, as well as applications to other quorum sensing networks.

  • Thumbnail for The Role of RNA-Binding Protein SUP-26 in Dendrite Morphogenesis in Caenorhabditis elegans
    The Role of RNA-Binding Protein SUP-26 in Dendrite Morphogenesis in Caenorhabditis elegans by Tyus , Courtney

    A neuron is a specialized cell that transmits nerve impulses. Dendrites of a neuron receive signals from other cells or the environment and transmit them to the soma. Dendrites branch out to cast a wide receptive field and establish neural connections that govern behavior, learning, and memory; therefore regulation of dendritic branching is essential for sensory reception. It is important to understand how these different processes form because many neurological diseases show atypical dendritic and axonal phenotypes (Kulkarni and Firestein 2012). RNA-binding proteins (RBPs) have become of particular interest as many RBPs have recently been implicated in the process of dendrite formation. RBPs are known to be important in post-transcriptional regulation of gene expression. A previous study showed that an RBP named Shep regulates dendrite development in Drosophila (Mapes et al., 2010). To determine if Shep is evolutionarily conserved in its role in dendrite development we tested its C. elegans ortholog (sup-26) for a role in dendrite development in the multidendritic PVD sensory neuron. Loss of sup-26 activity results in a significant reduction of terminal dendrites in the PVD neuron. Furthermore, time course analysis of dendrite development revealed sup-26 mutants have a dendrite maintenance defect. sup-26 is expressed in many cells including the PVD neuron and SUP-26 protein localizes to the cytoplasm, consistent with its role as a potential translational regulator. Dendrite defects are partially rescued by PVD-specific expression of the SUP-26::GFP fusion protein, which suggests that SUP-26 functions cell-autonomously within the PVD to regulate dendrites. We hypothesize that sup-26 acts as a translational repressor of mRNAs that are important for dendrite regulation. Because sup-26/shep functions in dendrite development in fly and worm, and has three human homologs expressed in the brain, it suggests that sup-26 orthologs may be important in the development of dendrites in humans as well.