Browsing by Author "Secor, Stephen M."
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Item The Burmese python genome reveals the molecular basis for extreme adaptation in snakes(National Academy of the Sciences, 2013) Castoe, Todd A.; de Koning, A. P. Jason; Hall, Kathryn T.; Card, Daren C.; Schield, Drew R.; Fujita, Matthew K.; Ruggiero, Robert P.; Degner, Jack F.; Daza, Juan M.; Gu, Wanjun; Reyes-Velasco, Jacobo; Shaney, Kyle J.; Castoe, Jill M.; Fox, Samuel E.; Poole, Alex W.; Polanco, Daniel; Dobry, Jason; Vandewege, Michael W.; Li, Qing; Schott, Ryan K.; Kapusta, Aurelie; Minx, Patrick; Feschotte, Cedric; Uetz, Peter; Ray, David A.; Hoffmann, Federico G.; Bogden, Robert; Smith, Eric N.; Chang, Belinda S. W.; Vonk, Freek J.; Casewell, Nicholas R.; Henkel, Christiaan V.; Richardson, Michael K.; Mackessy, Stephen P.; Bronikowsi, Anne M.; Yandell, Mark; Warren, Wesley C.; Secor, Stephen M.; Pollock, David D.; University of Colorado Anschutz Medical Campus; University of Texas Arlington; University of Calgary; Alberta Childrens Hospital; University of Chicago; Southeast University - China; Linfield University; Mississippi State University; University of Utah; University of Toronto; Washington University (WUSTL); Virginia Commonwealth University; Texas Tech University; Naturalis Biodiversity Center; Leiden University - Excl LUMC; Leiden University; Bangor University; University of Liverpool; Liverpool School of Tropical Medicine; University of Northern Colorado; Iowa State University; University of Alabama TuscaloosaSnakes possess many extreme morphological and physiological adaptations. Identification of the molecular basis of these traits can provide novel understanding for vertebrate biology and medicine. Here, we study snake biology using the genome sequence of the Burmese python (Python molurus bivittatus), a model of extreme physiological and metabolic adaptation. We compare the python and king cobra genomes along with genomic samples from other snakes and perform transcriptome analysis to gain insights into the extreme phenotypes of the python. We discovered rapid and massive transcriptional responses in multiple organ systems that occur on feeding and coordinate major changes in organ size and function. Intriguingly, the homologs of these genes in humans are associated with metabolism, development, and pathology. We also found that many snake metabolic genes have undergone positive selection, which together with the rapid evolution of mitochondrial proteins, provides evidence for extensive adaptive redesign of snake metabolic pathways. Additional evidence for molecular adaptation and gene family expansions and contractions is associated with major physiological and phenotypic adaptations in snakes; genes involved are related to cell cycle, development, lungs, eyes, heart, intestine, and skeletal structure, including GRB2-associated binding protein 1, SSH, WNT16, and bone morphogenetic protein 7. Finally, changes in repetitive DNA content, guanine-cytosine isochore structure, and nucleotide substitution rates indicate major shifts in the structure and evolution of snake genomes compared with other amniotes. Phenotypic and physiological novelty in snakes seems to be driven by system-wide coordination of protein adaptation, gene expression, and changes in the structure of the genome.Item Defensive Venoms: Is Pain Sufficient for Predator Deterrence?(MDPI, 2020) Niermann, Crystal N.; Tate, Travis G.; Suto, Amber L.; Barajas, Rolando; White, Hope A.; Guswiler, Olivia D.; Secor, Stephen M.; Rowe, Ashlee H.; Rowe, Matthew P.; Sam Houston State University; Michigan State University; University of Alabama Tuscaloosa; University of Oklahoma - NormanPain, though unpleasant, is adaptive in calling an animal's attention to potential tissue damage. A long list of animals representing diverse taxa possess venom-mediated, pain-inducing bites or stings that work by co-opting the pain-sensing pathways of potential enemies. Typically, such venoms include toxins that cause tissue damage or disrupt neuronal activity, rendering painful stings honest indicators of harm. But could pain alone be sufficient for deterring a hungry predator? Some venomologists have argued "no"; predators, in the absence of injury, would "see through" the bluff of a painful but otherwise benign sting or bite. Because most algogenic venoms are also toxic (although not vice versa), it has been difficult to disentangle the relative contributions of each component to predator deterrence. Southern grasshopper mice (Onychomys torridus) are voracious predators of arthropods, feeding on a diversity of scorpion species whose stings vary in painfulness, including painful Arizona bark scorpions (Centruroides sculpturatus) and essentially painless stripe-tailed scorpions (Paravaejovis spinigerus). Moreover, southern grasshopper mice have evolved resistance to the lethal toxins in bark scorpion venom, rendering a sting from these scorpions painful but harmless. Results from a series of laboratory experiments demonstrate that painful stings matter. Grasshopper mice preferred to prey on stripe-tailed scorpions rather than bark scorpions when both species could sting; the preference disappeared when each species had their stingers blocked. A painful sting therefore appears necessary for a scorpion to deter a hungry grasshopper mouse, but it may not always be sufficient: after first attacking and consuming a painless stripe-tailed scorpion, many grasshopper mice went on to attack, kill, and eat a bark scorpion even when the scorpion was capable of stinging. Defensive venoms that result in tissue damage or neurological dysfunction may, thus, be required to condition greater aversion than venoms causing pain alone.Item Fatty Acids Identified in the Burmese Python Promote Beneficial Cardiac Growth(American Association for the Advancement of Science, 2011) Riquelme, Cecilia A.; Magida, Jason A.; Harrison, Brooke C.; Wall, Christopher E.; Marr, Thomas G.; Secor, Stephen M.; Leinwand, Leslie A.; University of Colorado Boulder; University of Alabama TuscaloosaBurmese pythons display a marked increase in heart mass after a large meal. We investigated the molecular mechanisms of this physiological heart growth with the goal of applying this knowledge to the mammalian heart. We found that heart growth in pythons is characterized by myocyte hypertrophy in the absence of cell proliferation and by activation of physiological signal transduction pathways. Despite high levels of circulating lipids, the postprandial python heart does not accumulate triglycerides or fatty acids. Instead, there is robust activation of pathways of fatty acid transport and oxidation combined with increased expression and activity of superoxide dismutase, a cardioprotective enzyme. We also identified a combination of fatty acids in python plasma that promotes physiological heart growth when injected into either pythons or mice.Item Growth and stress response mechanisms underlying post- feeding regenerative organ growth in the Burmese python(BMC, 2017) Andrew, Audra L.; Perry, Blair W.; Card, Daren C.; Schield, Drew R.; Ruggiero, Robert P.; McGaugh, Suzanne E.; Choudhary, Amit; Secor, Stephen M.; Castoe, Todd A.; University of Texas Arlington; University of Minnesota Twin Cities; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of Alabama TuscaloosaBackground: Previous studies examining post-feeding organ regeneration in the Burmese python (Python molurus bivittatus) have identified thousands of genes that are significantly differentially regulated during this process. However, substantial gaps remain in our understanding of coherent mechanisms and specific growth pathways that underlie these rapid and extensive shifts in organ form and function. Here we addressed these gaps by comparing gene expression in the Burmese python heart, liver, kidney, and small intestine across pre- and post-feeding time points (fasted, one day post-feeding, and four days post-feeding), and by conducting detailed analyses of molecular pathways and predictions of upstream regulatory molecules across these organ systems. Results: Identified enriched canonical pathways and upstream regulators indicate that while downstream transcriptional responses are fairly tissue specific, a suite of core pathways and upstream regulator molecules are shared among responsive tissues. Pathways such as mTOR signaling, PPAR/LXR/RXR signaling, and NRF2-mediated oxidative stress response are significantly differentially regulated in multiple tissues, indicative of cell growth and proliferation along with coordinated cell-protective stress responses. Upstream regulatory molecule analyses identify multiple growth factors, kinase receptors, and transmembrane receptors, both within individual organs and across separate tissues. Downstream transcription factors MYC and SREBF are induced in all tissues. Conclusions: These results suggest that largely divergent patterns of post-feeding gene regulation across tissues are mediated by a core set of higher-level signaling molecules. Consistent enrichment of the NRF2-mediated oxidative stress response indicates this pathway may be particularly important in mediating cellular stress during such extreme regenerative growth.Item Identification of an integrated stress and growth response signaling switch that directs vertebrate intestinal regeneration(BMC, 2022) Westfall, Aundrea K.; Perry, Blair W.; Kamal, Abu H. M.; Hales, Nicole R.; Kay, Jarren C.; Sapkota, Madhab; Schield, Drew R.; Pellegrino, Mark W.; Secor, Stephen M.; Chowdhury, Saiful M.; Castoe, Todd A.; University of Texas Arlington; Baylor College of Medicine; University of North Texas Denton; University of Alabama Tuscaloosa; University of Texas Southwestern Medical Center DallasBackground: Snakes exhibit extreme intestinal regeneration following months-long fasts that involves unparalleled increases in metabolism, function, and tissue growth, but the specific molecular control of this process is unknown. Understanding the mechanisms that coordinate these regenerative phenotypes provides valuable opportunities to understand critical pathways that may control vertebrate regeneration and novel perspectives on vertebrate regenerative capacities. Results: Here, we integrate a comprehensive set of phenotypic, transcriptomic, proteomic, and phosphoproteomic data from boa constrictors to identify the mechanisms that orchestrate shifts in metabolism, nutrient uptake, and cellular stress to direct phases of the regenerative response. We identify specific temporal patterns of metabolic, stress response, and growth pathway activation that direct regeneration and provide evidence for multiple key central regulatory molecules kinases that integrate these signals, including major conserved pathways like mTOR signaling and the unfolded protein response. Conclusion: Collectively, our results identify a novel switch-like role of stress responses in intestinal regeneration that forms a primary regulatory hub facilitating organ regeneration and could point to potential pathways to understand regenerative capacity in vertebrates.Item The involvement of norepinephrine, neuropeptide Y, and endothelial nitric oxide synthase on cutaneous vascular responses to local skin warming(University of Alabama Libraries, 2012) Sparks, Paul Agnew; Hodges, Gary J.; University of Alabama TuscaloosaWe investigated the role of endothelial nitric oxide synthase (eNOS), norepinephrine (NE), and neuropeptide Y (NPY) in cutaneous vasodilation in response to local skin warming. In a two part study, we used four treatment sites on the skin of the forearm for insertion of microdialysis fibers, and placement of local skin heaters and laser-Doppler probes. We allowed an hour and a half for needle trauma resolution. We recorded 10 min of baseline data, begin drug perfusion for 50 min to ensure full receptor antagonism (alpha, beta, Y1) and enzyme inhibition. In both parts of the study, the local warming protocol was such that local skin temperature was increased from 33 to 42 °C at 0.5 °C * 15 s-1. In Part 1 of our study, we used three sites for drug treatment 1) L-NAA (eNOS inhibition), 2) Yohimbine (YOH) and Propranolol (PRO) (alpha- and beta-receptor antagonism), 3) a combination site (L-NAA+YOH+PRO), 4) untreated site for control. Treatments resulted in a reduction of vasodilation (P < 0.05) that did not differ (P > 0.05) from each other. In study 2 the same test procedure was utilized, with four treatment sites: 1) L-NAA, 2) BIBP (antagonize Y1-receptors), 3) L-NAA+BIBP, 4) control site. Treated sites resulted in a reduction (P < 0.05) of the vasodilator response when compared to control sites; again treatments did not differ (P > 0.05) from each other. These data indicate that NE and NPY are working via eNOS in cutaneous vasodilator response to local skin warming.Item Multi-species comparisons of snakes identify coordinated signalling networks underlying post-feeding intestinal regeneration(Royal Society of London, 2019) Perry, Blair W.; Andrews, Audra L.; Kamal, Abu Hena Mostafa; Card, Daren C.; Schield, Drew R.; Pasquesi, Giulia I. M.; Pellegrino, Mark W.; Mackessy, Stephen P.; Chowdhury, Saiful M.; Secor, Stephen M.; Castoe, Todd A.; University of Texas Arlington; University of Northern Colorado; University of Alabama TuscaloosaSeveral snake species that feed infrequently in nature have evolved the ability to massively upregulate intestinal form and function with each meal. While fasting, these snakes downregulate intestinal form and function, and upon feeding restore intestinal structure and function through major increases in cell growth and proliferation, metabolism and upregulation of digestive function. Previous studies have identified changes in gene expression that underlie this regenerative growth of the python intestine, but the unique features that differentiate this extreme regenerative growth from non-regenerative post-feeding responses exhibited by snakes that feed more frequently remain unclear. Here, we leveraged variation in regenerative capacity across three snake species-two distantly related lineages (Crotalus and Python) that experience regenerative growth, and one (Nerodia) that does not-to infer molecular mechanisms underlying intestinal regeneration using transcriptomic and proteomic approaches. Using a comparative approach, we identify a suite of growth, stress response and DNA damage response signalling pathways with inferred activity specifically in regenerating species, and propose a hypothesis model of interactivity between these pathways that may drive regenerative intestinal growth in snakes.Item Rapid changes in gene expression direct rapid shifts in intestinal form and function in the Burmese python after feeding(American Psyiological Society, 2015) Andrew, Audra L.; Card, Daren C.; Ruggiero, Robert P.; Schield, Drew R.; Adams, Richard H.; Pollock, David D.; Secor, Stephen M.; Castoe, Todd A.; University of Texas Arlington; University of Colorado Anschutz Medical Campus; University of Alabama TuscaloosaSnakes provide a unique and valuable model system for studying the extremes of physiological remodeling because of the ability of some species to rapidly upregulate organ form and function upon feeding. The predominant model species used to study such extreme responses has been the Burmese python because of the extreme nature of postfeeding response in this species. We analyzed the Burmese python intestine across a time series, before, during, and after feeding to understand the patterns and timing of changes in gene expression and their relationship to changes in intestinal form and function upon feeding. Our results indicate that >2,000 genes show significant changes in expression in the small intestine following feeding, including genes involved in intestinal morphology and function (e.g., hydrolases, microvillus proteins, trafficking and transport proteins), as well as genes involved in cell division and apoptosis. Extensive changes in gene expression occur surprisingly rapidly, within the first 6 h of feeding, coincide with changes in intestinal morphology, and effectively return to prefeeding levels within 10 days. Collectively, our results provide an unprecedented portrait of parallel changes in gene expression and intestinal morphology and physiology on a scale that is extreme both in the magnitude of changes, as well as in the incredibly short time frame of these changes, with up-and downregulation of expression and function occurring in the span of 10 days. Our results also identify conserved vertebrate signaling pathways that modulate these responses, which may suggest pathways for therapeutic modulation of intestinal function in humans.Item Regional differences in the control of the cutaneous circulation in humans(University of Alabama Libraries, 2012) Del Pozzi, Andrew Thomas; Bishop, Phillip A.; Hodges, Gary J.; University of Alabama TuscaloosaThe purpose of this series of studies was to compare regional skin blood flow (SkBF) in adult humans. Forearm and calf skin sites were instrumented with microdialysis fibers, local skin heaters, and laser-Doppler probes in nine healthy volunteers. Baseline cutaneous vascular conductance (CVC) (laser-Doppler flow / blood pressure) was measured at a local skin temperature (Tloc) of 33 °C and 42 °C. All data are expressed as CVC. In study 1, forearm and calf sites were compared to determine if SkBF differed by region. Baseline CVC was higher in the calf than in the forearm (24±2 and 16±1 %max) (P=0.04). At a Tloc of 42 °C, initial peak CVC was higher in the forearms (78±3 %max) than the calf (63±3 %max) (P=0.004). Plateau phase CVC was higher in forearms (90±2 %max) than calves (98±1 %max) (P=0.008). In study 2, the role of nitric oxide synthase (NOS) in the cutaneous vasodilator response in the skin of the forearms and calves using the NOS inhibitor L-NAME was investigated. Baseline CVC between control and L-NAME treated sites was higher (27±2 vs 17± 1%max, respectively; P=0.04) for the calf, but did not differ (P=0.26) for forearms. At a Tloc of 42°C, CVC at forearm and calf L-NAME sites did not differ (P=0.45). In study 3, bretylium tosylate (BT) was used to examine the role of sympathetic nerves on regional SkBF. Baseline BT sites differed between the forearm and calf (P=0.04). Initial peak CVC for forearm sites treated with BT (62±3 %max) were lower than the calf sites (78±2 %max) (P=0.02). CVC achieved at arm and calf BT sites did not differ at plateau (P=0.28). We conclude that differences exist in regional SkBF control at rest (thermoneutral) and in response to local skin warming. Differences observed suggest that the NOS contribution to basal vascular tone was higher in calves than forearms and accounts for the higher basal SkBF and vasodilator response to a Tloc of 42 °C in the legs. Initial peak CVC in the calf treated with BT increased which may, in part, indicate increased vasoconstrictor tone.Item Report from the First Snake Genomics and Integrative Biology Meeting(Genomic Standards Consortium, 2012) Castoe, Todd A.; Braun, Edward L.; Bronikowski, Anne M.; Cox, Christian L.; Rabosky, Alison R. Davis; de Koning, A. P. Jason; Dobry, Jason; Fujita, Matthew K.; Giorgianni, Matt W.; Hargreaves, Adam; Henkel, Christiaan V.; Mackessy, Stephen P.; O'Meally, Denis; Rokyta, Darin R.; Secor, Stephen M.; Streicher, Jeffrey W.; Wray, Kenneth P.; Yokoyama, Ken D.; Pollock, David D.; University of Colorado Anschutz Medical Campus; University of Florida; Iowa State University; University of Texas Arlington; University of California Berkeley; Harvard University; University of Wisconsin Madison; Bangor University; Leiden University - Excl LUMC; Leiden University; University of Northern Colorado; University of Canberra; Florida State University; University of Alabama TuscaloosaThis report summarizes the proceedings of the 1st Snake Genomics and Integrative Biology Meeting held in Vail, CO USA, 5-8 October 2011. The meeting had over twenty registered participants, and was conducted as a single session of presentations. Goals of the meeting included coordination of genomic data collection and fostering collaborative interactions among researchers using snakes as model systems.