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Abegglen L.M.,University of Utah | Caulin A.F.,University of Pennsylvania | Chan A.,University of Utah | Lee K.,University of Utah | And 10 more authors.
JAMA - Journal of the American Medical Association | Year: 2015

IMPORTANCE Evolutionary medicine may provide insights into human physiology and pathophysiology, including tumor biology. OBJECTIVE To identify mechanisms for cancer resistance in elephants and compare cellular response to DNA damage among elephants, healthy human controls, and cancer-prone patients with Li-Fraumeni syndrome (LFS). DESIGN, SETTING, AND PARTICIPANTS A comprehensive survey of necropsy datawas performed across 36 mammalian species to validate cancer resistance in large and long-lived organisms, including elephants (n = 644). The African and Asian elephant genomes were analyzed for potential mechanisms of cancer resistance. Peripheral blood lymphocytes from elephants, healthy human controls, and patients with LFS were tested in vitro in the laboratory for DNA damage response. The study included African and Asian elephants (n = 8), patients with LFS (n = 10), and age-matched human controls (n = 11). Human samples were collected at the University of Utah between June 2014 and July 2015. EXPOSURES Ionizing radiation and doxorubicin. MAIN OUTCOMES AND MEASURES Cancer mortality across specieswas calculated and compared by body size and life span. The elephant genome was investigated for alterations in cancer-related genes. DNA repair and apoptosis were compared in elephant vs human peripheral blood lymphocytes. RESULTS Across mammals, cancer mortality did not increase with body size and/or maximum life span (eg, for rock hyrax, 1% [95%CI, 0%-5%]; African wild dog, 8%[95%CI, 0%-16%]; lion, 2%[95%CI, 0%-7%]). Despite their large body size and long life span, elephants remain cancer resistant, with an estimated cancer mortality of 4.81% (95%CI, 3.14%-6.49%), compared with humans, who have 11% to 25%cancer mortality. While humans have 1 copy (2 alleles) of TP53, African elephants have at least 20 copies (40 alleles), including 19 retrogenes (38 alleles) with evidence of transcriptional activity measured by reverse transcription polymerase chain reaction. In response to DNA damage, elephant lymphocytes underwent p53-mediated apoptosis at higher rates than human lymphocytes proportional to TP53 status (ionizing radiation exposure: patients with LFS, 2.71% [95%CI, 1.93%-3.48%] vs human controls, 7.17%[95%CI, 5.91%-8.44%] vs elephants, 14.64%[95%CI, 10.91%-18.37%]; P <.001; doxorubicin exposure: human controls, 8.10% [95%CI, 6.55%-9.66%] vs elephants, 24.77%[95%CI, 23.0%-26.53%]; P <.001). CONCLUSIONS AND RELEVANCE Compared with other mammalian species, elephants appeared to have a lower-than-expected rate of cancer, potentially related to multiple copies of TP53. Compared with human cells, elephant cells demonstrated increased apoptotic response following DNA damage. These findings, if replicated, could represent an evolutionary-based approach for understanding mechanisms related to cancer suppression.

Muirhead C.A.,University of Rochester | Muirhead C.A.,Ronin Institute | Presgraves D.C.,University of Rochester
American Naturalist | Year: 2016

Under allopatric speciation, geographic barriers eliminate gene flow between eventual species at all loci in the genome simultaneously. There is increasing evidence, however, that speciation can be complex, with some loci experiencing gene flow during speciation or during bouts of secondary contact. In taxa with heteromorphic sex chromosomes—birds, butterflies, mammals, and Drosophila—the X (or Z) chromosome generally shows reduced levels of gene flow compared to autosomes. To investigate why, we develop population genetic models of secondary contact and gene flow at a neutral locus that is genetically linked to selected loci involved in hybrid incompatibilities and/or local adaptation. Using models that assume weak migration and strong selection, we compare gene flow at X-linked versus autosomal neutral loci as a function of linkage, dominance, sex-specific selection, and sex-specific recombination. For most cases, gene flow at neutral loci on the X is reduced relative to autosomes, as the greater efficacy of hemizygous selection in XY hybrids reduces the opportunity for neutral migrant alleles to escape their genetically linked, locally disfavored alleles via recombination. There are some circumstances, however, involving sex-limited selection and sex-limited recombination that allow neutral loci on the X to introgress more readily than those on autosomes. © 2015 by The University of Chicago. All rights reserved.

Belcheva A.,University of Toronto | Irrazabal T.,University of Toronto | Robertson S.J.,University of Toronto | Streutker C.,St Michaels Hospital | And 15 more authors.
Cell | Year: 2014

The etiology of colorectal cancer (CRC) has been linked to deficiencies in mismatch repair and adenomatous polyposis coli (APC) proteins, diet, inflammatory processes, and gut microbiota. However, the mechanism through which the microbiota synergizes with these etiologic factors to promote CRC is not clear. We report that altering the microbiota composition reduces CRC in APCMin/+MSH2-/- mice, and that a diet reduced in carbohydrates phenocopies this effect. Gut microbes did not induce CRC in these mice through an inflammatory response or the production of DNA mutagens but rather by providing carbohydrate-derived metabolites such as butyrate that fuel hyperproliferation of MSH2-/- colon epithelial cells. Further, we provide evidence that the mismatch repair pathway has a role in regulating β-catenin activity and modulating the differentiation of transit-amplifying cells in the colon. These data thereby provide an explanation for the interaction between microbiota, diet, and mismatch repair deficiency in CRC induction. PaperClip © 2014 Elsevier Inc.

Callier V.,Ronin Institute | Frederik Nijhout H.,Duke University
Current Opinion in Insect Science | Year: 2014

The hypoxia-induced reduction of body size in Drosophila and Manduca is ideal for understanding the mechanisms of body size plasticity. The mechanisms of size regulation are well-studied in these species, and the molecular mechanisms of oxygen sensing are also well-characterized. What is missing is the connection between oxygen sensing and the mechanisms that regulate body size in standard conditions. Oxygen functions both as a substrate for metabolism to produce energy and as a signaling molecule that activates specific cellular signaling networks. Hypoxia affects metabolism in a passive, generalized manner. Hypoxia also induces the activation of targeted signaling pathways, which may mediate the reduction in body size, or alternatively, compensate for the metabolic perturbations and attenuate the reduction in size. These alternative hypotheses await testing. Both perspectives - metabolism and information - are necessary to understand how oxygen affects body size. © 2014 Elsevier Inc.

Wounding induces systemic potentials in Arabidopsis thaliana that can be abolished by concomitant suppression of the GLUTAMATE RECEPTOR-LIKE GLR3.3 and GLR3.6 genes. However, the roles of specific GLR channels to these potentials remain unclear. Here I applied the Electrical Penetration Graph (EPG) to study the contribution of three GLR channels to wound-induced, systemically propagated electrical potentials in Arabidopsis thaliana. In contrast to recordings made with conventional rigs for whole-plant electrophysiology, the EPG allows for the unambiguous distinction of the phloem-propagated action potential (AP) from the electrical activity outside of the phloem. The data reported here suggest that: (a) the transmission of wound-induced, phloem-propagated AP to neighbor leaves, requires expression of GLR3.3 or GLR3.6, whereas GLR3.5 prevents its transmission to non-neighbor leaves; (b) the generation of wound-induced electrical signals outside the phloem network depends on GLR3.6 expression; and (c) wound-induced systemic potentials initiated in the shoot are transmitted to the root in the adult plant, which suggests a role for these electrical signals in coordinating the plant defenses in the shoot and in the root. Here, I propose a model for wound-induced systemic electrical signals at the molecular, cellular and anatomical level. In this model, GLR3.3 and GLR3.6 function as on switches for the propagation of woundinduced potentials beyond the wounded leaf, while GLR3.5 functions as an off switch that prevents the propagation of wound-induced electrical potentials to distal, non-neighbor leaves. © 2016 Taylor & Francis Group, LLC.

Salvador-Recatala V.,Ronin Institute
Plant Signaling and Behavior | Year: 2016

Soil salinization is a major cause of plant stress, partly due to the physicochemical similarities between Na+ and K+. Na+ ions compete with KC ions for their transport into root cells. However, the point of Na+ entry remains unidentified. Here, I have applied the Electrical Penetration Graph as a method for whole plant electrophysiology in order to test if (a) root exposure to NaCl induces depolarization waves that propagate from root to shoot via the phloem, and if (b) the electrophysiological effects of root exposure to NaCl require expression of the potassium channels AKT1 and/or AKT2. The data suggest that AKT2 subunit containing K+ channels mediate NaCl-induced depolarization of root cells, and that this depolarization does not propagate to leaves via the phloem. © 2016 Taylor & Francis Group, LLC.

Altenberg L.,Ronin Institute
Genetic Programming and Evolvable Machines | Year: 2014

Banzhaf provides a portal to the subject of emergence, noting contentious concepts while not getting sucked into fruitless debate. Banzhaf refutes arguments against downward causation much as Samuel Johnson kicks a stone to ref ute Berkeley - by pointing to concrete examples in genetic programming, such as the growth of repetitive patterns within programs. Repetitive patterns are theoretically predicted to emerge from the evolution of evolvability and robustness under subtree exchange. Selection and genetic operators are co-equal creators of these emergent phenomena. GP systems entirely formal, and thus their emergent phenomena are essentially mathematical. The emergence of Lagrangian distributions for tree shapes under subtree exchange, for example, gives a glimpse of the possibilities for mathematical understanding of emergence in GP. The mathematics underlying emergence in genetic programming should be pursued with vigor. © 2013 Springer Science+Business Media New York.

Desai S.,Ronin Institute
Astrophysics and Space Science | Year: 2016

Singleton et al. (arXiv:0912.0350, 2009) have argued that the flux of pulsars measured at 1400 MHz shows an apparent violation of the inverse-square law with distance (r), and instead the flux scales as 1 / r. They deduced this from the fact that the convergence error obtained in reconstructing the luminosity function of pulsars using an iterative maximum likelihood procedure is about 10 5 times larger for a distance exponent of two (corresponding to the inverse-square law) compared to an exponent of one. When we applied the same technique to this pulsar dataset with two different values for the trial luminosity function in the zeroth iteration, we find that neither of them can reproduce a value of 10 5 for the ratio of the convergence error between these distance exponents. We then reconstruct the differential pulsar luminosity function using Lynden-Bell’s C− method after positing both inverse-linear and inverse-square scalings with distance. We show that this method cannot help in discerning between the two exponents. Finally, when we tried to estimate the power-law exponent with a Bayesian regression procedure, we do not get a best-fit value of one for the distance exponent. The model residuals obtained from our fitting procedure are larger for the inverse-linear law compared to the inverse-square law. Moreover, the observed pulsar flux cannot be parameterized only by power-law functions of distance, period, and period derivative. Therefore, we conclude from our analysis using multiple methods that there is no evidence that the pulsar radio flux at 1400 MHz violates the inverse-square law or that the flux scales inversely with distance. © 2016, Springer Science+Business Media Dordrecht.

Kahya E.O.,Technical University of Istanbul | Desai S.,Ronin Institute
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2016

On 14th September 2015, a transient gravitational wave (GW150914) was detected by the two LIGO detectors at Hanford and Livingston from the coalescence of a binary black hole system located at a distance of about 400 Mpc. We point out that GW150914 experienced a Shapiro delay due to the gravitational potential of the mass distribution along the line of sight of about 1800 days. Also, the near-simultaneous arrival of gravitons over a frequency range of about 200 Hz within a 0.2 s window allows us to constrain any violations of Shapiro delay and Einstein's equivalence principle between the gravitons at different frequencies. From the calculated Shapiro delay and the observed duration of the signal, frequency-dependent violations of the equivalence principle for gravitons are constrained to an accuracy of O(10-9). © 2016 The Authors.

Wilkins J.F.,Ronin Institute
PLoS Biology | Year: 2014

Mammalian development involves significant interactions between offspring and mother. But is this interaction a carefully coordinated effort by two individuals with a common goal-offspring survival? Or is it an evolutionary battleground (a central idea in our understanding of reproduction). The conflict between parents and offspring extends to an offspring's genes, where paternally inherited genes favor demanding more from the mother, while maternally inherited genes favor restraint. This "intragenomic conflict" (among genes within a genome) is the dominant evolutionary explanation for "genomic imprinting." But a new study in PLOS Biology provides support for a different perspective: that imprinting might facilitate coordination between mother and offspring. According to this "coadaptation theory," paternally inherited genes might be inactivated because maternally inherited genes are adapted to function harmoniously with the mother. As discussed in this article, the growth effects associated with the imprinted gene Grb10 are consistent with this idea, but it remains to be seen just how general the pattern is. © 2014 Jon F.

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