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Search Results: 1 - 10 of 304051 matches for " J. Alex Parker "
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Heritable Transmission of Stress Resistance by High Dietary Glucose in Caenorhabditis elegans
Arnaud Tauffenberger,J. Alex Parker
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004346
Abstract: Glucose is a major energy source and is a key regulator of metabolism but excessive dietary glucose is linked to several disorders including type 2 diabetes, obesity and cardiac dysfunction. Dietary intake greatly influences organismal survival but whether the effects of nutritional status are transmitted to the offspring is an unresolved question. Here we show that exposing Caenorhabditis elegans to high glucose concentrations in the parental generation leads to opposing negative effects on fecundity, while having protective effects against cellular stress in the descendent progeny. The transgenerational inheritance of glucose-mediated phenotypes is dependent on the insulin/IGF-like signalling pathway and components of the histone H3 lysine 4 trimethylase complex are essential for transmission of inherited phenotypes. Thus dietary over-consumption phenotypes are heritable with profound effects on the health and survival of descendants.
Collisional Evolution of Ultra-Wide Trans-Neptunian Binaries
Alex H. Parker,J. J. Kavelaars
Physics , 2011, DOI: 10.1088/0004-637X/744/2/139
Abstract: The widely-separated, near-equal mass binaries hosted by the cold Classical Kuiper Belt are delicately bound and subject to disruption by many perturbing processes. We use analytical arguments and numerical simulations to determine their collisional lifetimes given various impactor size distributions, and include the effects of mass-loss and multiple impacts over the lifetime of each system. These collisional lifetimes constrain the population of small (R > ~1 km) objects currently residing in the Kuiper Belt, and confirm that the size distribution slope at small size cannot be excessively steep - likely q < ~3.5. We track mutual semi-major axis, inclination, and eccentricity evolution through our simulations, and show that it is unlikely that the wide binary population represents an evolved tail of the primordially-tight binary population. We find that if the wide binaries are a collisionally-eroded population, their primordial mutual orbit planes must have preferred to lie in the plane of the solar system. Finally, we find that current limits on the size distribution at small radii remain high enough that the prospect of detecting dust-producing collisions in real-time in the Kuiper Belt with future optical surveys is feasible.
TDP-1/TDP-43 Regulates Stress Signaling and Age-Dependent Proteotoxicity in Caenorhabditis elegans
Alexandra Vaccaro,Arnaud Tauffenberger,Peter E. A. Ash,Yari Carlomagno,Leonard Petrucelli,J. Alex Parker
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002806
Abstract: TDP-43 is a multifunctional nucleic acid binding protein linked to several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia. To learn more about the normal biological and abnormal pathological role of this protein, we turned to Caenorhabditis elegans and its orthologue TDP-1. We report that TDP-1 functions in the Insulin/IGF pathway to regulate longevity and the oxidative stress response downstream from the forkhead transcription factor DAF-16/FOXO3a. However, although tdp-1 mutants are stress-sensitive, chronic upregulation of tdp-1 expression is toxic and decreases lifespan. ALS–associated mutations in TDP-43 or the related RNA binding protein FUS activate the unfolded protein response and generate oxidative stress leading to the daf-16–dependent upregulation of tdp-1 expression with negative effects on neuronal function and lifespan. Consistently, deletion of endogenous tdp-1 rescues mutant TDP-43 and FUS proteotoxicity in C. elegans. These results suggest that chronic induction of wild-type TDP-1/TDP-43 by cellular stress may propagate neurodegeneration and decrease lifespan.
Mutant TDP-43 and FUS Cause Age-Dependent Paralysis and Neurodegeneration in C. elegans
Alexandra Vaccaro, Arnaud Tauffenberger, Dina Aggad, Guy Rouleau, Pierre Drapeau, J. Alex Parker
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031321
Abstract: Mutations in the DNA/RNA binding proteins TDP-43 and FUS are associated with Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration. Intracellular accumulations of wild type TDP-43 and FUS are observed in a growing number of late-onset diseases suggesting that TDP-43 and FUS proteinopathies may contribute to multiple neurodegenerative diseases. To better understand the mechanisms of TDP-43 and FUS toxicity we have created transgenic Caenorhabditis elegans strains that express full-length, untagged human TDP-43 and FUS in the worm's GABAergic motor neurons. Transgenic worms expressing mutant TDP-43 and FUS display adult-onset, age-dependent loss of motility, progressive paralysis and neuronal degeneration that is distinct from wild type alleles. Additionally, mutant TDP-43 and FUS proteins are highly insoluble while wild type proteins remain soluble suggesting that protein misfolding may contribute to toxicity. Populations of mutant TDP-43 and FUS transgenics grown on solid media become paralyzed over 7 to 12 days. We have developed a liquid culture assay where the paralysis phenotype evolves over several hours. We introduce C. elegans transgenics for mutant TDP-43 and FUS motor neuron toxicity that may be used for rapid genetic and pharmacological suppressor screening.
Deletion of C9ORF72 Results in Motor Neuron Degeneration and Stress Sensitivity in C. elegans
Martine Therrien, Guy A. Rouleau, Patrick A. Dion, J. Alex Parker
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0083450
Abstract: An expansion of the hexanucleotide GGGGCC repeat in the first intron of C9ORF72 gene was recently linked to amyotrophic lateral sclerosis. It is not known if the mutation results in a gain of function, a loss of function or if, perhaps both mechanisms are linked to pathogenesis. We generated a genetic model of ALS to explore the biological consequences of a null mutation of the Caenorhabditis elegans C9ORF72 orthologue, F18A1.6, also called alfa-1. alfa-1 mutants displayed age-dependent motility defects leading to paralysis and the specific degeneration of GABAergic motor neurons. alfa-1 mutants showed differential susceptibility to environmental stress where osmotic stress provoked neurodegeneration. Finally, we observed that the motor defects caused by loss of alfa-1 were additive with the toxicity caused by mutant TDP-43 proteins, but not by the mutant FUS proteins. These data suggest that a loss of alfa-1/C9ORF72 expression may contribute to motor neuron degeneration in a pathway associated with other known ALS genes.
An Online Environment for Democratic Deliberation: Motivations, Principles, and Design
Todd Davies,Brendan O'Connor,Alex Cochran,Jonathan J. Effrat,Andrew Parker,Benjamin Newman,Aaron Tam
Computer Science , 2013,
Abstract: We have created a platform for online deliberation called Deme (which rhymes with 'team'). Deme is designed to allow groups of people to engage in collaborative drafting, focused discussion, and decision making using the Internet. The Deme project has evolved greatly from its beginning in 2003. This chapter outlines the thinking behind Deme's initial design: our motivations for creating it, the principles that guided its construction, and its most important design features. The version of Deme described here was written in PHP and was deployed in 2004 and used by several groups (including organizers of the 2005 Online Deliberation Conference). Other papers describe later developments in the Deme project (see Davies et al. 2005, 2008; Davies and Mintz 2009).
The Intrinsic Neptune Trojan Orbit Distribution: Implications for the Primordial Disk and Planet Migration
Alex H. Parker
Physics , 2014, DOI: 10.1016/j.icarus.2014.09.043
Abstract: The present-day orbit distribution of the Neptune Trojans is a powerful probe of the dynamical environment of the outer solar system during the late stages of planet migration. In this work, I conservatively debias the inclination, eccentricity, and libration amplitude distributions of the Neptune Trojans by reducing a priori unknown discovery and follow-up survey properties to nuisance parameters and using a likelihood-free Bayesian rejection sampler for parameter estimation. Using this survey-agnostic approach, I confirm that the Neptune Trojans are a dynamically excited population: at $>$95% confidence, the Neptune Trojans' inclination width must be $\sigma_i > 11^\circ$. For comparison and motivation purposes, I also model the Jupiter Trojan orbit distributions in the same basis and produce new estimates of their parameters (Jupiter Trojan $\sigma_i=14.4^\circ \pm 0.5^\circ$, $\sigma_{L11} = 11.8^\circ \pm 0.5^\circ$, and $\sigma_e = 0.061\pm 0.002$). The debiased inclination, libration amplitude, and eccentricity distributions of the Neptune Trojans are nominally very similar to those of the Jupiter Trojans. I use these new constraints to inform a suite of simulations of Neptune Trojan capture by an eccentric, rapidly-migrating Neptune from an initially dynamically-hot disk. These simulations demonstrate that if migration and eccentricity-damping timescales were short ($\tau_a \lesssim 10$ Myr, $\tau_e \lesssim 1$ Myr), the disk that Neptune migrated into must have been pre-heated (prior to Neptune's appearance) to a width comparable to the Neptune Trojans' extant width to produce a captured population with an inclination distribution width consistent with that of the observed population.
Discovery and Characterization of Trans-Neptunian Binaries in Large-Scale Surveys
Alex H. Parker
Physics , 2012,
Abstract: The dynamically cold component of the Kuiper Belt is host to a population of very widely separated, near-equal mass binary systems. Such binaries, representing the tail of the separation distribution of the more common, more tightly-bound systems, are known to have on-sky separations up to ~4". Their wide separations make them highly valuable due to their delicacy and sensitivity to perturbation, and also makes them relatively easy targets to characterize from the ground. Parker et al. (2011) present a ground-based characterization of seven such systems with separations at discovery ranging from 0."5-4", and we will adopt these systems as the prototypes for the ultra-wide binaries of the Kuiper Belt. Here we present the prospects for using future large-scale ground-based optical surveys (with LSST as our baseline survey) to measure the orbital properties of a large sample of these widely separated Trans-Neptunian Binaries (TNBs).
Extinction in Lotka-Volterra model
Matthew Parker,Alex Kamenev
Quantitative Biology , 2009, DOI: 10.1103/PhysRevE.80.021129
Abstract: Competitive birth-death processes often exhibit an oscillatory behavior. We investigate a particular case where the oscillation cycles are marginally stable on the mean-field level. An iconic example of such a system is the Lotka-Volterra model of predator-prey competition. Fluctuation effects due to discreteness of the populations destroy the mean-field stability and eventually drive the system toward extinction of one or both species. We show that the corresponding extinction time scales as a certain power-law of the population sizes. This behavior should be contrasted with the extinction of models stable in the mean-field approximation. In the latter case the extinction time scales exponentially with size.
Methylene Blue Protects against TDP-43 and FUS Neuronal Toxicity in C. elegans and D. rerio
Alexandra Vaccaro, Shunmoogum A. Patten, Sorana Ciura, Claudia Maios, Martine Therrien, Pierre Drapeau, Edor Kabashi, J. Alex Parker
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042117
Abstract: The DNA/RNA-binding proteins TDP-43 and FUS are found in protein aggregates in a growing number of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and related dementia, but little is known about the neurotoxic mechanisms. We have generated Caenorhabditis elegans and zebrafish animal models expressing mutant human TDP-43 (A315T or G348C) or FUS (S57Δ or R521H) that reflect certain aspects of ALS including motor neuron degeneration, axonal deficits, and progressive paralysis. To explore the potential of our humanized transgenic C. elegans and zebrafish in identifying chemical suppressors of mutant TDP-43 and FUS neuronal toxicity, we tested three compounds with potential neuroprotective properties: lithium chloride, methylene blue and riluzole. We identified methylene blue as a potent suppressor of TDP-43 and FUS toxicity in both our models. Our results indicate that methylene blue can rescue toxic phenotypes associated with mutant TDP-43 and FUS including neuronal dysfunction and oxidative stress.
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