Nicotine exposure in the developing bullfrog: influences on neuroventilatory responses to CO₂

Thesis (M.S.) University of Alaska Fairbanks, 2008Developmental exposure to the neuroteratogen nicotine may affect ventilatory responses to hypercapnia. Developmental changes in normocapnic and hypercapnic neuroventilation of the isolated bullfrog brainstem preparation have been previously characterized. I investigated the effect of 3- and 10-wk chronic nicotine (30 [mu]g/L) exposure on lung burst frequency exhibited by early and late metamorphic bullfrog tadpoles during normocapnia (1.5 % CO₂) and hypercapnia (5.0 % CO₂). Chronic nicotine exposure impairs the hypercapnic neuroventilatory response of early metamorphic tadpoles following both 3- and 10-wk exposure. Late metamorphic tadpoles demonstrated an impaired hypercapnic neuroventilatory response only after 10-wk exposure. Chronic nicotine exposure had no effect on normocapnic neuroventilation. Brainstem preparations from early and late metamorphic tadpoles and juvenile bullfrogs were exposed acutely to 18 [mu]g/L nicotine. Acute nicotine had no effect on normocapnic or hypercapnic neuroventilation of early metamorphic tadpoles. Late metamorphic tadpoles and juvenile bullfrogs demonstrated depressed normocapnic neuroventilation in response to acute nicotine exposure, while late metamorphic tadpole brainstems responded significantly to hypercapnia during acute exposure. This suggests that bullfrogs have a differential response to acute nicotine exposure that increases with development. Collectively these data suggest that the consequences of developmental nicotine exposure differ between acute and chronic exposure and throughout bullfrog development.1. Timing and duration of developmental nicotine exposure contribute to attenuation of the tadpole hypercapnic response -- 2. Nicotine affects the normocapnic and hypercapnic neuroventilation of bullfrogs in a developmental stage dependent manner -- General conclusions -- Literature cited

Neuroplasticity And Neurotoxicology: Central Breathing Control Following Developmental Nicotine Or Ethanol Exposure

Thesis (Ph.D.) University of Alaska Fairbanks, 2010Nicotine or ethanol exposure early in development are both risk factors for Sudden Infant Death Syndrome (SIDS). I tested the hypothesis that both nicotine and ethanol may be linked to SIDS by impairing central breathing control responses to low oxygen (hypoxia) and high carbon dioxide (hypercapnia) stressors. Experiments were conducted in bullfrog tadpoles, a model system for respiratory neurotoxicology research. I addressed three specific aims: to characterize the effect of chronic ethanol on central responses to hypercapnia and hypoxia, to characterize the effect of chronic nicotine on central hypoxic responses, and to determine the persistence of hypercapnic impairments following 10-wk exposure to either nicotine or ethanol. 10-wk nicotine exposure resulted in neuroplastic changes that eliminated the central hypoxic responses of early but not late metamorphic tadpoles. Thus, central responses to both hypoxia and hypercapnia were impaired following nicotine exposure. The attenuated central hypercapnic response of nicotine-exposed tadpoles persisted for 1 - 3 wk. Following 10-wk chronic ethanol exposure central responses to hypercapnia and hypoxia were lost regardless of the developmental timing of exposure. Impairments in central hypercapnic responses persisted for 3 - 6 wk after ethanol exposure ended. The recovery of central hypercapnic responses in nicotine- and ethanol-exposed tadpoles may be an example of recuperative neuroplasticity resulting in either a reinstatement of network components and functions or an accommodation to deleterious nicotine- and ethanol-evoked neuroplastic changes. Collectively these data suggest that both nicotine and ethanol may target adaptive and compensatory mechanisms in central breathing control. The teratogen-induced impairments were developmentally dependent in the case of nicotine, and they persisted longer following ethanol exposure. The overall result of exposure to either neuroteratogen was an inability to respond to central breathing stressors, supporting the possible link to SIDS

Selfish Network Creation with Non-Uniform Edge Cost

Network creation games investigate complex networks from a game-theoretic point of view. Based on the original model by Fabrikant et al. [PODC'03] many variants have been introduced. However, almost all versions have the drawback that edges are treated uniformly, i.e. every edge has the same cost and that this common parameter heavily influences the outcomes and the analysis of these games. We propose and analyze simple and natural parameter-free network creation games with non-uniform edge cost. Our models are inspired by social networks where the cost of forming a link is proportional to the popularity of the targeted node. Besides results on the complexity of computing a best response and on various properties of the sequential versions, we show that the most general version of our model has constant Price of Anarchy. To the best of our knowledge, this is the first proof of a constant Price of Anarchy for any network creation game.Comment: To appear at SAGT'1

Anderson localization of solitons

At low temperature, a quasi-one-dimensional ensemble of atoms with attractive interaction forms a bright soliton. When exposed to a weak and smooth external potential, the shape of the soliton is hardly modified, but its center-of-mass motion is affected. We show that in a spatially correlated disordered potential, the quantum motion of a bright soliton displays Anderson localization. The localization length can be much larger than the soliton size and could be observed experimentally.Comment: version accepted for publication in Phys. Rev. Let

Finite-Temperature Fidelity-Metric Approach to the Lipkin-Meshkov-Glick Model

The fidelity metric has recently been proposed as a useful and elegant approach to identify and characterize both quantum and classical phase transitions. We study this metric on the manifold of thermal states for the Lipkin-Meshkov-Glick (LMG) model. For the isotropic LMG model, we find that the metric reduces to a Fisher-Rao metric, reflecting an underlying classical probability distribution. Furthermore, this metric can be expressed in terms of derivatives of the free energy, indicating a relation to Ruppeiner geometry. This allows us to obtain exact expressions for the (suitably rescaled) metric in the thermodynamic limit. The phase transition of the isotropic LMG model is signalled by a degeneracy of this (improper) metric in the paramagnetic phase. Due to the integrability of the isotropic LMG model, ground state level crossings occur, leading to an ill-defined fidelity metric at zero temperature.Comment: 18 pages, 3 figure

Geometric Network Creation Games

Network Creation Games are a well-known approach for explaining and analyzing the structure, quality and dynamics of real-world networks like the Internet and other infrastructure networks which evolved via the interaction of selfish agents without a central authority. In these games selfish agents which correspond to nodes in a network strategically buy incident edges to improve their centrality. However, past research on these games has only considered the creation of networks with unit-weight edges. In practice, e.g. when constructing a fiber-optic network, the choice of which nodes to connect and also the induced price for a link crucially depends on the distance between the involved nodes and such settings can be modeled via edge-weighted graphs. We incorporate arbitrary edge weights by generalizing the well-known model by Fabrikant et al.[PODC'03] to edge-weighted host graphs and focus on the geometric setting where the weights are induced by the distances in some metric space. In stark contrast to the state-of-the-art for the unit-weight version, where the Price of Anarchy is conjectured to be constant and where resolving this is a major open problem, we prove a tight non-constant bound on the Price of Anarchy for the metric version and a slightly weaker upper bound for the non-metric case. Moreover, we analyze the existence of equilibria, the computational hardness and the game dynamics for several natural metrics. The model we propose can be seen as the game-theoretic analogue of a variant of the classical Network Design Problem. Thus, low-cost equilibria of our game correspond to decentralized and stable approximations of the optimum network design.Comment: Accepted at 31st ACM Symposium on Parallelism in Algorithms and Architectures (SPAA '19). 33 pages, 11 figure

Four novel candidate causal variants for deficient homozygous haplotypes in Holstein cattle.

Mendelian variants can determine both insemination success and neonatal survival and thus influence fertility and rearing success of cattle. We present 24 deficient homozygous haplotype regions in the Holstein population of Switzerland and provide an overview of the previously identified haplotypes in the global Holstein breed. This study encompasses massive genotyping, whole-genome sequencing (WGS) and phenotype association analyses. We performed haplotype screenings on almost 53 thousand genotyped animals including 114 k SNP data with two different approaches. We revealed significant haplotype associations to several survival, birth and fertility traits. Within haplotype regions, we mined WGS data of hundreds of bovine genomes for candidate causal variants, which were subsequently evaluated by using a custom genotyping array in several thousand breeding animals. With this approach, we confirmed the known deleterious SMC2:p.Phe1135Ser missense variant associated with Holstein haplotype (HH) 3. For two previously reported deficient homozygous haplotypes that show negative associations to female fertility traits, we propose candidate causative loss-of-function variants: the HH13-related KIR2DS1:p.Gln159* nonsense variant and the HH21-related NOTCH3:p.Cys44del deletion. In addition, we propose the RIOX1:p.Ala133_Glu142del deletion as well as the PCDH15:p.Leu867Val missense variant to explain the unexpected low number of homozygous haplotype carriers for HH25 and HH35, respectively. In conclusion, we demonstrate that with mining massive SNP data in combination with WGS data, we can map several haplotype regions and unravel novel recessive protein-changing variants segregating at frequencies of 1 to 5%. Our findings both confirm previously identified loci and expand the spectrum of undesired alleles impairing reproduction success in Holstein cattle, the world's most important dairy breed

Mining massive genomic data of two Swiss Braunvieh cattle populations reveals six novel candidate variants that impair reproductive success

Background: This study was carried out on the two Braunvieh populations reared in Switzerland, the dairy Brown Swiss (BS) and the dual-purpose Original Braunvieh (OB). We performed a genome-wide analysis of array data of trios (sire, dam, and offspring) from the routine genomic selection to identify candidate regions showing missing homozygosity and phenotypic associations with five fertility, ten birth, and nine growth-related traits. In addition, genome-wide single SNP regression studies based on 114,890 single nucleotide polymorphisms (SNPs) for each of the two populations were performed. Furthermore, whole-genome sequencing data of 430 cattle including 70 putative haplotype carriers were mined to identify potential candidate variants that were validated by genotyping the current population using a custom array. Results: Using a trio-based approach, we identified 38 haplotype regions for BS and five for OB that segregated at low to moderate frequencies. For the BS population, we confirmed two known haplotypes, BH1 and BH2. Twenty-four variants that potentially explained the missing homozygosity and associated traits were detected, in addition to the previously reported TUBD1:p.His210Arg variant associated with BH2. For example, for BS we identified a stop-gain variant (p.Arg57*) in the MRPL55 gene in the haplotype region on chromosome 7. This region is associated with the ‘interval between first and last insemination’ trait in our data, and the MRPL55 gene is known to be associated with early pregnancy loss in mice. In addition, we discuss candidate missense variants in the CPT1C, MARS2, and ACSL5 genes for haplotypes mapped in BS. In OB, we highlight a haplotype region on chromosome 19, which is potentially caused by a frameshift variant (p.Lys828fs) in the LIG3 gene, which is reported to be associated with early embryonic lethality in mice. Furthermore, we propose another potential causal missense variant in the TUBGCP5 gene for a haplotype mapped in OB. Conclusions: We describe, for the first time, several haplotype regions that segregate at low to moderate frequencies and provide evidence of causality by trait associations in the two populations of Swiss Braunvieh. We propose a list of six protein-changing variants as potentially causing missing homozygosity. These variants need to be functionally validated and incorporated in the breeding program

Greedy Selfish Network Creation

We introduce and analyze greedy equilibria (GE) for the well-known model of selfish network creation by Fabrikant et al.[PODC'03]. GE are interesting for two reasons: (1) they model outcomes found by agents which prefer smooth adaptations over radical strategy-changes, (2) GE are outcomes found by agents which do not have enough computational resources to play optimally. In the model of Fabrikant et al. agents correspond to Internet Service Providers which buy network links to improve their quality of network usage. It is known that computing a best response in this model is NP-hard. Hence, poly-time agents are likely not to play optimally. But how good are networks created by such agents? We answer this question for very simple agents. Quite surprisingly, naive greedy play suffices to create remarkably stable networks. Specifically, we show that in the SUM version, where agents attempt to minimize their average distance to all other agents, GE capture Nash equilibria (NE) on trees and that any GE is in 3-approximate NE on general networks. For the latter we also provide a lower bound of 3/2 on the approximation ratio. For the MAX version, where agents attempt to minimize their maximum distance, we show that any GE-star is in 2-approximate NE and any GE-tree having larger diameter is in 6/5-approximate NE. Both bounds are tight. We contrast these positive results by providing a linear lower bound on the approximation ratio for the MAX version on general networks in GE. This result implies a locality gap of $\Omega(n)$ for the metric min-max facility location problem, where n is the number of clients.Comment: 28 pages, 8 figures. An extended abstract of this work was accepted at WINE'1