Functional Variation In The Mitochondrial Genome Of The Yeast Saccharomyces Cerevisiae

Mitochondrial haplotypes contribute to functional diversity in natural populations. Uniparental inheritance makes it difficult to characterize the genetic architecture of mitochondrially driven phenotypes. In this work I explored the natural diversity of mitochondrial genomes in the yeast Saccharomyces cerevisiae. Few complete mitochondrial genomes were available for S. cerevisiae owing to challenges in high-throughput sequencing. I developed sequencing strategies using new technologies to generate complete high quality yeast mitochondrial genomes. Comparisons of 100 complete yeast mitochondrial genomes demonstrated extensive variation between populations in coding sequences and variable introns. I demonstrated that these mitochondrial variants directly caused growth differences in strains with isogenic nuclear genomes but divergent mitochondrial genomes. Synthetic mitochondrial-nuclear combinations generally performed worse than coadapted combinations, consistent with mitonuclear coevolution. Using mitochondrial recombination that naturally occurs in S. cerevisiae I showed that the genetic architecture of these growth differences is complex and likely due to multiple loci. Mitochondrial recombinants showed poor growth in ecologically relevant conditions consistent with negative epistasis between mitochondrial loci (mito-mito epistasis). I generated recombinants between mitotypes from various populations and found significant estimates of mito-mito epistasis affecting growth that were more frequently negative in sign. Crosses between mitotypes from divergent populations also negative impacted fitness through the generation of progeny that cannot respire. Negative mito-mito epistasis may act in concert with mitochondrial-nuclear epistasis as a post-zygotic barrier contributing to speciation. I attempted to map mitochondrial variants that confer temperature dependent growth advantages through two methods. Using a bulk segregant approach I created large pools of mitochondrial recombinants and sequenced these pools before and after selection for high temperature growth to determine shifts in allele frequencies in response to selection. The sequencing pools showed evidence of low levels of recombination which were inconsistent with evidence of recombination events in sequencing reads. Simulations of recombination better support a low rate of recombination in the data. I also endeavored to map functional mitochondrial variants by identifying regions of the mitochondrial genome remaining after large deletions that still contained causative alleles. I did not identify a causative region but found evidence that several regions likely do not contain the causative site. The analyses presented here did not identify a causative site but did narrow the range of possibilities and showed that the rate of mitochondrial DNA recombination in S. cerevisiae is lower than prior estimates

Fiscal consolidation strategy: An update for the budget reform proposal of march 2013

Recently, we evaluated a fiscal consolidation strategy for the United States that would bring the government budget into balance by gradually reducing government spending relative to GDP to the ratio that prevailed prior to the crisis (Cogan et al, JEDC 2013). Specifically, we published an analysis of the macroeconomic consequences of the 2013 Budget Resolution that was passed by the U.S. House of Representatives in March 2012. In this note, we provide an update of our research that evaluates this year’s budget reform proposal that is to be discussed and voted on in the House of Representative in March 2013. Contrary to the views voiced by critics of fiscal consolidation, we show that such a reduction in government purchases and transfer payments can increase GDP immediately and permanently relative to a policy without spending restraint. Our research makes use of a modern structural model of the economy that incorporates the long-standing essential features of economics: opportunity costs, efficiency, foresight and incentives. GDP rises because households take into account that spending restraint helps avoid future increases in tax rates. Lower taxes imply less distorted incentives for work, investment and production relative to a scenario without fiscal consolidation and lead to higher growth

Fiscal consolidation strategy : [Version 21 September 2012]

In the aftermath of the global financial crisis and great recession, many countries face substantial deficits and growing debts. In the United States, federal government outlays as a ratio to GDP rose substantially from about 19.5 percent before the crisis to over 24 percent after the crisis. In this paper we consider a fiscal consolidation strategy that brings the budget to balance by gradually reducing this spending ratio over time to the level that prevailed prior to the crisis. A crucial issue is the impact of such a consolidation strategy on the economy. We use structural macroeconomic models to estimate this impact focussing primarily on a dynamic stochastic general equilibrium model with price and wage rigidities and adjustment costs. We separate out the impact of reductions in government purchases and transfers, and we allow for a reduction in both distortionary taxes and government debt relative to the baseline of no consolidation. According to the model simulations GDP rises in the short run upon announcement and implementation of this fiscal consolidation strategy and remains higher than the baseline in the long run. We explore the role of the mix of expenditure cuts and tax reductions as well as gradualism in achieving this policy outcome. Finally, we conduct sensitivity studies regarding the type of model used and its parameterization

Fiscal consolidation strategy

In the aftermath of the global financial crisis and great recession, many countries face substantial deficits and growing debts. In the United States, federal government outlays as a ratio to GDP rose substantially from about 19.5 percent before the crisis to over 24 percent after the crisis. In this paper we consider a fiscal consolidation strategy that brings the budget to balance by gradually reducing this spending ratio over time to the level that prevailed prior to the crisis. A crucial issue is the impact of such a consolidation strategy on the economy. We use structural macroeconomic models to estimate this impact focussing primarily on a dynamic stochastic general equilibrium model with price and wage rigidities and adjustment costs. We separate out the impact of reductions in government purchases and transfers, and we allow for a reduction in both distortionary taxes and government debt relative to the baseline of no consolidation. According to the model simulations GDP rises in the short run upon announcement and implementation of this fiscal consolidation strategy and remains higher than the baseline in the long run. We explore the role of the mix of expenditure cuts and tax reductions as well as gradualism in achieving this policy outcome. Finally, we conduct sensitivity studies regarding the type of model used and its parameterization

Towards Hybrid Architectures: Integrating Large Language Models in Informative Chatbots

Informative chatbots embedded in an organization-specific context can provide a reliable, interactive, and engaging source of information for users. However, traditional chatbot techniques have limitations in processing and understanding user input and generating human-like responses. On the other hand, the latest implementations of large language models show promising results in these domains but have limitations in providing accurate and up-to-date facts from domain-specific knowledge bases. With the advent of popular chatbots like ChatGPT, they are increasingly becoming part of organizations\u27 digital infrastructure. In this research-in-progress paper, we argue that the strengths and weaknesses of traditional techniques and large language models are complementary. Therefore, we propose a hybrid chatbot architecture that utilizes inter-agent communication to compensate for disadvantages while enhancing the chatbot\u27s abilities, as perceived by the user. This approach will form the basis for development and evaluation using Design Science Research (DSR) as part of our research

Population structure of mitochondrial genomes in Saccharomyces cerevisiae

Background: Rigorous study of mitochondrial functions and cell biology in the budding yeast, Saccharomyces cerevisiae has advanced our understanding of mitochondrial genetics. This yeast is now a powerful model for population genetics, owing to large genetic diversity and highly structured populations among wild isolates. Comparative mitochondrial genomic analyses between yeast species have revealed broad evolutionary changes in genome organization and architecture. A fine-scale view of recent evolutionary changes within S. cerevisiae has not been possible due to low numbers of complete mitochondrial sequences. Results: To address challenges of sequencing AT-rich and repetitive mitochondrial DNAs (mtDNAs), we sequenced two divergent S. cerevisiae mtDNAs using a single-molecule sequencing platform (PacBio RS). Using de novo assemblies, we generated highly accurate complete mtDNA sequences. These mtDNA sequences were compared with 98 additional mtDNA sequences gathered from various published collections. Phylogenies based on mitochondrial coding sequences and intron profiles revealed that intraspecific diversity in mitochondrial genomes generally recapitulated the population structure of nuclear genomes. Analysis of intergenic sequence indicated a recent expansion of mobile elements in certain populations. Additionally, our analyses revealed that certain populations lacked introns previously believed conserved throughout the species, as well as the presence of introns never before reported in S. cerevisiae. Conclusions: Our results revealed that the extensive variation in S. cerevisiae mtDNAs is often population specific, thus offering a window into the recent evolutionary processes shaping these genomes. In addition, we offer an effective strategy for sequencing these challenging AT-rich mitochondrial genomes for small scale projects

Electromagnetic Simulation and Design of a Novel Waveguide RF Wien Filter for Electric Dipole Moment Measurements of Protons and Deuterons

The conventional Wien filter is a device with orthogonal static magnetic and electric fields, often used for velocity separation of charged particles. Here we describe the electromagnetic design calculations for a novel waveguide RF Wien filter that will be employed to solely manipulate the spins of protons or deuterons at frequencies of about 0.1 to 2 MHz at the COoler SYnchrotron COSY at J\"ulich. The device will be used in a future experiment that aims at measuring the proton and deuteron electric dipole moments, which are expected to be very small. Their determination, however, would have a huge impact on our understanding of the universe.Comment: 10 pages, 10 figures, 4 table

E2 properties of nuclei far from stability and the proton-halo problem of 8B

E2 properties of A=6--10 nuclei, including those of nuclei far from stability, are studied by a $(0+2)\hbar\omega$ shell-model calculation which includes E2 core-polarization effects explicitly. The quadrupole moments and the E2 transition strengths in A=6--10 nuclei are described quite well by the present calculation. This result indicates that the relatively large value of the quadrupole moment of $^8$B can be understood without introducing the proton-halo in $^8$B. An interesting effect of the $2\hbar\omega$ core-polarization is found for effective charges used in the $0\hbar\omega$ shell model; although isoscalar effective-charges are almost constant as a function of nucleus, appreciable variations are needed for isovector effective-charges which play important roles in nuclei with high isospin-values.Comment: (LaTeX, 23 pages