Stretched Strings in Noncommutative Field Theory

Motivated by recent discussions of IR/UV mixing in noncommutative field theories, we perform a detailed analysis of the non-planar amplitudes of the bosonic open string in the presence of an external B-field at the one-loop level. We carefully isolate, at the string theory level, the contribution which is responsible for the IR/UV behavior in the field theory limit. We show that it is a pure open string effect by deriving it from the factorization of the one-loop amplitude into the disk amplitudes of intermediate open string insertions. We suggest that it is natural to understand IR/UV mixing as the creation of intermediate ``stretched strings''.Comment: 20 pages AMSLaTeX using JHEP.cls, 6 eps figures. Typos corrected and references adde

Deletion of the Mitochondrial Superoxide Dismutase sod-2 Extends Lifespan in Caenorhabditis elegans

The oxidative stress theory of aging postulates that aging results from the accumulation of molecular damage caused by reactive oxygen species (ROS) generated during normal metabolism. Superoxide dismutases (SODs) counteract this process by detoxifying superoxide. It has previously been shown that elimination of either cytoplasmic or mitochondrial SOD in yeast, flies, and mice results in decreased lifespan. In this experiment, we examine the effect of eliminating each of the five individual sod genes present in Caenorhabditis elegans. In contrast to what is observed in other model organisms, none of the sod deletion mutants shows decreased lifespan compared to wild-type worms, despite a clear increase in sensitivity to paraquat- and juglone-induced oxidative stress. In fact, even mutants lacking combinations of two or three sod genes survive at least as long as wild-type worms. Examination of gene expression in these mutants reveals mild compensatory up-regulation of other sod genes. Interestingly, we find that sod-2 mutants are long-lived despite a significant increase in oxidatively damaged proteins. Testing the effect of sod-2 deletion on known pathways of lifespan extension reveals a clear interaction with genes that affect mitochondrial function: sod-2 deletion markedly increases lifespan in clk-1 worms while clearly decreasing the lifespan of isp-1 worms. Combined with the mitochondrial localization of SOD-2 and the fact that sod-2 mutant worms exhibit phenotypes that are characteristic of long-lived mitochondrial mutants—including slow development, low brood size, and slow defecation—this suggests that deletion of sod-2 extends lifespan through a similar mechanism. This conclusion is supported by our demonstration of decreased oxygen consumption in sod-2 mutant worms. Overall, we show that increased oxidative stress caused by deletion of sod genes does not result in decreased lifespan in C. elegans and that deletion of sod-2 extends worm lifespan by altering mitochondrial function

List of ATFS-1 targets

mitochondrial Unfolded Protein Response ATFS-1 targetsRelated Publication:</p> High confidence ATFS-1 target genes for quantifying activation of the mitochondrial unfolded protein response</p> Van Raamsdonk, Jeremy 1 Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada 2 Metabolic Disorders and Complications Program, and Brain Repair and Integrative Neuroscience Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada 3 Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, Quebec, Canada 4 Department of Genetics, Harvard Medical School, Boston, MA, USA</p> microPublication Biology</p> 2021-09-27</p> https://doi.org/10.17912/micropub.biology.000484</p>engContact person: Van Raamsdonk, Jeremy [email protected]

Characterization and treatment of mouse models of Huntington disease

Huntington disease (HD) is an adult onset neurodegenerative disorder that is characterized by motor dysfunction, cognitive impairment and neuropsychiatric disturbances. HD patients exhibit progressive and selective neurodegeneration primarily in the striatum and cortex. There is currently no treatment that can prevent the development of HD or alter its progression. The major objectives of this thesis were to determine which symptoms of HD are recapitulated in Y A C transgenic mouse models of the disease, to develop a standardized protocol for therapeutic trials in these mice and to investigate potential treatments for HD. Two transgenic mouse models of HD were examined that express huntingtin (htt) with either 72 (YAC72 mice) or 128 (YAC128 mice) glutamines from a yeast artificial chromosome transgene. While YAC72 mice exhibit a mild phenotype, YAC128 mice show quantifiable abnormalities that recapitulate the motor and cognitive deficits in HD. Importantly, YAC128 mice also exhibit selective and progressive degeneration in the brain, including neuronal loss. To determine the feasibility of genetic modulation of the disease phenotype, we investigated the ability of over-expression of wild type htt to prevent striatal neuropathology in YAC128 mice based on a putative pro-survival function of wild type htt. We demonstrate for the first time that wild type htt is neuroprotective in the brain. In YAC128 mice, over-expression of wild type htt prevented atrophy of striatal neurons(but did not significantly improve striatal volume or striatal neuronal numbers. To determine the feasibility of pharmacologic therapeutic trials in YAC128 mice we treated mice with cystamine, a transglutaminase inhibitor with other beneficial characteristics. While cystamine treatment did not improve motor symptoms, this treatment ameliorated striatal volume loss, striatal neuronal loss and striatal neuronal atrophy. This trial validates the use of YAC128 mice in therapeutic trials for HD as we reproduced all of the differences between YAC128 and WT mice in this therapeutic trial. Overall, this thesis demonstrates that the YAC128 mouse model of HD recapitulates the progressive motor dysfunction, cognitive deficits and selective neurodegeneration of HD. As such, these mice can be used for studies of HD pathogenesis and in preclinical therapeutic trials for HD.Medicine, Faculty ofMedical Genetics, Department ofGraduat

Evolutionarily Conserved Role of Thioredoxin Systems in Determining Longevity

Thioredoxin and thioredoxin reductase are evolutionarily conserved antioxidant enzymes that protect organisms from oxidative stress. These proteins also play roles in redox signaling and can act as a redox-independent cellular chaperone. In most organisms, there is a cytoplasmic and mitochondrial thioredoxin system. A number of studies have examined the role of thioredoxin and thioredoxin reductase in determining longevity. Disruption of either thioredoxin or thioredoxin reductase is sufficient to shorten lifespan in model organisms including yeast, worms, flies and mice, thereby indicating conservation across species. Similarly, increasing the expression of thioredoxin or thioredoxin reductase can extend longevity in multiple model organisms. In humans, there is an association between a specific genetic variant of thioredoxin reductase and lifespan. Overall, the cytoplasmic and mitochondrial thioredoxin systems are both important for longevity

RNA Sequencing of Pooled Samples Effectively Identifies Differentially Expressed Genes

Analysis of gene expression changes across the genome provides a powerful, unbiased tool for gaining insight into molecular mechanisms. We have effectively used RNA sequencing to identify differentially expressed genes in long-lived genetic mutants in C. elegans to advance our understanding of the genetic pathways that control longevity. Although RNA sequencing costs have come down, cost remains a barrier to examining multiple strains and time points with a sufficient number of biological replicates. To circumvent this, we have examined the efficacy of identifying differentially expressed genes by sequencing a pooled RNA sample from long-lived isp-1 mitochondrial mutant worms. We found that sequencing a pooled RNA sample could effectively identify genes that were found to be significantly upregulated in the two individually sequenced RNA-seq experiments. Finally, we compared the genes significantly upregulated in the two individually sequenced RNA-seq experiments to two previous microarray experiments to come up with a high-confidence list of modulated genes in long-lived isp-1 mutant worms. Overall, this work demonstrates that RNA sequencing of pooled RNA samples can be used to identify differentially expressed genes

Endosomal trafficking protein TBC-2 is required for the longevity of long-lived mitochondrial mutants

Mutations that result in a mild impairment of mitochondrial function can extend longevity. Previous studies have shown that the increase in lifespan is dependent on stress responsive transcription factors, including DAF-16/FOXO, which exhibits increased nuclear localization in long-lived mitochondrial mutants. We recently found that the localization of DAF-16 within the cell is dependent on the endosomal trafficking protein TBC-2. Based on the important role of DAF-16 in both longevity and resistance to stress, we examined the effect of disrupting tbc-2 on lifespan and stress resistance in the long-lived mitochondrial mutants nuo-6 and isp-1 in Caenorhabditis elegans. Loss of tbc-2 markedly reduced the long lifespans of both mitochondrial mutants. Disruption of tbc-2 also decreased resistance to chronic oxidative stress in nuo-6 and isp-1 mutants but had little or no detrimental effect on resistance to other stressors. In contrast, tbc-2 inhibition had no effect on oxidative stress resistance or lifespan in isp-1 worms when DAF-16 is absent, suggesting that the effect of tbc-2 on mitochondrial mutant lifespan may be mediated by mislocalization of DAF-16. However, this result is complicated by the fact that deletion of daf-16 markedly decreases both phenotypes in isp-1 worms, which could result in a floor effect. In exploring the contribution of DAF-16 further, we found that disruption of tbc-2 did not affect the nuclear localization of DAF-16 in isp-1 worms or prevent the upregulation of DAF-16 target genes in the long-lived mitochondrial mutants. This suggests the possibility that the effect of tbc-2 on lifespan and stress resistance in the long-lived mitochondrial mutants is at least partially independent of its effects on DAF-16 localization. Overall, this work demonstrates the importance of endosomal trafficking for the extended longevity and enhanced stress resistance resulting from mild impairment of mitochondrial function

Wild-type huntingtin ameliorates striatal neuronal atrophy but does not prevent other abnormalities in the YAC128 mouse model of Huntington disease

Background. Huntington disease (HD) is an adult onset neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin (htt) protein. Htt function is essential for embryonic survival as well as normal function during the postnatal period. In addition to having roles in transcription and transport, recent evidence demonstrates that wild-type htt is neuroprotective in vivo. To determine whether treatment with wild-type htt would be beneficial in HD, we crossed the YAC128 mouse model of HD with mice that over-express wild-type htt (YAC18 mice) to generate YAC128 mice that over-express wild-type htt (YAC18/128 mice). Results YAC18/128 mice were found to express mutant htt at the same level as YAC128 mice and wild-type htt at the same level as YAC18 mice. YAC18/128 mice show no significant behavioural improvement compared to YAC128 mice in the rotarod test of motor coordination or in an automated open field test. In the brain, YAC18/128 mice show no significant improvement in striatal volume, striatal neuronal numbers or striatal DARPP-32 expression compared to YAC128 mice. In contrast, striatal neuronal cross-sectional area showed significant improvement in YAC18/128 mice compared to YAC128 mice. Conclusion While the over-expression of wild-type htt results in a mild improvement in striatal neuropathology in YAC128 mice, our findings suggest that treatment with wild-type htt may not be sufficient to ameliorate the symptoms of HD in this model.Medical Genetics, Department ofMedicine, Faculty ofMolecular Medicine and Therapeutics, Centre forNon UBCReviewedFacult