Chemical activation of a food deprivation signal extends lifespan

Model organisms subject to dietary restriction (DR) generally live longer. Accompanying this lifespan extension are improvements in overall health, based on multiple metrics. This indicates that pharmacological treatments that mimic the effects of DR could improve health in humans. To find new chemical structures that extend lifespan, we screened 30 000 synthetic, diverse drug-like chemicals in Caenorhabditis elegans and identified several structurally related compounds that acted through DR mechanisms. The most potent of these NP1 impinges upon a food perception pathway by promoting glutamate signaling in the pharynx. This results in the overriding of a GPCR pathway involved in the perception of food and which normally acts to decrease glutamate signals. Our results describe the activation of a dietary restriction response through the pharmacological masking of a novel sensory pathway that signals the presence of food. This suggests that primary sensory pathways may represent novel targets for human pharmacology

Amyotrophic lateral sclerosis alters the metabolic aging profile in patient derived fibroblasts

Aging is a major risk factor for neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). As metabolic alterations are a hallmark of aging and have previously been observed in ALS, it is important to examine the effect of aging in the context of ALS metabolic function. Here, using a newly established phenotypic metabolic approach, we examined the effect of aging on the metabolic profile of fibroblasts derived from ALS cases compared to controls. We found that ALS fibroblasts have an altered metabolic profile, which is influenced by age. In control cases, we found significant increases with age in NADH metabolism in the presence of several metabolites including lactic acid, trehalose, uridine and fructose, which was not recapitulated in ALS cases. Conversely, we found a reduction of NADH metabolism with age of biopsy, age of onset and age of death in the presence of glycogen in the ALS cohort. Furthermore, we found that NADH production correlated with disease progression rates in relation to a number of metabolites including inosine and α-ketoglutaric acid. Inosine or α-ketoglutaric acid supplementation in ALS fibroblasts was bioenergetically favourable. Overall, we found aging related defects in energy substrates that feed carbon into glycolysis at various points as well as the tricarboxylic acid (TCA) cycle in ALS fibroblasts, which was validated in induced neuronal progenitor cell derived iAstrocytes. Our results suggest that supplementing those pathways may protect against age related metabolic dysfunction in ALS

Minor-minimal non-projective planar graphs with an internal 3-separation

The property that a graph has an embedding in the projective plane is closed under taking minors. Thus by the well known Graph Minor theorem of Robertson and Seymour, there exists a finite list of minor-minimal graphs, call it L, such that a given graph G is projective planar if and only if G does not contain any graph isomorphic to a member of L as a minor. Glover, Huneke and Wang found 35 graphs in L, and Archdeacon proved that those are all the members of L, but Archdeacon's proof never appeared in any refereed journal. In this thesis we develop a modern approach and technique for finding the list L, independent of previous work. Our approach is based on conditioning on the connectivity of a member of L. Assume G is a member of L. If G is not 3-connected then the structure of G is well understood. In the case that G is 3-connected, the problem breaks down into two main cases, either G has an internal separation of order three or G is internally 4-connected. In this thesis we find the set of all 3-connected minor minimal non-projective planar graphs with an internal 3-separation. For proving our main result, we use a technique which can be considered as a variation and generalization of the method that Robertson, Seymour and Thomas used for non-planar extension of planar graphs. Using this technique, besides our main result, we also classify the set of minor minimal obstructions for a-, ac-, abc-planarity for rooted graphs. (A rooted graph (G,a,b,c) is a-planar if there exists a split of the vertex a to a' and a' in G such that the new graph G' obtained by the split has an embedding in a disk such that the vertices a', b, a', c are on the boundary of the disk in the order listed. We define b- and c-planarity analogously. We say that the rooted graph (G,a,b,c) is ab-planar if it is a-planar or b-planar, and we define abc-planarity analogously.)PhDCommittee Chair: Thomas, Robin; Committee Member: Cook, William; Committee Member: Tetali, Prasad; Committee Member: Trotter, William; Committee Member: Yu, Xingxin

The role of vitamin D in the age of COVID-19: A systematic review and meta-analysis

Background: Evidence recommends that vitamin D might be a crucial supportive agent for the immune system, mainly in cytokine response regulation against COVID-19. Hence, we carried out a systematic review and meta-analysis in order to maximise the use of everything that exists about the role of vitamin D in the COVID-19. Methods: A systematic search was performed in PubMed, Scopus, Embase and Web of Science up to December 18, 2020. Studies focused on the role of vitamin D in confirmed COVID-19 patients were entered into the systematic review. Results: Twenty-three studies containing 11 901 participants entered into the meta-analysis. The meta-analysis indicated that 41 of COVID-19 patients were suffering from vitamin D deficiency (95 CI, 29-55), and in 42 of patients, levels of vitamin D were insufficient (95 CI, 24-63). The serum 25-hydroxyvitamin D concentration was 20.3 ng/mL among all COVID-19 patients (95 CI, 12.1-19.8). The odds of getting infected with SARS-CoV-2 are 3.3 times higher among individuals with vitamin D deficiency (95 CI, 2.5-4.3). The chance of developing severe COVID-19 is about five times higher in patients with vitamin D deficiency (OR: 5.1, 95 CI, 2.6-10.3). There is no significant association between vitamin D status and higher mortality rates (OR: 1.6, 95 CI, 0.5-4.4). Conclusion: This study found that most of the COVID-19 patients were suffering from vitamin D deficiency/insufficiency. Also, there is about three times higher chance of getting infected with SARS-CoV-2 among vitamin-D-deficient individuals and about five times higher probability of developing the severe disease in vitamin-D-deficient patients. Vitamin D deficiency showed no significant association with mortality rates in this population. © 2021 John Wiley & Sons Lt