A Novel Caloric Restriction-Like Mimetic Affects Longevity in Yeast by Reprogramming Core Metabolic Pathways

Glucose limitation is a simple intervention that extends yeast replicative lifespan (RLS) via the same pathway(s) thought to mediate the benefits of caloric restriction (CR) in mammals. Here we report on “C1”, a small molecule that mimics key aspects of CR. C1 was identified in a high throughput screen for drug-like molecules that reverse the RLS shortening effect of the sirtuin inhibitor and NAD+ precursor nicotinamide. C1 reduces the cellular dependence on glycolysis and the pentose phosphate pathway, even in the presence of glucose, and compensates by elevating fatty acid -oxidation to maintain acetyl-CoA levels. C1 acts either downstream of Sir2 or in an independent CR pathway. In this regard, chemical-genetic interactions indicate that C1 influences Tor2 signaling via effects on phosphoinositide pools. Key activities of C1 extend to mammals. C1 stimulates -oxidation in mammalian cells, and in mice, reduces levels of triacylglycerides and cholesterol in livers of lean and obese mice. C1 confers oxidative resistance to diamide in both yeast and mammalian cells. In conclusion, C1 induces global changes in metabolism in yeast and mammalian cells that mimic aspects of CR. Future work will be aimed at identifying the cellular target of C1

Security Theorems via Model Theory

A model-theoretic approach can establish security theorems for cryptographic protocols. Formulas expressing authentication and non-disclosure properties of protocols have a special form. They are quantified implications for all xs . (phi implies for some ys . psi). Models (interpretations) for these formulas are *skeletons*, partially ordered structures consisting of a number of local protocol behaviors. Realized skeletons contain enough local sessions to explain all the behavior, when combined with some possible adversary behaviors. We show two results. (1) If phi is the antecedent of a security goal, then there is a skeleton A_phi such that, for every skeleton B, phi is satisfied in B iff there is a homomorphism from A_phi to B. (2) A protocol enforces for all xs . (phi implies for some ys . psi) iff every realized homomorphic image of A_phi satisfies psi. Hence, to verify a security goal, one can use the Cryptographic Protocol Shapes Analyzer CPSA (TACAS, 2007) to identify minimal realized skeletons, or "shapes," that are homomorphic images of A_phi. If psi holds in each of these shapes, then the goal holds

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Analysis of the interaction between Nvj1 and the inner nuclear membrane

Thesis (Ph. D.)--University of Rochester. Dept. of Biology, 2009.Nvj1 is an interesting yeast protein that is part of the only known apparatus for interorganelle contact, the nucleus-vacuole (NV) junction. NV junctions are essential for a novel form of autophagy known as piecemeal microautophagy of the nucleus (PMN). During PMN, both the inner nuclear membrane (INM) and the outer nuclear membrane (ONM) exvaginate into the vacuole, delivering a non-essential portion of the nucleus for degradation. The N-terminus of Nvj1 is required for strict localization to the perinuclear endoplasmic reticulum (ER). In this study I present evidence that the N-terminus of Nvj1 is anchored in the INM through a combination of a hydrophobic stretch of amino acids and flanking basic residues. To help assess genetic, physiological and environmental factors that affect PMN I developed a quantitative immunoblot assay that measures PMN throughput. To address the nature of the interaction that occurs between the Nvj1 N-terminus and the INM, I present data showing that several INM proteins do not play a role in anchoring Nvj1 to the INM. Furthermore, I show that these INM proteins are not required for efficient PMN. Our current working hypothesis is that the Nvj1 membrane anchor inserts directly into the lipid bilayer of the INM

Metabolic syndrome and serum carotenoids: Findings of a cross-sectional study in Queensland, Australia

Several components of the metabolic syndrome, particularly diabetes and cardiovascular disease, are known to be oxidative stress-related conditions and there is research to suggest that antioxidant nutrients may play a protective role in these conditions. Carotenoids are compounds derived primarily from plants and several have been shown to be potent antioxidant nutrients. The aim of this study was to examine the associations between metabolic syndrome status and major serum carotenoids in adult Australians. Data on the presence of the metabolic syndrome, based on International Diabetes Federation 2005 criteria, were collected from 1523 adults aged 25 years and over in six randomly selected urban centers in Queensland, Australia, using a cross-sectional study design. Weight, height, BMI, waist circumference, blood pressure, fasting and 2-hour blood glucose and lipids were determined, as well as five serum carotenoids. Mean serum alpha-carotene, beta-carotene and the sum of the five carotenoid concentrations were significantly lower (p<0.05) in persons with the metabolic syndrome (after adjusting for age, sex, education, BMI status, alcohol intake, smoking, physical activity status and vitamin/mineral use) than persons without the syndrome. Alpha, beta and total carotenoids also decreased significantly (p<0.05) with increased number of components of the metabolic syndrome, after adjusting for these confounders. These differences were significant among former smokers and non-smokers, but not in current smokers. Low concentrations of serum alpha-carotene, beta-carotene and the sum of five carotenoids appear to be associated with metabolic syndrome status. Additional research, particularly longitudinal studies, may help to determine if these associations are causally related to the metabolic syndrome, or are a result of the pathologies of the syndrome

Lifespan extending properties of Kalanchoe daigremontiana plant extracts in Saccharomyces cerevisiae

Kalanchoe daigremontiana, commonly known as mother of thousands and the alligator plant, is a traditional remedy that has been used in various countries to treat inflammation and related disorders. The long-standing use of this plant makes it a promising candidate for the discovery of new anti-inflammatory and anti-aging compounds. Varying concentrations of K. daigremontiana extract (water (H2O), hexane (Hex), methanol (MeOH), chloroform (CHCl3) and ethyl acetate (EtOAc)) were tested on Saccharomyces cerevisiae and the yeast were tolerant of all extract concentrations examined. The extracts were then tested for lifespan altering effects in yeast utilizing the growth-based lifespan measuring DeaD (Death of Daughters) assay. It was found that each extract under multiple concentrations increased replicative lifespan. Furthermore, extracts from the EtOAc extract were able to overcome the powerful lifespan shortening effects of the sirtuin inhibitor nicotinamide. The increase in yeast lifespan with the addition of these extracts, indicates the value of K. daigremontiana in the study of lifespan and the potential for the development of drugs to combat age-related disease, inflammation and to extend healthspan/ lifespan

A Novel Caloric Restriction-Like Mimetic Affects Longevity in Yeast by Reprogramming Core Metabolic Pathways

Glucose limitation is a simple intervention that extends yeast replicative lifespan (RLS) via the same pathway(s) thought to mediate the benefits of caloric restriction (CR) in mammals. Here we report on “C1”, a small molecule that mimics key aspects of CR. C1 was identified in a high throughput screen for drug-like molecules that reverse the RLS shortening effect of the sirtuin inhibitor and NAD+ precursor nicotinamide. C1 reduces the cellular dependence on glycolysis and the pentose phosphate pathway, even in the presence of glucose, and compensates by elevating fatty acid -oxidation to maintain acetyl-CoA levels. C1 acts either downstream of Sir2 or in an independent CR pathway. In this regard, chemical-genetic interactions indicate that C1 influences Tor2 signaling via effects on phosphoinositide pools. Key activities of C1 extend to mammals. C1 stimulates -oxidation in mammalian cells, and in mice, reduces levels of triacylglycerides and cholesterol in livers of lean and obese mice. C1 confers oxidative resistance to diamide in both yeast and mammalian cells. In conclusion, C1 induces global changes in metabolism in yeast and mammalian cells that mimic aspects of CR. Future work will be aimed at identifying the cellular target of C1

Whose hearts and whose minds? The curious case of global counter-insurgency

Traditionally regarded as a secondary activity in military thinking and practice, the notion of counter-insurgency (COIN) has undergone a remarkable renaissance. This analysis traces the origins of this renaissance to two distinctive schools: a neo-classical school and a global insurgency school. The global insurgency school critiques neo-classical thought and presents itself as a more sophisticated appreciation of current security problems. An examination of the evolution of these two schools of counter-insurgency reveals how the interplay between them ultimately leaves us with a confused and contradictory understanding of the phenomenon of insurgency and the policies and strategies necessary to combat it

The Transcription Factor Encyclopedia

Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe .Medical Genetics, Department ofMedicine, Faculty ofMolecular Medicine and Therapeutics, Centre forScience, Faculty ofNon UBCReviewedFacult