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Guy Zinman

Bio: Guy Zinman is an academic researcher from Carnegie Mellon University. The author has contributed to research in topics: Gene & Innate immune system. The author has an hindex of 7, co-authored 7 publications receiving 918 citations.

Papers
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Journal ArticleDOI
08 Mar 2012-Nature
TL;DR: Male, but not female, transgenic mice overexpressing Sirt6 have a significantly longer lifespan than wild-type mice, and has important therapeutic implications for age-related diseases.
Abstract: The significant increase in human lifespan during the past century confronts us with great medical challenges. To meet these challenges, the mechanisms that determine healthy ageing must be understood and controlled. Sirtuins are highly conserved deacetylases that have been shown to regulate lifespan in yeast, nematodes and fruitflies. However, the role of sirtuins in regulating worm and fly lifespan has recently become controversial. Moreover, the role of the seven mammalian sirtuins, SIRT1 to SIRT7 (homologues of the yeast sirtuin Sir2), in regulating lifespan is unclear. Here we show that male, but not female, transgenic mice overexpressing Sirt6 (ref. 4) have a significantly longer lifespan than wild-type mice. Gene expression analysis revealed significant differences between male Sirt6-transgenic mice and male wild-type mice: transgenic males displayed lower serum levels of insulin-like growth factor 1 (IGF1), higher levels of IGF-binding protein 1 and altered phosphorylation levels of major components of IGF1 signalling, a key pathway in the regulation of lifespan. This study shows the regulation of mammalian lifespan by a sirtuin family member and has important therapeutic implications for age-related diseases.

877 citations

Journal ArticleDOI
TL;DR: This work collected comprehensive high-throughput interaction datasets for four model organisms and carried out systematic analyses to explain the apparent lower conservation of interaction data when compared to the conservation of sequence data, showing that conservation is maintained between species, but mainly at the module level.
Abstract: Orthologous genes are highly conserved between closely related species and biological systems often utilize the same genes across different organisms. However, while sequence similarity often implies functional similarity, interaction data is not well conserved even for proteins with high sequence similarity. Several recent studies comparing high throughput data including expression, protein-protein, protein-DNA, and genetic interactions between close species show conservation at a much lower rate than expected. In this work we collected comprehensive high-throughput interaction datasets for four model organisms (S. cerevisiae, S. pombe, C. elegans, and D. melanogaster) and carried out systematic analyses in order to explain the apparent lower conservation of interaction data when compared to the conservation of sequence data. We first showed that several previously proposed hypotheses only provide a limited explanation for such lower conservation rates. We combined all interaction evidences into an integrated network for each species and identified functional modules from these integrated networks. We then demonstrate that interactions that are part of functional modules are conserved at much higher rates than previous reports in the literature, while interactions that connect between distinct functional modules are conserved at lower rates. We show that conservation is maintained between species, but mainly at the module level. Our results indicate that interactions within modules are much more likely to be conserved than interactions between proteins in different modules. This provides a network based explanation to the observed conservation rates that can also help explain why so many biological processes are well conserved despite the lower levels of conservation for the interactions of proteins participating in these processes. Accompanying website: http://www.sb.cs.cmu.edu/CrossSP

47 citations

Journal ArticleDOI
TL;DR: It is found that only Saccharomyces becomes more azole resistant in ergosterol-supplemented media; that this depends on sterol importers Aus1 and Pdr11; and that transgenic expression of sterolImporters in Kluyveromyces alleviates its drug sensitivity.
Abstract: Fungal infections are an emerging health risk, especially those involving yeast that are resistant to antifungal agents. To understand the range of mechanisms by which yeasts can respond to anti-fungals, we compared gene expression patterns across three evolutionarily distant species - Saccharomyces cerevisiae, Candida glabrata and Kluyveromyces lactis - over time following fluconazole exposure. Conserved and diverged expression patterns were identified using a novel soft clustering algorithm that concurrently clusters data from all species while incorporating sequence orthology. The analysis suggests complementary strategies for coping with ergosterol depletion by azoles - Saccharomyces imports exogenous ergosterol, Candida exports fluconazole, while Kluyveromyces does neither, leading to extreme sensitivity. In support of this hypothesis we find that only Saccharomyces becomes more azole resistant in ergosterol-supplemented media; that this depends on sterol importers Aus1 and Pdr11; and that transgenic expression of sterol importers in Kluyveromyces alleviates its drug sensitivity. We have compared the dynamic transcriptional responses of three diverse yeast species to fluconazole treatment using a novel clustering algorithm. This approach revealed significant divergence among regulatory programs associated with fluconazole sensitivity. In future, such approaches might be used to survey a wider range of species, drug concentrations and stimuli to reveal conserved and divergent molecular response pathways.

36 citations

Journal ArticleDOI
TL;DR: This work developed ExpressionBlast, a computational method that uses automated text analysis to identify and merge replicates and determine the type of each array in the series, which allowed us to create the largest collection of computationally annotated expression data currently available.
Abstract: The uniform processing of the data allows users to compare a query from their own new experiments (Fig. 1c) with GEO data from the same or different species, using one of several supported distance functions including Euclidean, correlation and negative correlation (Supplementary Fig. 2). The resulting matches are displayed as a heat map and analyzed to determine the significance of the match (Fig. 1d). Additional information for matches, including publication abstracts, significant common keywords selected from a predefined compendium of words (Supplementary Results) and enrichment for GO categories, is also provided (Fig. 1e). For cross-species comparisons, we use ExpressionBlast: mining large, unstructured expression databases To the Editor: The amount of gene expression data deposited in public repositories has grown exponentially over the last decade (Supplementary Fig. 1). Specifically, Gene Expression Omnibus (GEO)1 is one of largest expression-data repositories (Supplementary Table 1), containing hundreds of thousands of microarray and RNA-seq experiment results grouped into tens of thousands of series. Although accessible, data deposited in GEO are not well organized. Even among data sets for a single species there are many different platforms with different probe identifiers, different value scales and very limited annotations of the condition profiled by each array. Current methods for using GEO data to study signaling and other cellular networks either do not scale or cannot fully use the available information (Supplementary Table 2 and Supplementary Results). To enable quer ies of such l arge expression databases, we developed ExpressionBlast (http://www.expression. cs.cmu.edu/): a computational method that uses automated text analysis to identify and merge replicates and determine the type of each array in the series (treatment or control; Fig. 1a and Supplementary Methods) . Using this information, ExpressionBlast uniformly processes expression data sets in GEO across all experiments, species and platforms. This is achieved by standardizing the data in terms of gene identifiers, the meaning of the expression values (log ratios) and the distribution of these values (Fig. 1b and Supplementary Methods). Our processing steps achieved a high accuracy in identifying replicates and treatment control cases (Supplementary Results and Supplementary Table 3). We applied these processing steps to arrays from more than 900,000 individual samples collected from >40,000 studies in GEO (new series are updated on a weekly basis), which allowed us to create, to our knowledge, the largest collection of computationally annotated expression data currently available (Supplementary Results and Supplementary Table 4). rep3 rep1

36 citations

Journal ArticleDOI
18 Jul 2011-PLOS ONE
TL;DR: A core set of genes, activated in both species and across all pathogens that were predominantly part of the interferon response pathway were identified and identified similarities across species in the way innate immune cells respond to lethal versus non-lethal pathogens.
Abstract: Viral and bacterial infections of the lower respiratory tract are major causes of morbidity and mortality worldwide. Alveolar macrophages line the alveolar spaces and are the first cells of the immune system to respond to invading pathogens. To determine the similarities and differences between the responses of mice and macaques to invading pathogens we profiled alveolar macrophages from these species following infection with two viral (PR8 and Fuj/02 influenza A) and two bacterial (Mycobacterium tuberculosis and Francisella tularensis Schu S4) pathogens. Cells were collected at 6 time points following each infection and expression profiles were compared across and between species. Our analyses identified a core set of genes, activated in both species and across all pathogens that were predominantly part of the interferon response pathway. In addition, we identified similarities across species in the way innate immune cells respond to lethal versus non-lethal pathogens. On the other hand we also found several species and pathogen specific response patterns. These results provide new insights into mechanisms by which the innate immune system responds to, and interacts with, invading pathogens.

25 citations


Cited by
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Journal ArticleDOI
06 Jun 2013-Cell
TL;DR: Nine tentative hallmarks that represent common denominators of aging in different organisms are enumerated, with special emphasis on mammalian aging, to identify pharmaceutical targets to improve human health during aging, with minimal side effects.

9,980 citations

Journal ArticleDOI
TL;DR: This review summarizes how NAD(+) metabolism links energy status with adaptive cellular and organismal responses and how this knowledge can be therapeutically exploited.

1,061 citations

Journal ArticleDOI
TL;DR: The combination of sirtuin activation and NAD(+) intermediate supplementation may be an effective antiaging intervention, providing hope to aging societies worldwide.

907 citations

Journal ArticleDOI
04 Dec 2015-Science
TL;DR: Factors that regulate NAD+ and how supplementation with NAD+ precursors may represent a new therapeutic opportunity for aging and its associated disorders, particularly neurodegenerative diseases are reviewed.
Abstract: Nicotinamide adenine dinucleotide (NAD + ) is a coenzyme found in all living cells. It serves both as a critical coenzyme for enzymes that fuel reduction-oxidation reactions, carrying electrons from one reaction to another, and as a cosubstrate for other enzymes such as the sirtuins and poly(adenosine diphosphate–ribose) polymerases. Cellular NAD + concentrations change during aging, and modulation of NAD + usage or production can prolong both health span and life span. Here we review factors that regulate NAD + and discuss how supplementation with NAD + precursors may represent a new therapeutic opportunity for aging and its associated disorders, particularly neurodegenerative diseases.

837 citations

Journal ArticleDOI
TL;DR: SIRT1 plays a critical role in metabolic health by deacetylating many target proteins in numerous tissues, including liver, muscle, adipose tissue, heart, and endothelium.
Abstract: Sirtuins such as SIRT1 are conserved protein NAD(+)-dependent deacylases and thus their function is intrinsically linked to cellular metabolism. Over the past two decades, accumulating evidence has indicated that sirtuins are not only important energy status sensors but also protect cells against metabolic stresses. Sirtuins regulate the aging process and are themselves regulated by diet and environmental stress. The versatile functions of sirtuins including, more specifically, SIRT1 are supported by their diverse cellular location allowing cells to sense changes in energy levels in the nucleus, cytoplasm, and mitochondrion. SIRT1 plays a critical role in metabolic health by deacetylating many target proteins in numerous tissues, including liver, muscle, adipose tissue, heart, and endothelium. This sirtuin also exerts important systemic effects via the hypothalamus. This review will cover these topics and suggest that strategies to maintain sirtuin activity may be on the horizon to forestall diseases of aging.

752 citations