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Chris Carrico, Jesse G Meyer, Wenjuan He, Brad W Gibson, Eric Verdin
Post-translational modification of lysine residues via reversible acylation occurs on proteins from diverse pathways, functions, and organisms. While nuclear protein acylation reflects the competing activities of enzymatic acyltransferases and deacylases, mitochondrial acylation appears to be driven mostly via a non-enzymatic mechanism. Three protein deacylases, SIRT3, SIRT4, and SIRT5, reside in the mitochondria and remove these modifications from targeted proteins in an NAD+ -dependent manner. Recent proteomic surveys of mitochondrial protein acylation have identified the sites of protein acetylation, succinylation, glutarylation, and malonylation and their regulation by SIRT3 and SIRT5...
March 6, 2018: Cell Metabolism
Eric Verdin, Armelle Marais, Catherine Wipf-Scheibel, Chantal Faure, Brigitte Pelletier, Perrine David, Laurence Svanella-Dumas, Clement Poisblaud, Herve' Lecoq, Thierry Candresse
An emerging systemic necrosis disease of corn salad was first observed in the Nantes region of France in the late 2000's. Classical virology and high-throughput sequencing approaches demonstrated that the disease is associated with four different necroviruses, tobacco necrosis virus A (TNVA), tobacco necrosis virus D (TNVD), olive mild mosaic virus (OMMV) and a novel recombinant Alphanecrovirus for which the name corn salad necrosis virus (CSNV) is proposed. Satellite tobacco necrosis virus (STNV) was also frequently observed...
February 28, 2018: Phytopathology
Stefanie Wagner, Frédéric Lagane, Andaine Seguin-Orlando, Mikkel Schubert, Thibault Leroy, Erwan Guichoux, Emilie Chancerel, Inger Bech-Hebelstrup, Vincent Bernard, Cyrille Billard, Yves Billaud, Matthias Bolliger, Christophe Croutsch, Katarina Čufar, Frédérique Eynaud, Karl Uwe Heussner, Joachim Köninger, Fabien Langenegger, Frédéric Leroy, Christine Lima, Nicoletta Martinelli, Garry Momber, André Billamboz, Oliver Nelle, Antoni Palomo, Raquel Piqué, Marianne Ramstein, Roswitha Schweichel, Harald Stäuble, Willy Tegel, Xavier Terradas, Florence Verdin, Christophe Plomion, Antoine Kremer, Ludovic Orlando
Reconstructing the colonization and demographic dynamics that gave rise to extant forests is essential to forecasts of forest responses to environmental changes. Classical approaches to map how population of trees changed through space and time largely rely on pollen distribution patterns, with only a limited number of studies exploiting DNA molecules preserved in wooden tree archaeological and subfossil remains. Here, we advance such analyses by applying high throughput (HTS) DNA sequencing to wood archaeological and subfossil material for the first time, using a comprehensive sample of 167 European white oak waterlogged remains spanning a large temporal (from 550 to 9,800 years) and geographical range across Europe...
February 7, 2018: Molecular Ecology
Ibraheem Ali, Ryan J Conrad, Eric Verdin, Melanie Ott
Post-translational acetylation of lysine residues has emerged as a key regulatory mechanism in all eukaryotic organisms. Originally discovered in 1963 as a unique modification of histones, acetylation marks are now found on thousands of nonhistone proteins located in virtually every cellular compartment. Here we summarize key findings in the field of protein acetylation over the past 20 years with a focus on recent discoveries in nuclear, cytoplasmic, and mitochondrial compartments. Collectively, these findings have elevated protein acetylation as a major post-translational modification, underscoring its physiological relevance in gene regulation, cell signaling, metabolism, and disease...
February 6, 2018: Chemical Reviews
Lijian Xu, Yan Li, John B Biggins, Brian R Bowman, Gregory L Verdine, James B Gloer, J Andrew Alspaugh, Gerald F Bills
We used a temperature differential assay with the opportunistic fungal pathogen Cryptococcus neoformans as a simple screening platform to detect small molecules with antifungal activity in natural product extracts. By screening of a collection extracts from two different strains of the coprophilous fungus, Amphichorda felina, we detected strong, temperature-dependent antifungal activity using a two-plate agar zone of inhibition assay at 25 and 37 °C. Bioassay-guided fractionation of the crude extract followed by liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance spectroscopy (NMR) identified cyclosporin C (CsC) as the main component of the crude extract responsible for growth inhibition of C...
February 2, 2018: Applied Microbiology and Biotechnology
Jason G Wood, Bjoern Schwer, Priyan C Wickremesinghe, Davis A Hartnett, Lucas Burhenn, Meyrolin Garcia, Michael Li, Eric Verdin, Stephen L Helfand
Sirtuins are an evolutionarily conserved family of NAD+-dependent deacylases that control metabolism, stress response, genomic stability, and longevity. Here, we show the sole mitochondrial sirtuin in Drosophila melanogaster, Sirt4, regulates energy homeostasis and longevity. Sirt4 knockout flies have a short lifespan, with increased sensitivity to starvation and decreased fertility and activity. In contrast, flies overexpressing Sirt4 either ubiquitously or specifically in the fat body are long-lived. Despite rapid starvation, Sirt4 knockout flies paradoxically maintain elevated levels of energy reserves, including lipids, glycogen, and trehalose, while fasting, suggesting an inability to properly catabolize stored energy...
January 29, 2018: Proceedings of the National Academy of Sciences of the United States of America
Rachel Johnson, Abe Osbourne, Jessica Rispoli, Craig Verdin
The diabetic foot assessment is a key component in the care of a patient with diabetes. The assessment includes risk factor identification in both the diabetic patient's history and physical examination, foot care education, treatment, and referrals as needed. The foot complications related to diabetes such as peripheral neuropathy, foot ulceration, and amputation can be life altering. The American Diabetes Association recommends a diabetic foot examination annually for patients with diabetes with foot care education...
January 2018: Orthopaedic Nursing
John H McGee, So Youn Shim, Seung-Joo Lee, Paige K Swanson, Yanting Jiang, Michael A Durney, Gregory L Verdine
The Ras proteins are aberrantly activated in a wide range of human cancers, often endowing tumors with aggressive properties and resistance to therapy. Decades of effort to develop direct Ras inhibitors for clinical use have thus far failed, largely because of a lack of adequate small-molecule binding pockets on the Ras surface. Here, we report the discovery of Ras-binding miniproteins from a naive library, and their evolution to afford versions with mid-picomolar affinity to Ras. A series of biochemical experiments indicated that these miniproteins bind to the Ras effector domain as dimers, and high-resolution crystal structures revealed that these miniprotein dimers bind Ras in an unprecedented mode, in which the Ras effector domain is remodeled to expose an extended pocket that connects two isolated pockets previously found to engage small-molecule ligands...
December 27, 2017: Journal of Biological Chemistry
Dorien Baetens, Tülay Güran, Berenice B Mendonca, Nathalia L Gomes, Lode De Cauwer, Frank Peelman, Hannah Verdin, Marnik Vuylsteke, Malaïka Van der Linden, Hans Stoop, Leendert H Looijenga, Karolien De Bosscher, Martine Cools, Elfride De Baere
PurposeDisorders or differences of sex development (DSDs) are rare congenital conditions characterized by atypical sex development. Despite advances in genomic technologies, the molecular cause remains unknown in 50% of cases.MethodsHomozygosity mapping and whole-exome sequencing revealed an ESR2 variant in an individual with syndromic 46,XY DSD. Additional cases with 46,XY DSD underwent whole-exome sequencing and targeted next-generation sequencing of ESR2. Functional characterization of the identified variants included luciferase assays and protein structure analysis...
October 26, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Jonathan Harold Shrimp, Julie Garlick, Tugsan Tezil, Alex W Sorum, Andrew J Worth, Ian Alexander Blair, Eric Verdin, Nathaniel W Snyder, Jordan L Meier
Non-steroidal anti-inflammatory drugs (NSAIDs) are well known for their effects on inflammatory gene expression. Although NSAIDs are known to impact multiple cellular signaling mechanisms, a recent finding is that the NSAID salicylate can disrupt histone acetylation, in part through direct inhibition of the lysine acetyltransferase (KAT) p300/CBP. While salicylate is a relatively weak KAT inhibitor, its CoA-linked metabolite is more potent; however, the ability of NSAID metabolites to inhibit KAT enzymes biochemically and in cells remains relatively unexplored...
December 14, 2017: Molecular Pharmaceutics
Shaina Kelly, Carlos Torres-Verdín, Matthew T Balhoff
Spontaneous liquid imbibition is a dominant mechanism for moving fluids in confinements with extremely high hydrodynamic resistance; i.e. nanopores. We demonstrate the impact of hydrophilicity and liquid polarity on nanoscale imbibition with dynamic measurements of the uptake of water-isopropanol (polar) and heptane (nonpolar) within 2D glass-silica nanochannels exposed to varied drying conditions and rehydration (rehydroxylation) cycles. The Lucas-Washburn equation, which does not consider interfacial fluidity effects, predicts that water-IPA and heptane should imbibe at similar speeds...
December 20, 2017: Physical Chemistry Chemical Physics: PCCP
Mark Y Jeng, Philip A Hull, Mingjian Fei, Hye-Sook Kwon, Chia-Lin Tsou, Herb Kasler, Che-Ping Ng, David E Gordon, Jeffrey Johnson, Nevan Krogan, Eric Verdin, Melanie Ott
The expansion of CD8+ CD28- T cells, a population of terminally differentiated memory T cells, is one of the most consistent immunological changes in humans during aging. CD8+ CD28- T cells are highly cytotoxic, and their frequency is linked to many age-related diseases. As they do not accumulate in mice, many of the molecular mechanisms regulating their fate and function remain unclear. In this paper, we find that human CD8+ CD28- T cells, under resting conditions, have an enhanced capacity to use glycolysis, a function linked to decreased expression of the NAD+ -dependent protein deacetylase SIRT1...
January 2, 2018: Journal of Experimental Medicine
Galileo A Gonzalez-Conchas, Laura Rodriguez-Romo, David Hernandez-Barajas, Juan F Gonzalez-Guerrero, Ivan A Rodriguez-Fernandez, Adrian Verdines-Perez, Arnoud J Templeton, Alberto Ocana, Bostjan Seruga, Ian F Tannock, Eitan Amir, Francisco E Vera-Badillo
BACKGROUND: The epidermal growth factor receptor (EGFR) is a member of the ErbB family of membrane tyrosine-kinase receptors. Studies exploring the prognostic role of EGFR-overexpression in early breast cancer have shown variable results, and the true prognostic value of EGFR is unknown. METHODS: A systematic review of identified publications exploring the association between EGFR-overexpression (as defined from different techniques and cut-offs) and outcomes [disease-free (DFS) and, overall survival (OS)] in women with early breast cancer...
January 2018: Cancer Treatment Reviews
S López-Verdín, J-J Soto-Avila, A-L Zamora-Perez, B-P Lazalde-Ramos, M-L Martínez-Fierro, R González-González, N Molina-Frechero, M-A Isiordia-Espinoza, R Bologna-Molina
BACKGROUND: The objective of this study was to assess the potential clinical value of the concentration of soluble salivary E-cadherin (sE-cadherin) compared with the clinical value of the presence of membranous E-cadherin (mE-cadherin) in oral squamous cell carcinoma tumor tissues. MATERIAL AND METHODS: Data regarding patient demographics, clinical stage, saliva and tumor tissue samples were collected. The saliva was analyzed for sE-cadherin protein levels and was compared to the mE-cadherin immunohistochemical expression levels in tumor tissues, which were assessed via the HercepTest® method...
November 1, 2017: Medicina Oral, Patología Oral y Cirugía Bucal
Deepti Ramachandran, Rosmarie Clara, Shahana Fedele, Junmin Hu, Endre Lackzo, Jing-Yi Huang, Eric Verdin, Wolfgang Langhans, Abdelhak Mansouri
OBJECTIVE: Intestinal metabolism might play a greater role in regulating whole body metabolism than previously believed. We aimed to enhance enterocyte metabolism in mice and investigate if it plays a role in diet-induced obesity (DIO) and its comorbidities. METHODS: Using the cre-loxP system, we overexpressed the mitochondrial NAD(+) dependent protein deacetylase SIRT3 in enterocytes of mice (iSIRT3 mice). We chronically fed iSIRT3 mice and floxed-SIRT3 control (S3fl) mice a low-fat, control diet (CD) or a high-fat diet (HFD) and then phenotyped the mice...
October 2017: Molecular Metabolism
Omar O Abudayyeh, Jonathan S Gootenberg, Patrick Essletzbichler, Shuo Han, Julia Joung, Joseph J Belanto, Vanessa Verdine, David B T Cox, Max J Kellner, Aviv Regev, Eric S Lander, Daniel F Voytas, Alice Y Ting, Feng Zhang
RNA has important and diverse roles in biology, but molecular tools to manipulate and measure it are limited. For example, RNA interference can efficiently knockdown RNAs, but it is prone to off-target effects, and visualizing RNAs typically relies on the introduction of exogenous tags. Here we demonstrate that the class 2 type VI RNA-guided RNA-targeting CRISPR-Cas effector Cas13a (previously known as C2c2) can be engineered for mammalian cell RNA knockdown and binding. After initial screening of 15 orthologues, we identified Cas13a from Leptotrichia wadei (LwaCas13a) as the most effective in an interference assay in Escherichia coli...
October 12, 2017: Nature
Shreya Mitra, Jeffrey E Montgomery, Matthew J Kolar, Gang Li, Kang J Jeong, Bo Peng, Gregory L Verdine, Gordon B Mills, Raymond E Moellering
Recent evidence has established a role for the small GTPase RAB25, as well as related effector proteins, in enacting both pro-oncogenic and anti-oncogenic phenotypes in specific cellular contexts. Here we report the development of all-hydrocarbon stabilized peptides derived from the RAB-binding FIP-family of proteins to target RAB25. Relative to unmodified peptides, optimized stapled peptides exhibit increased structural stability, binding affinity, cell permeability, and inhibition of RAB25:FIP complex formation...
September 22, 2017: Nature Communications
Julia Joung, Jesse M Engreitz, Silvana Konermann, Omar O Abudayyeh, Vanessa K Verdine, Francois Aguet, Jonathan S Gootenberg, Neville E Sanjana, Jason B Wright, Charles P Fulco, Yuen-Yi Tseng, Charles H Yoon, Jesse S Boehm, Eric S Lander, Feng Zhang
This corrects the article DOI: 10.1038/nature23451.
September 20, 2017: Nature
Linh Ho, Liping Wang, Theresa M Roth, Yong Pan, Eric M Verdin, Edward C Hsiao, Robert A Nissenson
Sirtuin-3 (Sirt3) is an essential metabolic regulatory enzyme that plays an important role in mitochondrial metabolism, but its role in bone marrow and skeletal homeostasis remains largely unknown. In this study, we hypothesize that increased expression of Sirt3 plays a role in skeletal aging. Using mice that overexpress Sirt3 [i.e., Sirt3 transgenic (Sirt3Tg)], we show that Sirt3 is a positive regulator of adipogenesis and osteoclastogenesis and a negative regulator of skeletal homeostasis. Sirt3Tg mice exhibited more adipocytes in the tibia compared with control mice...
September 1, 2017: Endocrinology
John C Newman, Anthony J Covarrubias, Minghao Zhao, Xinxing Yu, Philipp Gut, Che-Ping Ng, Yu Huang, Saptarsi Haldar, Eric Verdin
Ketogenic diets recapitulate certain metabolic aspects of dietary restriction such as reliance on fatty acid metabolism and production of ketone bodies. We investigated whether an isoprotein ketogenic diet (KD) might, like dietary restriction, affect longevity and healthspan in C57BL/6 male mice. We find that Cyclic KD, KD alternated weekly with the Control diet to prevent obesity, reduces midlife mortality but does not affect maximum lifespan. A non-ketogenic high-fat diet (HF) fed similarly may have an intermediate effect on mortality...
September 5, 2017: Cell Metabolism
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