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https://www.readbyqxmd.com/read/29282294/exceptionally-high-affinity-ras-binders-that-remodel-its-effector-domain
#1
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
https://www.readbyqxmd.com/read/29261182/biallelic-and-monoallelic-esr2-variants-associated-with-46-xy-disorders-of-sex-development
#2
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
https://www.readbyqxmd.com/read/29240439/defining-metabolic-and-non-metabolic-regulation-of-histone-acetylation-by-a-nsaid-chemotype
#3
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
https://www.readbyqxmd.com/read/29211072/influences-of-polarity-and-hydration-cycles-on-imbibition-hysteresis-in-silica-nanochannels
#4
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 6, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/29191913/metabolic-reprogramming-of-human-cd8-memory-t-cells-through-loss-of-sirt1
#5
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
https://www.readbyqxmd.com/read/29126017/epidermal-growth-factor-receptor-overexpression-and-outcomes-in-early-breast-cancer-a-systematic-review-and-a-meta-analysis
#6
REVIEW
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
https://www.readbyqxmd.com/read/29053653/patients-with-advanced-oral-squamous-cell-carcinoma-have-high-levels-of-soluble-e-cadherin-in-the-saliva
#7
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
https://www.readbyqxmd.com/read/29031725/intestinal-sirt3-overexpression-in-mice-improves-whole-body-glucose-homeostasis-independent-of-body-weight
#8
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
https://www.readbyqxmd.com/read/28976959/rna-targeting-with-crispr-cas13
#9
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
https://www.readbyqxmd.com/read/28939823/stapled-peptide-inhibitors-of-rab25-target-context-specific-phenotypes-in-cancer
#10
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
https://www.readbyqxmd.com/read/28933431/erratum-genome-scale-activation-screen-identifies-a-lncrna-locus-regulating-a-gene-neighbourhood
#11
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
https://www.readbyqxmd.com/read/28911171/sirtuin-3-promotes-adipogenesis-osteoclastogenesis-and-bone-loss-in-aging-male-mice
#12
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
https://www.readbyqxmd.com/read/28877458/ketogenic-diet-reduces-midlife-mortality-and-improves-memory-in-aging-mice
#13
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
https://www.readbyqxmd.com/read/28877456/distinct-circadian-signatures-in-liver-and-gut-clocks-revealed-by-ketogenic-diet
#14
Paola Tognini, Mari Murakami, Yu Liu, Kristin L Eckel-Mahan, John C Newman, Eric Verdin, Pierre Baldi, Paolo Sassone-Corsi
The circadian clock orchestrates rhythms in physiology and behavior, allowing organismal adaptation to daily environmental changes. While food intake profoundly influences diurnal rhythms in the liver, how nutritional challenges are differentially interpreted by distinct tissue-specific clocks remains poorly explored. Ketogenic diet (KD) is considered to have metabolic and therapeutic value, though its impact on circadian homeostasis is virtually unknown. We show that KD has profound and differential effects on liver and intestine clocks...
September 5, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28829437/control-of-phosphorothioate-stereochemistry-substantially-increases-the-efficacy-of-antisense-oligonucleotides
#15
Naoki Iwamoto, David C D Butler, Nenad Svrzikapa, Susovan Mohapatra, Ivan Zlatev, Dinah W Y Sah, Meena, Stephany M Standley, Genliang Lu, Luciano H Apponi, Maria Frank-Kamenetsky, Jason Jingxin Zhang, Chandra Vargeese, Gregory L Verdine
Whereas stereochemical purity in drugs has become the standard for small molecules, stereoisomeric mixtures containing as many as a half million components persist in antisense oligonucleotide (ASO) therapeutics because it has been feasible neither to separate the individual stereoisomers, nor to synthesize stereochemically pure ASOs. Here we report the development of a scalable synthetic process that yields therapeutic ASOs having high stereochemical and chemical purity. Using this method, we synthesized rationally designed stereopure components of mipomersen, a drug comprising 524,288 stereoisomers...
September 2017: Nature Biotechnology
https://www.readbyqxmd.com/read/28826372/%C3%AE-hydroxybutyrate-a-signaling-metabolite
#16
REVIEW
John C Newman, Eric Verdin
Various mechanisms in the mammalian body provide resilience against food deprivation and dietary stress. The ketone body β-hydroxybutyrate (BHB) is synthesized in the liver from fatty acids and represents an essential carrier of energy from the liver to peripheral tissues when the supply of glucose is too low for the body's energetic needs, such as during periods of prolonged exercise, starvation, or absence of dietary carbohydrates. In addition to its activity as an energetic metabolite, BHB is increasingly understood to have cellular signaling functions...
August 21, 2017: Annual Review of Nutrition
https://www.readbyqxmd.com/read/28792927/genome-scale-activation-screen-identifies-a-lncrna-locus-regulating-a-gene-neighbourhood
#17
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
Mammalian genomes contain thousands of loci that transcribe long noncoding RNAs (lncRNAs), some of which are known to carry out critical roles in diverse cellular processes through a variety of mechanisms. Although some lncRNA loci encode RNAs that act non-locally (in trans), there is emerging evidence that many lncRNA loci act locally (in cis) to regulate the expression of nearby genes-for example, through functions of the lncRNA promoter, transcription, or transcript itself. Despite their potentially important roles, it remains challenging to identify functional lncRNA loci and distinguish among these and other mechanisms...
August 17, 2017: Nature
https://www.readbyqxmd.com/read/28758782/shape-up-an-eye-tracking-study-of-preschoolers-shape-name-processing-and-spatial-development
#18
Brian N Verdine, Ann Bunger, Angeliki Athanasopoulou, Roberta Michnick Golinkoff, Kathy Hirsh-Pasek
Learning the names of geometric shapes is at the intersection of early spatial, mathematical, and language skills, all important for school-readiness and predictors of later abilities in science, technology, engineering, and mathematics (STEM). We investigated whether socioeconomic status (SES) influenced children's processing of shape names and whether differences in processing were predictive of later spatial skills. Three-year-olds (N = 79) with mothers of varying education levels participated in an eye-tracking task that required them to look at named shapes...
October 2017: Developmental Psychology
https://www.readbyqxmd.com/read/28751388/rhizospheric-microbiome-profiling-of-capsicum-annuum-l-cultivated-in-amended-soils-by-16s-and-internal-transcribed-spacer-2-rrna-amplicon-metagenome-sequencing
#19
Ali Asaff-Torres, Mariana Armendáriz-Ruiz, Manuel Kirchmayr, Raúl Rodríguez-Heredia, Marcos Orozco, Juan Carlos Mateos-Díaz, Luis Figueroa-Yáñez, Itzamná Baqueiro-Peña, Jorge Verdín
Rhizospheric microbiomes of Capsicum annuum L. cultivated either conventionally or amended with a synthetic microbial consortium or a root exudate inductor, were characterized by 16S/internal transcribed spacer 2 (ITS2) rRNA amplicon metagenome sequencing. The most abundant taxa found, although differently represented in each treatment, were Gammaproteobacteria, Alphaproteobacteria, Actinobacteria, and Bacilli, as well as Chytridiomycetes and Mortierellomycotina.
July 27, 2017: Genome Announcements
https://www.readbyqxmd.com/read/28749477/mapping-the-genomic-landscape-of-inherited-retinal-disease-genes-prioritizes-genes-prone-to-coding-and-noncoding-copy-number-variations
#20
Kristof Van Schil, Sarah Naessens, Stijn Van de Sompele, Marjolein Carron, Alexander Aslanidis, Caroline Van Cauwenbergh, Anja Kathrin Mayer, Mattias Van Heetvelde, Miriam Bauwens, Hannah Verdin, Frauke Coppieters, Michael E Greenberg, Marty G Yang, Marcus Karlstetter, Thomas Langmann, Katleen De Preter, Susanne Kohl, Timothy J Cherry, Bart P Leroy, Elfride De Baere
PurposePart of the hidden genetic variation in heterogeneous genetic conditions such as inherited retinal diseases (IRDs) can be explained by copy-number variations (CNVs). Here, we explored the genomic landscape of IRD genes listed in RetNet to identify and prioritize those genes susceptible to CNV formation.MethodsRetNet genes underwent an assessment of genomic features and of CNV occurrence in the Database of Genomic Variants and literature. CNVs identified in an IRD cohort were characterized using targeted locus amplification (TLA) on extracted genomic DNA...
July 27, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
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