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Waters EM, Mazid S, Dodos M, Puri R, Janssen WG, Morrison JH, McEwen BS, Milner TA
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Effects of estrogen and aging on synaptic morphology and distribution of phosphorylated Tyr1472 NR2B in the female rat hippocampus

NEUROBIOLOGY OF AGING 2019 JAN; 73(?):200-210
Age and estrogens may impact the mobility of N-methyl-D-aspartate receptors (NMDARs) in hippocampal synapses. Here, we used serial section immunogold electron microscopy to examine whether phosphorylated tyrosine 1472 NR2B (pY1472), which is involved in the surface expression of NMDARs, is altered in the dorsal hippocampus of young (3-4 months old) and aged ( similar to 24 months old) ovariectomized rats treated with 17 beta-estradiol or vehicle for 2 days. The number of gold particles labeling pY1472 was higher in presynaptic and postsynaptic compartments of aged rats with low estradiol (vehicle-treated) compared to other groups. In terminals, pY1472 levels were elevated in aged rats but reduced by estradiol treatment to levels seen in young rats. Conversely, the mitochondria number was lower in aged females but was restored to young levels by estradiol. In the postsynaptic density and dendritic spines, estradiol reduced pY1472 in young and aged rats. As phosphorylation at Y1472 blocks NR2B endocytosis, reduction of pY1472 by estradiol suggests another mechanism through which estrogen enhances synaptic plasticity by altering localization of NMDAR subunits within synapses. (C) 2018 Elsevier Inc. All rights reserved.
Nasca C, Rasgon N, McEwen B
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An emerging epigenetic framework of systemic and central mechanisms underlying stress-related disorders

NEUROPSYCHOPHARMACOLOGY 2019 JAN; 44(1):235-236
Desharnais RA, Reuman DC, Costantino RF, Cohen JE
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Temporal scale of environmental correlations affects ecological synchrony

ECOLOGY LETTERS 2018 DEC; 21(12):1800-1811
Population densities of a species measured in different locations are often correlated over time, a phenomenon referred to as synchrony. Synchrony results from dispersal of individuals among locations and spatially correlated environmental variation, among other causes. Synchrony is often measured by a correlation coefficient. However, synchrony can vary with timescale. We demonstrate theoretically and experimentally that the timescale-specificity of environmental correlation affects the overall magnitude and timescale-specificity of synchrony, and that these effects are modified by population dispersal. Our laboratory experiments linked populations of flour beetles by changes in habitat size and dispersal. Linear filter theory, applied to a metapopulation model for the experimental system, predicted the observed timescale-specific effects. The timescales at which environmental covariation occurs can affect the population dynamics of species in fragmented habitats.
Kim J, Lee J, Gonzalez J, Fuentes-Duculan J, Garcet S, Krueger JG
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Proportion of CD4(+)CD49b(+)LAG-3(+) Type 1 Regulatory T Cells in the Blood of Psoriasis Patients Inversely Correlates with Psoriasis Area and Severity Index

JOURNAL OF INVESTIGATIVE DERMATOLOGY 2018 DEC; 138(12):2669-2672
Li X, Li XM, Jiang YX, Liu Z, Cui YW, Fung KY, van der Beelen SHE, Tian GF, Wan LL, Shi XB, Allis CD, Li HT, Li YY, Li XD
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Structure-guided development of YEATS domain inhibitors by targeting pi-pi-pi stacking

NATURE CHEMICAL BIOLOGY 2018 DEC; 14(12):1140-1149
Chemical probes of epigenetic 'readers' of histone post-translational modifications (PTMs) have become powerful tools for mechanistic and functional studies of their target proteins in normal physiology and disease pathogenesis. Here we report the development of the first class of chemical probes of YEATS domains, newly identified 'readers' of histone lysine acetylation (Kac) and crotonylation (Kcr). Guided by the structural analysis of a YEATS-Kcr complex, we developed a series of peptide-based inhibitors of YEATS domains by targeting a unique pi-pi-pi stacking interaction at the proteins' Kcr recognition site. Further structure optimization resulted in the selective inhibitors preferentially binding to individual YEATS-containing proteins including AF9 and ENL with submicromolar affinities. We demonstrate that one of the ENL YEATS-selective inhibitors, XL-13m, engages with endogenous ENL, perturbs the recruitment of ENL onto chromatin, and synergizes the BET and DOT1L inhibition-induced downregulation of oncogenes in MLL-rearranged acute leukemia.
Galea S, Vaughan RD
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The Public Conversation and the Public's Health: A Public Health of Consequence, December 2018

AMERICAN JOURNAL OF PUBLIC HEALTH 2018 DEC; 108(12):1590-1591
Mo CY, Marraffini LA
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If You'd Like to Stop a Type III CRISPR Ribonuclease, Then You Should Put a Ring (Nuclease) on It

MOLECULAR CELL 2018 NOV 15; 72(4):608-609
Athukoralage et al. (2018) identify a new class of nuclease that degrades cyclic oligoadenylate (cOA), a second messenger that activates non-specific RNA degradation by the type III CRISPR-Cas accessory RNase Csm6/Csx1. This discovery provides a mechanism for regulating the degradation of foreign transcripts during the type III CRISPR immune response.
Matthews BJ, Dudchenko O, Kingan SB, Koren S, Antoshechkin I, Crawford JE, Glassford WJ, Herre M, Redmond SN, Rose NH, Weedall GD, Wu Y, Batra SS, Brito-Sierra CA, Buckingham SD, Campbell CL, Chan SK, Cox E, Evans BR, Fansiri T, Filipovic I, Fontaine A, Gloria-Soria A, Hall R, Joardar VS, Jones AK, Kay RGG, Kodali VK, Lee J, Lycett GJ, Mitchell SN, Muehling J, Murphy MR, Omer AD, Partridge FA, Peluso P, Aiden AP, Ramasamy V, Rasic G, Roy S, Saavedra-Rodriguez K, Sharan S, Sharma A, Smith ML, Turner J, Weakley AM, Zhao ZL, Akbari OS, Black WC, Cao H, Darby AC, Hill CA, Johnston JS, Murphy TD, Raikhel AS, Sattelle DB, Sharakhov IV, White BJ, Zhao L, Aiden EL, Mann RS, Lambrechts L, Powell JR, Sharakhova MV, Tu ZJ, Robertson HM, McBride CS, Hastic AR, Korlach J, Neafsey DE, Phillippy AM, Vosshall LB
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Improved reference genome of Aedes aegypti informs arbovirus vector control

NATURE 2018 NOV 22; 563(7732):501-507
Female Aedes aegypti mosquitoes infect more than 400 million people each year with dangerous viral pathogens including dengue, yellow fever, Zika and chikungunya. Progress in understanding the biology of mosquitoes and developing the tools to fight them has been slowed by the lack of a high-quality genome assembly. Here we combine diverse technologies to produce the markedly improved, fully re-annotated AaegL5 genome assembly, and demonstrate how it accelerates mosquito science. We anchored physical and cytogenetic maps, doubled the number of known chemosensory ionotropic receptors that guide mosquitoes to human hosts and egg-laying sites, provided further insight into the size and composition of the sex-determining M locus, and revealed copy-number variation among glutathione S-transferase genes that are important for insecticide resistance. Using high-resolution quantitative trait locus and population genomic analyses, we mapped new candidates for dengue vector competence and insecticide resistance. AaegL5 will catalyse new biological insights and intervention strategies to fight this deadly disease vector.
Hagl B, Spielberger BD, Thoene S, Bonnal S, Mertes C, Winter C, Nijman IJ, Verduin S, Eberherr AC, Puel A, Schindler D, Ruland J, Meitinger T, Gagneur J, Orange JS, van Gijn ME, Renner ED
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Somatic alterations compromised molecular diagnosis of DOCK8 hyper-IgE syndrome caused by a novel intronic splice site mutation

SCIENTIFIC REPORTS 2018 NOV 13; 8(?):? Article 16719
In hyper-IgE syndromes (HIES), a group of primary immunodeficiencies clinically overlapping with atopic dermatitis, early diagnosis is crucial to initiate appropriate therapy and prevent irreversible complications. Identification of underlying gene defects such as in DOCKS and STAT3 and corresponding molecular testing has improved diagnosis.Yet, in a child and her newborn sibling with HIES phenotype molecular diagnosis was misleading. Extensive analyses driven by the clinical phenotype identified an intronic homozygous DOCKS variant c.4626 76A > G creating a novel splice site as disease-causing. While the affected newborn carrying the homozygous variant had no expression of DOCK8 protein, in the index patient molecular diagnosis was compromised due to expression of altered and wildtype DOCKS transcripts and DOCK8 protein as well as defective STAT3 signaling. Sanger sequencing of lymphocyte subsets revealed that somatic alterations and reversions revoked the predominance of the novel over the canonical splice site in the index patient explaining DOCK8 protein expression, whereas defective STAT3 responses in the index patient were explained by a T cell phenotype skewed towards central and effector memory T cells. Hence, somatic alterations and skewed immune cell phenotypes due to selective pressure may compromise molecular diagnosis and need to be considered with unexpected clinical and molecular findings.
Lee YA, Noon LA, Akat KM, Ybanez MD, Lee TF, Berres ML, Fujiwara N, Goossens N, Chou HI, Parvin-Nejad FP, Khambu B, Kramer EGM, Gordon R, Pfleger C, Germain D, John GR, Campbell KN, Yue ZY, Yin XM, Cuervo AM, Czaja MJ, Fiel MI, Hoshida Y, Friedman SL
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Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap

NATURE COMMUNICATIONS 2018 NOV 23; 9(?):? Article 4962
Activation of the Hippo pathway effector Yap underlies many liver cancers, however no germline or somatic mutations have been identified. Autophagy maintains essential metabolic functions of the liver, and autophagy-deficient murine models develop benign adenomas and hepatomegaly, which have been attributed to activation of the p62/Sqstm1-Nrf2 axis. Here, we show that Yap is an autophagy substrate and mediator of tissue remodeling and hepatocarcinogenesis independent of the p62/Sqstm1-Nrf2 axis. Hepatocyte-specific deletion of Atg7 promotes liver size, fibrosis, progenitor cell expansion, and hepatocarcinogenesis, which is rescued by concurrent deletion of Yap. Our results shed new light on mechanisms of Yap degradation and the sequence of events that follow disruption of autophagy, which is impaired in chronic liver disease.