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Ouyang J, Garner E, Hallet A, Nguyen HD, Rickman KA, Gill G, Smogorzewska A, Zou L
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Noncovalent Interactions with SUMO and Ubiquitin Orchestrate Distinct Functions of the SLX4 Complex in Genome Maintenance
MOLECULAR CELL 2015 JAN 8; 57(1):108-122
SLX4, a coordinator of multiple DNA structure-specific endonucleases, is important for several DNA repair pathways. Noncovalent interactions of SLX4 with ubiquitin are required for localizing SLX4 to DNA interstrand crosslinks (ICLs), yet how SLX4 is targeted to other functional contexts remains unclear. Here, we show that SLX4 binds SUMO-2/3 chains via SUMO-interacting motifs (SIMs). The SIMs of SLX4 are dispensable for ICL repair but important for processing CPT-induced replication intermediates, suppressing fragile site instability, and localizing SLX4 to ALT telomeres. The localization of SLX4 to laser-induced DNA damage also requires the SIMs, as well as DNA end resection, UBC9, and MDC1. Furthermore, the SUMO binding of SLX4 enhances its interaction with specific DNA-damage sensors or telomere-binding proteins, including RPA, MRE11-RAD50-NBS1, and TRF2. Thus, the interactions of SLX4 with SUMO and ubiquitin increase its affinity for factors recognizing different DNA lesions or telomeres, helping to direct the SLX4 complex in distinct functional contexts.
Petrov AI, Kay SJE, Gibson R, Kulesha E, Staines D, Bruford EA, Wright MW, Burge S, Finn RD, Kersey PJ, Cochrane G, Bateman A, Griffiths-Jones S, Harrow J, Chan PP, Lowe TM, Zwieb CW, Wower J, Williams KP, Hudson CM, Gutell R, Clark MB, Dinger M, Quek XC, Bujnicki JM, Chua NH, Liu J, Wang H, Skogerbo G, Zhao Y, Chen RS, Zhu WM, Cole JR, Chai BL, Huang HD, Huang HY, Cherry JM, Hatzigeorgiou A, Pruitt KD
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RNAcentral: an international database of ncRNA sequences
NUCLEIC ACIDS RESEARCH 2015 JAN 28; 43(D1):D123-D129
The field of non-coding RNA biology has been hampered by the lack of availability of a comprehensive, up-to-date collection of accessioned RNA sequences. Here we present the first release of RNAcentral, a database that collates and integrates information from an international consortium of established RNA sequence databases. The initial release contains over 8.1 million sequences, including representatives of all major functional classes. A web portal (http://rnacentral.org) provides free access to data, search functionality, cross-references, source code and an integrated genome browser for selected species.
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K, Kress M, Leonardo N, Pegna DL, Maroussov V, Merkel P, Miller DH, Neumeister N, Radburn-Smith BC, Shi X, Shipsey I, Silvers D, Svyatkovskiy A, Wang F, Xie W, Xu L, Yoo HD, Zablocki J, Zheng Y, Parashar N, Stupak J, Adair A, Akgun B, Ecklund KM, Geurts FJM, Li W, Michlin B, Padley BP, Redjimi R, Roberts J, Zabel J, Betchart B, Bodek A, Covarelli R, de Barbaro P, Demina R, Eshaq Y, Ferbel T, Garcia-Bellido A, Goldenzweig P, Han J, Harel A, Khukhunaishvili A, Petrillo G, Vishnevskiy D, Ciesielski R, Demortier L, Goulianos K, Lungu G, Mesropian C, Arora S, Barker A, Chou JP, Contreras-Campana C, Contreras-Campana E, Duggan D, Ferencek D, Gershtein Y, Gray R, Halkiadakis E, Hidas D, Kaplan S, Lath A, Panwalkar S, Park M, Patel R, Salur S, Schnetzer S, Somalwar S, Stone R, Thomas S, Thomassen P, Walker M, Rose K, Spanier S, York A, Bouhali O, Hernandez AC, Eusebi R, Flanagan W, Gilmore J, Kamon T, Khotilovich V, Krutelyov V, Montalvo R, Osipenkov I, Pakhotin Y, Perloff A, Roe J, Rose A, Safonov A, Sakuma T, Suarez I, Tatarinov A, Akchurin N, Cowden C, Damgov J, Dragoiu C, Dudero PR, Faulkner J, Kovitanggoon K, Kunori S, Lee SW, Libeiro T, Volobouev I, Appelt E, Delannoy AG, Greene S, Gurrola A, Johns W, Maguire C, Mao Y, Melo A, Sharma M, Sheldon P, Snook B, Tuo S, Velkovska J, Arenton MW, Boutle S, Cox B, Francis B, Goodell J, Hirosky R, Ledovskoy A, Li H, Lin C, Neu C, Wood J, Clarke C, Harr R, Karchin PE, Don CKK, Lamichhane P, Sturdy J, Belknap DA, Carlsmith D, Cepeda M, Dasu S, Dodd L, Duric S, Friis E, Hall-Wilton R, Herndon M, Herve A, Klabbers P, Lanaro A, Lazaridis C, Levine A, Loveless R, Mohapatra A, Ojalvo I, Perry T, Pierro GA, Polese G, Ross I, Sarangi T, Savin A, Smith WH, Vuosalo C, Woods N
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Measurement of Prompt psi(2S) to J/psi. Yield Ratios in Pb-Pb and p-p Collisions at root sNN=2.76 TeV
PHYSICAL REVIEW LETTERS 2014 DEC 31; 113(26):? Article 262301
The ratio between the prompt psi (2S) and J/psi yields, reconstructed via their decays into mu(-)mu(-) is measured in Pb-Pb and p-p collisions at root sNN = 2.76 TeV. The analysis is based on Pb-Pb and p-p data samples collected by CMS at the Large Hadron Collider, corresponding to integrated luminosities of 150 mu b(-1) and 5.4 mu b(-1), respectively. The double ratio of measured yields (N phi((2S))/NJ/(Pb-Pb)/N-psi(2S)/NJ/psi)(p-p) is computed in three Pb-Pb collision centrality bins and two kinematic ranges: one at midrapidity, vertical bar y vertical bar < 1.6, covering the transverse momentum range 6.5 < pT < 30 GeV= c, and the other at forward rapidity, 1.6 < vertical bar y vertical bar < 2.4, extending to lower pT values, 3 < pT < 30 GeV/c. The centralityintegrated double ratio changes from 0.45 +/- 0.13(stat) +/- 0.07dsyst_ in the first range to 1.67 +/- 0.34(stat) +/- 0.27dsyst_ in the second. This difference is most pronounced in the most central collisions.
McGuire AT, Dreyer AM, Carbonetti S, Lippy A, Glenn J, Scheid JF, Mouquet H, Stamatatos L
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Antigen modification regulates competition of broad and narrow neutralizing HIV antibodies
SCIENCE 2014 DEC 12; 346(6215):1380-1383
Some HIV-infected individuals develop broadly neutralizing antibodies (bNAbs), whereas most develop antibodies that neutralize only a narrow range of viruses (nNAbs). bNAbs, but not nNAbs, protect animals from experimental infection and are likely a key component of an effective vaccine. nNAbs and bNAbs target the same regions of the viral envelope glycoprotein (Env), but for reasons that remain unclear only nNAbs are elicited by Env immunization. We show that in contrast to germline-reverted (gl) bNAbs, glnNAbs recognized diverse recombinant Envs. Moreover, owing to binding affinity differences, nNAb B cell progenitors had an advantage in becoming activated and internalizing Env compared with bNAb B cell progenitors. We then identified an Env modification strategy that minimized the activation of nNAb B cells targeting epitopes that overlap those of bNAbs.
Sagi Y, Heiman M, Peterson JD, Musatov S, Kaplitt MG, Surmeier DJ, Heintz N, Greengard P
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Nitric oxide regulates synaptic transmission between spiny projection neurons
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2014 DEC 9; 111(49):17636-17641
Recurrent axon collaterals are a major means of communication between spiny projection neurons (SPNs) in the striatum and profoundly affect the function of the basal ganglia. However, little is known about the molecular and cellular mechanisms that underlie this communication. We show that intrastriatal nitric oxide (NO) signaling elevates the expression of the vesicular GABA transporter (VGAT) within recurrent collaterals of SPNs. Down-regulation of striatal NO signaling resulted in an attenuation of GABAergic signaling in SPN local collaterals, down-regulation of VGAT expression in local processes of SPNs, and impaired motor behavior. PKG1 and cAMP response element-binding protein are involved in the signal transduction that transcriptionally regulates VGAT by NO. These data suggest that transcriptional control of the vesicular GABA transporter by NO regulates GABA transmission and action selection.
Fridy PC, Li YY, Keegan S, Thompson MK, Nudelman I, Scheid JF, Oeffinger M, Nussenzweig MC, Fenyo D, Chait BT, Routany MP
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A robust pipeline for rapid production of versatile nanobody repertoires
NATURE METHODS 2014 DEC; 11(12):1253-+
Nanobodies are single-domain antibodies derived from the variable regions of Camelidae atypical immunoglobulins. They show promise as high-affinity reagents for research, diagnostics and therapeutics owing to their high specificity, small size (similar to 15 kDa) and straightforward bacterial expression. However, identification of repertoires with sufficiently high affinity has proven time consuming and difficult, hampering nanobody implementation. Our approach generates large repertoires of readily expressible recombinant nanobodies with high affinities and specificities against a given antigen. We demonstrate the efficacy of this approach through the production of large repertoires of nanobodies against two antigens, GFP and mCherry, with K-d values into the subnanomolar range. After mapping diverse epitopes on GFP, we were also able to design ultrahigh-affinity dimeric nanobodies with Kd values as low as similar to 30 pM. The approach presented here is well suited for the routine production of high-affinity capture reagents for various biomedical applications.
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Search for supersymmetry with razor variables in pp collisions at root s=7 TeV
PHYSICAL REVIEW D 2014 DEC 1; 90(11):? Article 112001
The razor approach to search for R-parity conserving supersymmetric particles is described in detail. Two analyses are considered: an inclusive search for new heavy particle pairs decaying to final states with at least two jets and missing transverse energy, and a dedicated search for final states with at least one jet originating from a bottom quark. For both the inclusive study and the study requiring a bottom-quark jet, the data are examined in exclusive final states corresponding to all-hadronic, single-lepton, and dilepton events. The study is based on the data set of proton-proton collisions at root s = 7 TeV collected with the CMS detector at the LHC in 2011, corresponding to an integrated luminosity of 4.7 fb(-1). The study consists of a shape analysis performed in the plane of two kinematic variables, denoted M-R and R-2, that correspond to the mass and transverse energy flow, respectively, of pair-produced, heavy, new-physics particles. The data are found to be compatible with the background model, defined by studying event simulations and data control samples. Exclusion limits for squark and gluino production are derived in the context of the constrained minimal supersymmetric standard model (CMSSM) and also for simplified-model spectra (SMS). Within the CMSSM parameter space considered, squark and gluino masses up to 1350 GeV are excluded at 95% confidence level, depending on the model parameters. For SMS scenarios, the direct production of pairs of top or bottom squarks is excluded for masses as high as 400 GeV.
Calis JJA, Rosenberg BR
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Characterizing immune repertoires by high throughput sequencing: strategies and applications
TRENDS IN IMMUNOLOGY 2014 DEC; 35(12):581-590
As the key cellular effectors of adaptive immunity, T and B lymphocytes utilize specialized receptors to recognize, respond to, and neutralize a diverse array of extrinsic threats. These receptors (immunoglobulins in B lymphocytes, T cell receptors in T lymphocytes) are incredibly variable, the products of specialized genetic diversification mechanisms that generate complex lymphocyte repertoires with extensive collections of antigen specificities. Recent advances in high throughput sequencing (HTS) technologies have transformed our ability to examine antigen receptor repertoires at single nucleotide, and more recently, single cell, resolution. Here we review current approaches to examining antigen receptor repertoires by HIS, and discuss inherent biological and technical challenges. We further describe emerging applications of this powerful methodology for exploring the adaptive immune system.
Wang CQF, Suarez-Farinas M, Nograles KE, Mimoso CA, Shrom D, Dow ER, Heffernan MP, Hoffman RW, Krueger JG
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IL-17 Induces Inflammation-Associated Gene Products in Blood Monocytes, and Treatment with Ixekizumab Reduces Their Expression in Psoriasis Patient Blood
JOURNAL OF INVESTIGATIVE DERMATOLOGY 2014 DEC; 134(12):2990-2993
Gerstberger S, Hafner M, Tuschl T
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A census of human RNA-binding proteins
NATURE REVIEWS GENETICS 2014 DEC; 15(12):829-845
Post-transcriptional gene regulation (PTGR) concerns processes involved in the maturation, transport, stability and translation of coding and non-coding RNAs. RNA-binding proteins (RBPs) and ribonucleoproteins coordinate RNA processing and PTGR. The introduction of large-scale quantitative methods, such as next-generation sequencing and modern protein mass spectrometry, has renewed interest in the investigation of PTGR and the protein factors involved at a systems-biology level. Here, we present a census of 1,542 manually curated RBPs that we have analysed for their interactions with different classes of RNA, their evolutionary conservation, their abundance and their tissue-specific expression. Our analysis is a critical step towards the comprehensive characterization of proteins involved in human RNA metabolism.