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Recent Publications

Association analysis identifies 65 new breast cancer risk loci.

Association analysis identifies 65 new breast cancer risk loci.

Nature. 2017 Oct 23;:

Authors: Michailidou K, Lindström S, Dennis J, Beesley J, Hui S, Kar S, Lemaçon A, Soucy P, Glubb D, Rostamianfar A, Bolla MK, Wang Q, Tyrer J, Dicks E, Lee A, Wang Z, Allen J, Keeman R, Eilber U, French JD, Qing Chen X, Fachal L, McCue K, McCart Reed AE, Ghoussaini M, Carroll JS, Jiang X, Finucane H, Adams M, Adank MA, Ahsan H, Aittomäki K, Anton-Culver H, Antonenkova NN, Arndt V, Aronson KJ, Arun B, Auer PL, Bacot F, Barrdahl M, Baynes C, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Bernstein L, Blomqvist C, Bogdanova NV, Bojesen SE, Bonanni B, Børresen-Dale AL, Brand JS, Brauch H, Brennan P, Brenner H, Brinton L, Broberg P, Brock IW, Broeks A, Brooks-Wilson A, Brucker SY, Brüning T, Burwinkel B, Butterbach K, Cai Q, Cai H, Caldés T, Canzian F, Carracedo A, Carter BD, Castelao JE, Chan TL, David Cheng TY, Seng Chia K, Choi JY, Christiansen H, Clarke CL, NBCS Collaborators, Collée M, Conroy DM, Cordina-Duverger E, Cornelissen S, Cox DG, Cox A, Cross SS, Cunningham JM, Czene K, Daly MB, Devilee P, Doheny KF, Dörk T, Dos-Santos-Silva I, Dumont M, Durcan L, Dwek M, Eccles DM, Ekici AB, Eliassen AH, Ellberg C, Elvira M, Engel C, Eriksson M, Fasching PA, Figueroa J, Flesch-Janys D, Fletcher O, Flyger H, Fritschi L, Gaborieau V, Gabrielson M, Gago-Dominguez M, Gao YT, Gapstur SM, García-Sáenz JA, Gaudet MM, Georgoulias V, Giles GG, Glendon G, Goldberg MS, Goldgar DE, González-Neira A, Grenaker Alnæs GI, Grip M, Gronwald J, Grundy A, Guénel P, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hamann U, Hamel N, Hankinson S, Harrington P, Hart SN, Hartikainen JM, Hartman M, Hein A, Heyworth J, Hicks B, Hillemanns P, Ho DN, Hollestelle A, Hooning MJ, Hoover RN, Hopper JL, Hou MF, Hsiung CN, Huang G, Humphreys K, Ishiguro J, Ito H, Iwasaki M, Iwata H, Jakubowska A, Janni W, John EM, Johnson N, Jones K, Jones M, Jukkola-Vuorinen A, Kaaks R, Kabisch M, Kaczmarek K, Kang D, Kasuga Y, Kerin MJ, Khan S, Khusnutdinova E, Kiiski JI, Kim SW, Knight JA, Kosma VM, Kristensen VN, Krüger U, Kwong A, Lambrechts D, Le Marchand L, Lee E, Lee MH, Lee JW, Neng Lee C, Lejbkowicz F, Li J, Lilyquist J, Lindblom A, Lissowska J, Lo WY, Loibl S, Long J, Lophatananon A, Lubinski J, Luccarini C, Lux MP, Ma ESK, MacInnis RJ, Maishman T, Makalic E, Malone KE, Kostovska IM, Mannermaa A, Manoukian S, Manson JE, Margolin S, Mariapun S, Martinez ME, Matsuo K, Mavroudis D, McKay J, McLean C, Meijers-Heijboer H, Meindl A, Menéndez P, Menon U, Meyer J, Miao H, Miller N, Taib NAM, Muir K, Mulligan AM, Mulot C, Neuhausen SL, Nevanlinna H, Neven P, Nielsen SF, Noh DY, Nordestgaard BG, Norman A, Olopade OI, Olson JE, Olsson H, Olswold C, Orr N, Pankratz VS, Park SK, Park-Simon TW, Lloyd R, Perez JIA, Peterlongo P, Peto J, Phillips KA, Pinchev M, Plaseska-Karanfilska D, Prentice R, Presneau N, Prokofyeva D, Pugh E, Pylkäs K, Rack B, Radice P, Rahman N, Rennert G, Rennert HS, Rhenius V, Romero A, Romm J, Ruddy KJ, Rüdiger T, Rudolph A, Ruebner M, Rutgers EJT, Saloustros E, Sandler DP, Sangrajrang S, Sawyer EJ, Schmidt DF, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Schumacher F, Schürmann P, Scott RJ, Scott C, Seal S, Seynaeve C, Shah M, Sharma P, Shen CY, Sheng G, Sherman ME, Shrubsole MJ, Shu XO, Smeets A, Sohn C, Southey MC, Spinelli JJ, Stegmaier C, Stewart-Brown S, Stone J, Stram DO, Surowy H, Swerdlow A, Tamimi R, Taylor JA, Tengström M, Teo SH, Beth Terry M, Tessier DC, Thanasitthichai S, Thöne K, Tollenaar RAEM, Tomlinson I, Tong L, Torres D, Truong T, Tseng CC, Tsugane S, Ulmer HU, Ursin G, Untch M, Vachon C, van Asperen CJ, Van Den Berg D, van den Ouweland AMW, van der Kolk L, van der Luijt RB, Vincent D, Vollenweider J, Waisfisz Q, Wang-Gohrke S, Weinberg CR, Wendt C, Whittemore AS, Wildiers H, Willett W, Winqvist R, Wolk A, Wu AH, Xia L, Yamaji T, Yang XR, Har Yip C, Yoo KY, Yu JC, Zheng W, Zheng Y, Zhu B, Ziogas A, Ziv E, ABCTB Investigators, ConFab/AOCS Investigators, Lakhani SR, Antoniou AC, Droit A, Andrulis IL, Amos CI, Couch FJ, Pharoah PDP, Chang-Claude J, Hall P, Hunter DJ, Milne RL, García-Closas M, Schmidt MK, Chanock SJ, Dunning AM, Edwards SL, Bader GD, Chenevix-Trench G, Simard J, Kraft P, Easton DF

Abstract
Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10(-8). The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

PMID: 29059683 [PubMed - as supplied by publisher]



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Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.

Nat Genet. 2017 Oct 23;:

Authors: Milne RL, Kuchenbaecker KB, Michailidou K, Beesley J, Kar S, Lindström S, Hui S, Lemaçon A, Soucy P, Dennis J, Jiang X, Rostamianfar A, Finucane H, Bolla MK, McGuffog L, Wang Q, Aalfs CM, ABCTB Investigators, Adams M, Adlard J, Agata S, Ahmed S, Ahsan H, Aittomäki K, Al-Ejeh F, Allen J, Ambrosone CB, Amos CI, Andrulis IL, Anton-Culver H, Antonenkova NN, Arndt V, Arnold N, Aronson KJ, Auber B, Auer PL, Ausems MGEM, Azzollini J, Bacot F, Balmaña J, Barile M, Barjhoux L, Barkardottir RB, Barrdahl M, Barnes D, Barrowdale D, Baynes C, Beckmann MW, Benitez J, Bermisheva M, Bernstein L, Bignon YJ, Blazer KR, Blok MJ, Blomqvist C, Blot W, Bobolis K, Boeckx B, Bogdanova NV, Bojesen A, Bojesen SE, Bonanni B, Børresen-Dale AL, Bozsik A, Bradbury AR, Brand JS, Brauch H, Brenner H, Bressac-de Paillerets B, Brewer C, Brinton L, Broberg P, Brooks-Wilson A, Brunet J, Brüning T, Burwinkel B, Buys SS, Byun J, Cai Q, Caldés T, Caligo MA, Campbell I, Canzian F, Caron O, Carracedo A, Carter BD, Castelao JE, Castera L, Caux-Moncoutier V, Chan SB, Chang-Claude J, Chanock SJ, Chen X, Cheng TD, Chiquette J, Christiansen H, Claes KBM, Clarke CL, Conner T, Conroy DM, Cook J, Cordina-Duverger E, Cornelissen S, Coupier I, Cox A, Cox DG, Cross SS, Cuk K, Cunningham JM, Czene K, Daly MB, Damiola F, Darabi H, Davidson R, De Leeneer K, Devilee P, Dicks E, Diez O, Ding YC, Ditsch N, Doheny KF, Domchek SM, Dorfling CM, Dörk T, Dos-Santos-Silva I, Dubois S, Dugué PA, Dumont M, Dunning AM, Durcan L, Dwek M, Dworniczak B, Eccles D, Eeles R, Ehrencrona H, Eilber U, Ejlertsen B, Ekici AB, Eliassen AH, EMBRACE, Engel C, Eriksson M, Fachal L, Faivre L, Fasching PA, Faust U, Figueroa J, Flesch-Janys D, Fletcher O, Flyger H, Foulkes WD, Friedman E, Fritschi L, Frost D, Gabrielson M, Gaddam P, Gammon MD, Ganz PA, Gapstur SM, Garber J, Garcia-Barberan V, García-Sáenz JA, Gaudet MM, Gauthier-Villars M, Gehrig A, GEMO Study Collaborators, Georgoulias V, Gerdes AM, Giles GG, Glendon G, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Goodfellow P, Greene MH, Alnæs GIG, Grip M, Gronwald J, Grundy A, Gschwantler-Kaulich D, Guénel P, Guo Q, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hallberg E, Hamann U, Hamel N, Hankinson S, Hansen TVO, Harrington P, Hart SN, Hartikainen JM, Healey CS, HEBON, Hein A, Helbig S, Henderson A, Heyworth J, Hicks B, Hillemanns P, Hodgson S, Hogervorst FB, Hollestelle A, Hooning MJ, Hoover B, Hopper JL, Hu C, Huang G, Hulick PJ, Humphreys K, Hunter DJ, Imyanitov EN, Isaacs C, Iwasaki M, Izatt L, Jakubowska A, James P, Janavicius R, Janni W, Jensen UB, John EM, Johnson N, Jones K, Jones M, Jukkola-Vuorinen A, Kaaks R, Kabisch M, Kaczmarek K, Kang D, Kast K, kConFab/AOCS Investigators, Keeman R, Kerin MJ, Kets CM, Keupers M, Khan S, Khusnutdinova E, Kiiski JI, Kim SW, Knight JA, Konstantopoulou I, Kosma VM, Kristensen VN, Kruse TA, Kwong A, Lænkholm AV, Laitman Y, Lalloo F, Lambrechts D, Landsman K, Lasset C, Lazaro C, Le Marchand L, Lecarpentier J, Lee A, Lee E, Lee JW, Lee MH, Lejbkowicz F, Lesueur F, Li J, Lilyquist J, Lincoln A, Lindblom A, Lissowska J, Lo WY, Loibl S, Long J, Loud JT, Lubinski J, Luccarini C, Lush M, MacInnis RJ, Maishman T, Makalic E, Kostovska IM, Malone KE, Manoukian S, Manson JE, Margolin S, Martens JWM, Martinez ME, Matsuo K, Mavroudis D, Mazoyer S, McLean C, Meijers-Heijboer H, Menéndez P, Meyer J, Miao H, Miller A, Miller N, Mitchell G, Montagna M, Muir K, Mulligan AM, Mulot C, Nadesan S, Nathanson KL, NBSC Collaborators, Neuhausen SL, Nevanlinna H, Nevelsteen I, Niederacher D, Nielsen SF, Nordestgaard BG, Norman A, Nussbaum RL, Olah E, Olopade OI, Olson JE, Olswold C, Ong KR, Oosterwijk JC, Orr N, Osorio A, Pankratz VS, Papi L, Park-Simon TW, Paulsson-Karlsson Y, Lloyd R, Pedersen IS, Peissel B, Peixoto A, Perez JIA, Peterlongo P, Peto J, Pfeiler G, Phelan CM, Pinchev M, Plaseska-Karanfilska D, Poppe B, Porteous ME, Prentice R, Presneau N, Prokofieva D, Pugh E, Pujana MA, Pylkäs K, Rack B, Radice P, Rahman N, Rantala J, Rappaport-Fuerhauser C, Rennert G, Rennert HS, Rhenius V, Rhiem K, Richardson A, Rodriguez GC, Romero A, Romm J, Rookus MA, Rudolph A, Ruediger T, Saloustros E, Sanders J, Sandler DP, Sangrajrang S, Sawyer EJ, Schmidt DF, Schoemaker MJ, Schumacher F, Schürmann P, Schwentner L, Scott C, Scott RJ, Seal S, Senter L, Seynaeve C, Shah M, Sharma P, Shen CY, Sheng X, Shimelis H, Shrubsole MJ, Shu XO, Side LE, Singer CF, Sohn C, Southey MC, Spinelli JJ, Spurdle AB, Stegmaier C, Stoppa-Lyonnet D, Sukiennicki G, Surowy H, Sutter C, Swerdlow A, Szabo CI, Tamimi RM, Tan YY, Taylor JA, Tejada MI, Tengström M, Teo SH, Terry MB, Tessier DC, Teulé A, Thöne K, Thull DL, Tibiletti MG, Tihomirova L, Tischkowitz M, Toland AE, Tollenaar RAEM, Tomlinson I, Tong L, Torres D, Tranchant M, Truong T, Tucker K, Tung N, Tyrer J, Ulmer HU, Vachon C, van Asperen CJ, Van Den Berg D, van den Ouweland AMW, van Rensburg EJ, Varesco L, Varon-Mateeva R, Vega A, Viel A, Vijai J, Vincent D, Vollenweider J, Walker L, Wang Z, Wang-Gohrke S, Wappenschmidt B, Weinberg CR, Weitzel JN, Wendt C, Wesseling J, Whittemore AS, Wijnen JT, Willett W, Winqvist R, Wolk A, Wu AH, Xia L, Yang XR, Yannoukakos D, Zaffaroni D, Zheng W, Zhu B, Ziogas A, Ziv E, Zorn KK, Gago-Dominguez M, Mannermaa A, Olsson H, Teixeira MR, Stone J, Offit K, Ottini L, Park SK, Thomassen M, Hall P, Meindl A, Schmutzler RK, Droit A, Bader GD, Pharoah PDP, Couch FJ, Easton DF, Kraft P, Chenevix-Trench G, García-Closas M, Schmidt MK, Antoniou AC, Simard J

Abstract
Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10(-8) with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

PMID: 29058716 [PubMed - as supplied by publisher]



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A General Strategy for Discovery of Inhibitors and Activators of RING and U-box E3 Ligases with Ubiquitin Variants.

Read Full Article on External Site Related Articles

A General Strategy for Discovery of Inhibitors and Activators of RING and U-box E3 Ligases with Ubiquitin Variants.

Mol Cell. 2017 Oct 19;68(2):456-470.e10

Authors: Gabrielsen M, Buetow L, Nakasone MA, Ahmed SF, Sibbet GJ, Smith BO, Zhang W, Sidhu SS, Huang DT

Abstract
RING and U-box E3 ubiquitin ligases regulate diverse eukaryotic processes and have been implicated in numerous diseases, but targeting these enzymes remains a major challenge. We report the development of three ubiquitin variants (UbVs), each binding selectively to the RING or U-box domain of a distinct E3 ligase: monomeric UBE4B, phosphorylated active CBL, or dimeric XIAP. Structural and biochemical analyses revealed that UbVs specifically inhibited the activity of UBE4B or phosphorylated CBL by blocking the E2∼Ub binding site. Surprisingly, the UbV selective for dimeric XIAP formed a dimer to stimulate E3 activity by stabilizing the closed E2∼Ub conformation. We further verified the inhibitory and stimulatory functions of UbVs in cells. Our work provides a general strategy to inhibit or activate RING/U-box E3 ligases and provides a resource for the research community to modulate these enzymes.

PMID: 29053960 [PubMed - indexed for MEDLINE]



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Reporter-Based Synthetic Genetic Array Analysis: A Functional Genomics Approach for Investigating Transcript or Protein Abundance Using Fluorescent Proteins in Saccharomyces cerevisiae.

Reporter-Based Synthetic Genetic Array Analysis: A Functional Genomics Approach for Investigating Transcript or Protein Abundance Using Fluorescent Proteins in Saccharomyces cerevisiae.

Methods Mol Biol. 2018;1672:613-629

Authors: Göttert H, Mattiazzi Usaj M, Rosebrock AP, Andrews BJ

Abstract
Fluorescent reporter genes have long been used to quantify various cell features such as transcript and protein abundance. Here, we describe a method, reporter synthetic genetic array (R-SGA) analysis, which allows for the simultaneous quantification of any fluorescent protein readout in thousands of yeast strains using an automated pipeline. R-SGA combines a fluorescent reporter system with standard SGA analysis and can be used to examine any array-based strain collection available to the yeast community. This protocol describes the R-SGA methodology for screening different arrays of yeast mutants including the deletion collection, a collection of temperature-sensitive strains for the assessment of essential yeast genes and a collection of inducible overexpression strains. We also present an alternative pipeline for the analysis of R-SGA output strains using flow cytometry of cells in liquid culture. Data normalization for both pipelines is discussed.

PMID: 29043651 [PubMed - in process]



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DNA Replication Profiling Using Deep Sequencing.

DNA Replication Profiling Using Deep Sequencing.

Methods Mol Biol. 2018;1672:195-207

Authors: Saayman X, Ramos-Pérez C, Brown GW

Abstract
Profiling of DNA replication during progression through S phase allows a quantitative snap-shot of replication origin usage and DNA replication fork progression. We present a method for using deep sequencing data to profile DNA replication in S. cerevisiae.

PMID: 29043626 [PubMed - in process]



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Abstracts and Workshops 7th National Spinal Cord Injury Conference November 9 - 11, 2017 Fallsview Casino Resort Niagara Falls, Ontario, Canada.

Abstracts and Workshops 7th National Spinal Cord Injury Conference November 9 - 11, 2017 Fallsview Casino Resort Niagara Falls, Ontario, Canada.

J Spinal Cord Med. 2017 Nov;40(6):813-869

Authors: Shojaei MH, Alavinia M, Craven BC, Cheng CL, Plashkes T, Shen T, Fallah N, Humphreys S, O'Connell C, Linassi AG, Ho C, Short C, Ethans K, Charbonneau R, Paquet J, Noonan VK, Furlan JC, Fehlings MG, Craven BC, Likitlersuang J, Sumitro E, Kalsi-Ryan S, Zariffa J, Wolfe D, Cornell S, Gagliardi J, Marrocco S, Rivers CS, Fallah NN, Noonan VK, Whitehurst D, Schwartz C, Finkelstein J, Craven BC, Ethans K, O'Connell C, Truchon C, Ho C, Linassi AG, Short C, Tsai E, Drew B, Ahn H, Dvorak MF, Paquet J, Fehlings MG, Noreau L, Lenz K, Bailey KA, Allison D, Ditor D, Baron J, Tomasone J, Curran D, Miller T, Grimshaw J, Moineau B, Alizadeh-Meghrazi M, Stefan G, Masani K, Popovic MR, Sumitro E, Likitlersuang J, Kalsi-Ryan S, Zariffa J, Garcia-Garcia MG, Marquez-Chin C, Popovic MR, Furlan JC, Gulasingam S, Craven BC, Furlan JC, Gulasingam S, Craven BC, Khan A, Pujol C, Laylor M, Unic N, Pakosh M, Musselman K, Brisbois LM, Catharine Craven B, Verrier MC, Jones MK, O'Shea R, Valika S, Holtz K, Szefer E, Noonan V, Kwon B, Mills P, Morin C, Harris A, Cheng C, Aspinall A, Plashkes T, Noonan VK, Chan K, Verrier MC, Craven BC, Alappat C, Flett HM, Furlan JC, Musselman KE, Milligan J, Hillier LM, Bauman C, Donaldson L, Lee J, Milligan J, Lee J, Hillier LM, Slonim K, Wolfe D, Sleeth L, Jeske S, Kras-Dupuis A, Marrocco S, McRae S, Flett H, Mokry J, Zee J, Bayley M, Lemay JF, Roy A, Gagnon HD, Jones MK, O'Shea R, Theiss R, Flett H, Guy K, Johnston G, Kokotow M, Mills S, Mokry J, Bain P, Scovil C, Houghton P, Lala D, Orr L, Holyoke P, Wolfe D, Orr L, Brooke J, Holyoke P, Lala D, Houghton P, Martin Ginis KA, Shaw RB, Stork MJ, McBride CB, Furlan JC, Craven BC, Giangregorio L, Hitzig S, Kapadia N, Popovic MR, Zivanovic V, Valiante T, Popovic MR, Patsakos E, Brisbois L, Farahani F, Kaiser A, Craven BC, Patsakos E, Kaiser A, Brisbois L, Farahani F, Craven BC, Mortenson B, MacGillivray M, Mahsa S, Adams J, Sawatzky B, Mills P, Arbour-Nicitopoulos K, Bassett-Gunter R, Leo J, Sharma R, Latimer-Cheung A, Olds T, Martin Ginis K, Graco M, Cross S, Thiyagarajan C, Shafazand S, Ayas N, Schembri R, Booker L, Nicholls C, Burns P, Nash M, Green S, Berlowitz DJ, Taran S, Rocchi M, Martin Ginis KA, Sweet SN, Caron JG, Sweet SN, Rocchi MA, Zelaya W, Sweet SN, Bergquist AJ, Del Castillo-Valenzuela MF, Popovic MR, Masani K, Ethans K, Casey A, Namaka M, Krassiokov-Enns D, Marquez-Chin C, Marquis A, Desai N, Zivanovic V, Hebert D, Popovic MR, Furlan JC, Craven BC, McLeod J, Hicks A, Gauthier C, Arel J, Brosseau R, Hicks AL, Gagnon DH, Nejatbakhsh N, Kaiser A, Hitzig SL, Cappe S, McGillivray C, Singh H, Sam J, Flett H, Craven BC, Verrier M, Musselman K, Koh RGL, Garai P, Zariffa J, Unger J, Oates AR, Arora T, Musselman K, Moshe B, Anthony B, Gulasingam S, Craven BC, Michalovic E, Gainforth HL, Baron J, Graham ID, Sweet SN, Chan B, Craven BC, Wodchis W, Cadarette S, Krahn M, Mittmann N, Chemtob K, Rocchi MA, Arbour-Nicitopoulos K, Kairy D, Sweet SN, Sabetian P, Koh RGL, Zariffa J, Yoo P, Iwasa SN, Babona-Pilipos R, Schneider P, Velayudhan P, Ahmed U, Popovic MR, Morshead CM, Yoo J, Shinya M, Milosevic M, Masani K, Gabison S, Mathur S, Nussbaum E, Popovic M, Verrier MC, Musselman K, Lemay JF, McCullum S, Guy K, Walden K, Zariffa J, Kalsi-Ryan S, Alizadeh-Meghrazi M, Lee J, Milligan J, Smith M, Athanasopoulos P, Jeji T, Howcroft J, Howcroft J, Townson A, Willms R, Plashkes T, Mills S, Flett H, Scovil C, Mazzella F, Morris H, Ventre A, Loh E, Guy S, Kramer J, Jeji T, Xia N, Mehta S, Martin Ginis KA, McBride CB, Shaw RB, West C, Ethans K, O'Connell C, Charlifue S, Gagnon DH, Escalona Castillo MJ, Vermette M, Carvalho LP, Karelis A, Kairy D, Aubertin-Leheudre M, Duclos C, Houghton PE, Orr L, Holyoke P, Kras-Dupuis A, Wolfe D, Munro B, Sweeny M, Craven BC, Flett H, Hitzig S, Farahani F, Alavinia SM, Omidvar M, Bayley M, Sweet SN, Gassaway J, Shaw R, Hong M, Everhart-Skeels S, Houlihan B, Burns A, Bilsky G, Lanig I, Graco M, Cross S, Thiyagarajan C, Shafazand S, Ayas N, Schembri R, Booker L, Nicholls C, Burns P, Nash M, Green S, Berlowitz D, Furlan JC, Kalsi-Ryan S

PMID: 29034821 [PubMed - in process]



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Emerging and evolving concepts in gene essentiality.

Related Articles

Emerging and evolving concepts in gene essentiality.

Nat Rev Genet. 2017 Oct 16;:

Authors: Rancati G, Moffat J, Typas A, Pavelka N

Abstract
Gene essentiality is a founding concept of genetics with important implications in both fundamental and applied research. Multiple screens have been performed over the years in bacteria, yeasts, animals and more recently in human cells to identify essential genes. A mounting body of evidence suggests that gene essentiality, rather than being a static and binary property, is both context dependent and evolvable in all kingdoms of life. This concept of a non-absolute nature of gene essentiality changes our fundamental understanding of essential biological processes and could directly affect future treatment strategies for cancer and infectious diseases.

PMID: 29033457 [PubMed - as supplied by publisher]



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Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition.

Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition.

Elife. 2017 Oct 13;6:

Authors: Mahadevan V, Khademullah CS, Dargaei Z, Chevrier J, Uvarov P, Kwan J, Bagshaw RD, Pawson T, Emili A, De Koninck Y, Anggono V, Airaksinen M, Woodin MA

Abstract
KCC2 is a neuron-specific K(+)-Cl(-) cotransporter essential for establishing the Cl(-) gradient required for hyperpolarizing inhibition in the central nervous system (CNS). KCC2 is highly localized to excitatory synapses where it regulates spine morphogenesis and AMPA receptor confinement. Aberrant KCC2 function contributes to human neurological disorders including epilepsy and neuropathic pain. Using functional proteomics, we identified the KCC2-interactome in the mouse brain to determine KCC2-protein interactions that regulate KCC2 function. Our analysis revealed that KCC2 interacts with diverse proteins, and its most predominant interactors play important roles in postsynaptic receptor recycling. The most abundant KCC2 interactor is a neuronal endocytic regulatory protein termed PACSIN1 (SYNDAPIN1). We verified the PACSIN1-KCC2 interaction biochemically and demonstrated that shRNA knockdown of PACSIN1 in hippocampal neurons increases KCC2 expression and hyperpolarizes the reversal potential for Cl(-). Overall, our global native-KCC2 interactome and subsequent characterization revealed PACSIN1 as a novel and potent negative regulator of KCC2.

PMID: 29028184 [PubMed - in process]



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The Anti-CRISPR Story: A Battle for Survival.

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The Anti-CRISPR Story: A Battle for Survival.

Mol Cell. 2017 Oct 05;68(1):8-14

Authors: Maxwell KL

Abstract
The last decade has seen the fields of molecular biology and genetics transformed by the development of CRISPR-based gene editing technologies. These technologies were derived from bacterial defense systems that protect against viral invasion. Elegant studies focused on the evolutionary battle between CRISPR-encoding bacteria and the viruses that infect and kill them revealed the next step in this arms race, the anti-CRISPR proteins. Investigation of these proteins has provided important new insight into how CRISPR-Cas systems work and how bacterial genomes evolve. They have also led to the development of important biotechnological tools that can be used for genetic engineering, including off switches for CRISPR-Cas9 genome editing in human cells.

PMID: 28985512 [PubMed - indexed for MEDLINE]



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A panel of synthetic antibodies that selectively recognize and antagonize members of the interferon alpha family.

A panel of synthetic antibodies that selectively recognize and antagonize members of the interferon alpha family.

Protein Eng Des Sel. 2017 Aug 30;:1-8

Authors: Miersch S, Kuruganti S, Walter MR, Sidhu SS

Abstract
The 12 distinct subtypes that comprise the interferon alpha (IFNα) family of cytokines possess anti-viral, anti-proliferative and immunomodulatory activities. They are implicated in the etiology and progression of many diseases, and also used as therapeutic agents for viral and oncologic disorders. However, a deeper understanding of their role in disease is limited by a lack of tools to evaluate single subtypes at the protein level. Antibodies that selectively inhibit single IFNα subtypes could enable interrogation of each protein in biological samples and could be used for characterization and treatment of disease. Using phage-displayed synthetic antibody libraries, we have conducted selections against 12 human IFNα subtypes to explore our ability to obtain fine-specificity antibodies that recognize and antagonize the biological signals induced by a single IFNα subtype. For the first time, we have isolated antibodies that specifically recognize individual IFNα subtypes (IFNα2a/b, IFNα6, IFNα8b and IFNα16) with high affinity that antagonize signaling. Our results show that highly specific antibodies capable of distinguishing between closely related cytokines can be isolated from synthetic libraries and can be used to characterize cytokine abundance and function.

PMID: 28981904 [PubMed - as supplied by publisher]



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