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Institution

Howard Hughes Medical Institute

NonprofitChevy Chase, Maryland, United States
About: Howard Hughes Medical Institute is a nonprofit organization based out in Chevy Chase, Maryland, United States. It is known for research contribution in the topics: Gene & RNA. The organization has 20371 authors who have published 34677 publications receiving 5247143 citations. The organization is also known as: HHMI & hhmi.org.


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Journal ArticleDOI
TL;DR: In this article, a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B.
Abstract: We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 x 10(12) vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of approximately 8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression.

1,930 citations

Journal ArticleDOI
TL;DR: A practical guide to using smFRET, focusing on the study of immobilized molecules that allow measurements of single-molecule reaction trajectories from 1 ms to many minutes, is provided.
Abstract: Single-molecule fluorescence resonance energy transfer (smFRET) is one of the most general and adaptable single-molecule techniques. Despite the explosive growth in the application of smFRET to answer biological questions in the last decade, the technique has been practiced mostly by biophysicists. We provide a practical guide to using smFRET, focusing on the study of immobilized molecules that allow measurements of single-molecule reaction trajectories from 1 ms to many minutes. We discuss issues a biologist must consider to conduct successful smFRET experiments, including experimental design, sample preparation, single-molecule detection and data analysis. We also describe how a smFRET-capable instrument can be built at a reasonable cost with off-the-shelf components and operated reliably using well-established protocols and freely available software.

1,929 citations

Journal ArticleDOI
28 Apr 2011-Nature
TL;DR: It is shown that different viruses are targeted by unique sets of ISGs, and that each viral species is susceptible to multiple antiviral genes, which together encompass a range of inhibitory activities.
Abstract: The type I interferon response protects cells against invading viral pathogens. The cellular factors that mediate this defence are the products of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified since their discovery more than 25 years ago, only a few have been characterized with respect to antiviral activity. For most ISG products, little is known about their antiviral potential, their target specificity and their mechanisms of action. Using an overexpression screening approach, here we show that different viruses are targeted by unique sets of ISGs. We find that each viral species is susceptible to multiple antiviral genes, which together encompass a range of inhibitory activities. To conduct the screen, more than 380 human ISGs were tested for their ability to inhibit the replication of several important human and animal viruses, including hepatitis C virus, yellow fever virus, West Nile virus, chikungunya virus, Venezuelan equine encephalitis virus and human immunodeficiency virus type-1. Broadly acting effectors included IRF1, C6orf150 (also known as MB21D1), HPSE, RIG-I (also known as DDX58), MDA5 (also known as IFIH1) and IFITM3, whereas more targeted antiviral specificity was observed with DDX60, IFI44L, IFI6, IFITM2, MAP3K14, MOV10, NAMPT (also known as PBEF1), OASL, RTP4, TREX1 and UNC84B (also known as SUN2). Combined expression of pairs of ISGs showed additive antiviral effects similar to those of moderate type I interferon doses. Mechanistic studies uncovered a common theme of translational inhibition for numerous effectors. Several ISGs, including ADAR, FAM46C, LY6E and MCOLN2, enhanced the replication of certain viruses, highlighting another layer of complexity in the highly pleiotropic type I interferon system.

1,926 citations

Journal ArticleDOI
07 Nov 1986-Cell
TL;DR: Results are consistent with a function for P-glycoprotein as an energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.

1,914 citations

Journal ArticleDOI
Paul Bastard1, Paul Bastard2, Paul Bastard3, Lindsey B. Rosen4, Qian Zhang2, Eleftherios Michailidis2, Hans-Heinrich Hoffmann2, Yu Zhang4, Karim Dorgham3, Quentin Philippot3, Quentin Philippot1, Jérémie Rosain3, Jérémie Rosain1, Vivien Béziat3, Vivien Béziat1, Vivien Béziat2, Jeremy Manry1, Jeremy Manry3, Elana Shaw4, Liis Haljasmägi5, Pärt Peterson5, Lazaro Lorenzo1, Lazaro Lorenzo3, Lucy Bizien1, Lucy Bizien3, Sophie Trouillet-Assant6, Kerry Dobbs4, Adriana Almeida de Jesus4, Alexandre Belot6, Anne Kallaste7, Emilie Catherinot, Yacine Tandjaoui-Lambiotte1, Jérémie Le Pen2, Gaspard Kerner3, Gaspard Kerner1, Benedetta Bigio2, Yoann Seeleuthner1, Yoann Seeleuthner3, Rui Yang2, Alexandre Bolze, András N Spaan8, András N Spaan2, Ottavia M. Delmonte4, Michael S. Abers4, Alessandro Aiuti9, Giorgio Casari9, Vito Lampasona9, Lorenzo Piemonti9, Fabio Ciceri9, Kaya Bilguvar10, Richard P. Lifton10, Richard P. Lifton2, Marc Vasse, David M. Smadja3, Mélanie Migaud1, Mélanie Migaud3, Jérôme Hadjadj3, Benjamin Terrier3, Darragh Duffy11, Lluis Quintana-Murci12, Lluis Quintana-Murci11, Diederik van de Beek13, Lucie Roussel14, Donald C. Vinh14, Stuart G. Tangye15, Stuart G. Tangye16, Filomeen Haerynck17, David Dalmau18, Javier Martinez-Picado19, Javier Martinez-Picado20, Petter Brodin21, Petter Brodin22, Michel C. Nussenzweig23, Michel C. Nussenzweig2, Stéphanie Boisson-Dupuis3, Stéphanie Boisson-Dupuis2, Stéphanie Boisson-Dupuis1, Carlos Rodríguez-Gallego, Guillaume Vogt3, Trine H. Mogensen24, Trine H. Mogensen25, Andrew J. Oler4, Jingwen Gu4, Peter D. Burbelo4, Jeffrey I. Cohen4, Andrea Biondi26, Laura Rachele Bettini26, Mariella D'Angiò26, Paolo Bonfanti26, Patrick Rossignol27, Julien Mayaux3, Frédéric Rieux-Laucat3, Eystein S. Husebye28, Eystein S. Husebye29, Eystein S. Husebye30, Francesca Fusco, Matilde Valeria Ursini, Luisa Imberti31, Alessandra Sottini31, Simone Paghera31, Eugenia Quiros-Roldan32, Camillo Rossi, Riccardo Castagnoli33, Daniela Montagna33, Amelia Licari33, Gian Luigi Marseglia33, Xavier Duval, Jade Ghosn3, Hgid Lab4, Covid Clinicians5, Covid-Storm Clinicians§4, CoV-Contact Cohort§3, Amsterdam Umc Covid Biobank1, Amsterdam Umc Covid Biobank2, Amsterdam Umc Covid Biobank3, Covid Human Genetic Effort2, John S. Tsang4, Raphaela Goldbach-Mansky4, Kai Kisand5, Michail S. Lionakis4, Anne Puel2, Anne Puel1, Anne Puel3, Shen-Ying Zhang2, Shen-Ying Zhang3, Shen-Ying Zhang1, Steven M. Holland4, Guy Gorochov3, Emmanuelle Jouanguy1, Emmanuelle Jouanguy3, Emmanuelle Jouanguy2, Charles M. Rice2, Aurélie Cobat1, Aurélie Cobat3, Aurélie Cobat2, Luigi D. Notarangelo4, Laurent Abel3, Laurent Abel2, Laurent Abel1, Helen C. Su4, Jean-Laurent Casanova 
23 Oct 2020-Science
TL;DR: A means by which individuals at highest risk of life-threatening COVID-19 can be identified is identified, and the hypothesis that neutralizing auto-Abs against type I IFNs may underlie critical CO VID-19 is tested.
Abstract: Interindividual clinical variability in the course of SARS-CoV-2 infection is immense. We report that at least 101 of 987 patients with life-threatening COVID-19 pneumonia had neutralizing IgG auto-Abs against IFN-ω (13 patients), the 13 types of IFN-α (36), or both (52), at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1,227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 were men. A B cell auto-immune phenocopy of inborn errors of type I IFN immunity underlies life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

1,913 citations


Authors

Showing all 20486 results

NameH-indexPapersCitations
Bert Vogelstein247757332094
Richard A. Flavell2311328205119
Steven A. Rosenberg2181204199262
Kenneth W. Kinzler215640243944
Robert J. Lefkowitz214860147995
Rob Knight2011061253207
Irving L. Weissman2011141172504
Ronald M. Evans199708166722
Francis S. Collins196743250787
Craig B. Thompson195557173172
Thomas C. Südhof191653118007
Joan Massagué189408149951
Stuart H. Orkin186715112182
John P. A. Ioannidis1851311193612
Eric R. Kandel184603113560
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Performance
Metrics
No. of papers from the Institution in previous years
YearPapers
202330
2022228
20211,583
20201,587
20191,591
20181,394