Advance online publication
The latest research papers, published online ahead of print. These online versions are definitive and may be cited using the digital object identifier (DOI).
About advance online publicationArticles
A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q– syndrome
Jillian L Barlow, Lesley F Drynan, Duncan R Hewett, Luke R Holmes, Silvia Lorenzo-Abalde, Alison L Lane, Helen E Jolin, Richard Pannell, Angela J Middleton, See Heng Wong, Alan J Warren, James S Wainscoat, Jacqueline Boultwood & Andrew N J McKenzie
Published online: 22 November 2009 | doi:10.1038/nm.2063
In individuals with 5q– syndrome, deletion within chromosome 5q is associated with hematological abnormalities. Jillian Barlow et al. now create an animal model of the disease using chromosomal engineering to remove a corresponding region of the mouse genome. The resulting hematological abnormalities resemble those in the human disease, and the authors provide genetic evidence that p53 activation contributes to the disease process.
Abstract - | Full Text - A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q– syndrome | PDF (1,348 KB) - A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q– syndrome | Supplementary information
A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6–dependent B cell lymphomas
Leandro C Cerchietti, Eloisi C Lopes, Shao Ning Yang, Katerina Hatzi, Karen L Bunting, Lucas A Tsikitas, Alka Mallik, Ana I Robles, Jennifer Walling, Lyuba Varticovski, Rita Shaknovich, Kapil N Bhalla, Gabriela Chiosis & Ari Melnick
Published online: 22 November 2009 | doi:10.1038/nm.2059
By taking advantage of the direct interaction between heat shock protein 90 (Hsp90) and the transcriptional repressor Bcl-6, a purine-derived inhibitor of Hsp90 selectively kills diffuse large B cell lymphomas that depend on the expression of Bcl-6 for their survival.
Abstract - | Full Text - A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6–dependent B cell lymphomas | PDF (1,117 KB) - A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6–dependent B cell lymphomas | Supplementary information
Enhanced tonic GABAA inhibition in typical absence epilepsy
David W Cope,
Giuseppe Di Giovanni,
Sarah J Fyson,
Gergely Orbán,
Adam C Errington,
Magor L L
rincz,
Timothy M Gould,
David A Carter
&
Vincenzo Crunelli
Published online: 22 November 2009 | doi:10.1038/nm.2058
Contrary to the widely held view that impaired 
-aminobutyric acid (GABA)-mediated neurotransmission underlies epileptic activity, extrasynaptic GABA-dependent thalamocortical inhibition caused by reduced GABA uptake is reported to be increased in diverse models of absence seizures.
Abstract - | Full Text - Enhanced tonic GABAA inhibition in typical absence epilepsy | PDF (901 KB) - Enhanced tonic GABAA inhibition in typical absence epilepsy | Supplementary information
Commensal bacteria regulate Toll-like receptor 3–dependent inflammation after skin injury
Yuping Lai, Anna Di Nardo, Teruaki Nakatsuji, Anke Leichtle, Yan Yang, Anna L Cogen, Zi-Rong Wu, Lora V Hooper, Richard R Schmidt, Sonja von Aulock, Katherine A Radek, Chun-Ming Huang, Allen F Ryan & Richard L Gallo
Published online: 22 November 2009 | doi:10.1038/nm.2062
Gallo and his colleagues report that commensal bacteria on the skin help to dampen inflammation caused by skin injury in mice. They show that, after wounding, necrotic cells release RNA that triggers TLR3 on keratinocytes, causing inflammatory cytokine release. Commensal bacteria in the skin suppress this inflammatory response through triggering TLR2 on the keratinocytes.
Abstract - | Full Text - Commensal bacteria regulate Toll-like receptor 3–dependent inflammation after skin injury | PDF (720 KB) - Commensal bacteria regulate Toll-like receptor 3–dependent inflammation after skin injury | Supplementary information
Role of NMDA receptor–dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries
Changiz Taghibiglou, Henry G S Martin, Ted Weita Lai, Taesup Cho, Shiv Prasad, Luba Kojic, Jie Lu, Yitao Liu, Edmund Lo, Shu Zhang, Julia Z Z Wu, Yu Ping Li, Yan Hua Wen, Joon-Hyuk Imm, Max S Cynader & Yu Tian Wang
Published online: 22 November 2009 | doi:10.1038/nm.2064
Excitotoxicity mediated by over activation of glutamate receptors results in neuronal loss after ischemia. Activation of sterol regulatory element–binding protein-1 is now shown to be crucial for glutamate-mediated excitotoxic neuronal death in a mouse model of stroke.
Abstract - | Full Text - Role of NMDA receptor–dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries | PDF (1,487 KB) - Role of NMDA receptor–dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries | Supplementary information
Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin
Shu-ichi Okamoto, Mahmoud A Pouladi, Maria Talantova, Dongdong Yao, Peng Xia, Dagmar E Ehrnhoefer, Rameez Zaidi, Arjay Clemente, Marcus Kaul, Rona K Graham, Dongxian Zhang, H-S Vincent Chen, Gary Tong, Michael R Hayden & Stuart A Lipton
Published online: 15 November 2009 | doi:10.1038/nm.2056
In a mouse model of Huntington's disease, synaptic activation of NMDA receptors induces the formation of huntingtin-containing inclusions, rendering neurons more resistant to death in vivo and in vitro. In contrast, stimulation of extrasynaptic NMDA receptors increases neuronal vulnerability by preventing inclusion formation.
Abstract - | Full Text - Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin | PDF (941 KB) - Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin | Supplementary information
Synovial fibroblasts spread rheumatoid arthritis to unaffected joints
Stephanie Lefèvre, Anette Knedla, Christoph Tennie, Andreas Kampmann, Christina Wunrau, Robert Dinser, Adelheid Korb, Eva-Maria Schnäker, Ingo H Tarner, Paul D Robbins, Christopher H Evans, Henning Stürz, Jürgen Steinmeyer, Steffen Gay, Jürgen Schölmerich, Thomas Pap, Ulf Müller-Ladner & Elena Neumann
Published online: 08 November 2009 | doi:10.1038/nm.2050
Rheumatoid arthritis usually begins in one joint but spreads to other joints as the disease progresses. Elena Neumann and her colleagues show that rheumatoid arthritis synovial fibroblasts (RASFs) may be key mediators of this process. They show, using a SCID mouse model, that human RASFs can migrate long distances through the bloodstream from diseased cartilage to unaffected cartilage, where they can mount a new attack.
Abstract - | Full Text - Synovial fibroblasts spread rheumatoid arthritis to unaffected joints | PDF (1,001 KB) - Synovial fibroblasts spread rheumatoid arthritis to unaffected joints | Supplementary information
Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype
Daniel T Starczynowski, Florian Kuchenbauer, Bob Argiropoulos, Sandy Sung, Ryan Morin, Andrew Muranyi, Martin Hirst, Donna Hogge, Marco Marra, Richard A Wells, Rena Buckstein, Wan Lam, R Keith Humphries & Aly Karsan
Published online: 08 November 2009 | doi:10.1038/nm.2054
For myelodysplastic syndromes caused by deletion of chromosome 5q, Daniel Starczynowski et al. provide evidence that decreased expression of two miRNAs in this region—miR-145 and miR-146a—contributes to abnormal megakaryocyte differentiation and platelet production and progression of the disease to either bone marrow failure or leukemia. The authors also provide a mechanistic explanation for these effects by which loss of these two miRNAs leads to derepression of innate immune signaling.
Abstract - | Full Text - Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype | PDF (1,288 KB) - Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype | Supplementary information
Letter
Modulating hedgehog signaling can attenuate the severity of osteoarthritis
Alvin C Lin, Brian L Seeto, Justyna M Bartoszko, Michael A Khoury, Heather Whetstone, Louisa Ho, Claire Hsu, Amanda S Ali & Benjamin A Alman
Published online: 15 November 2009 | doi:10.1038/nm.2055
In a new report, Benjamin Alman and his colleagues find that the morphogenic pathway activated by Hedgehog signaling is a key mediator of osteoarthritis, a condition that is marked by irreversible degeneration of the joints and with no current treatment. They also found that blockade of Hedgehog signaling prevented osteoarthritis in a mouse model, suggesting this pathway as a possible target to treat this devastating disease.
Abstract - | Full Text - Modulating hedgehog signaling can attenuate the severity of osteoarthritis | PDF (1,028 KB) - Modulating hedgehog signaling can attenuate the severity of osteoarthritis | Supplementary information
Technical Report
Comprehensive genomic access to vector integration in clinical gene therapy
Richard Gabriel, Ralph Eckenberg, Anna Paruzynski, Cynthia C Bartholomae, Ali Nowrouzi, Anne Arens, Steven J Howe, Alessandra Recchia, Claudia Cattoglio, Wei Wang, Katrin Faber, Kerstin Schwarzwaelder, Romy Kirsten, Annette Deichmann, Claudia R Ball, Kamaljit S Balaggan, Rafael J Yáñez-Muñoz, Robin R Ali, H Bobby Gaspar, Luca Biasco, Alessandro Aiuti, Daniela Cesana, Eugenio Montini, Luigi Naldini, Odile Cohen-Haguenauer, Fulvio Mavilio, Adrian J Thrasher, Hanno Glimm, Christof von Kalle, William Saurin & Manfred Schmidt
Published online: 22 November 2009 | doi:10.1038/nm.2057
Adverse events stemming from the use of retroviral vectors in humans has prompted the search for methods predicting the fate and biological consequences of gene-modified cells after vector insertion. Methods of integration site analysis, such as linear amplification-mediated PCR (LAM-PCR), rely on use of restriction enzymes and identify only a fraction of all genomic integrants. This report describes a non–restriction enzyme–based LAM-PCR technique that provides comprehensive, unbiased integration site analysis.
First Paragraph - | Full Text - Comprehensive genomic access to vector integration in clinical gene therapy | PDF (824 KB) - Comprehensive genomic access to vector integration in clinical gene therapy | Supplementary information
Until print versions of AOP papers are published, they should be cited in the style "Author(s) Nature Medicine advance online publication, day month year (doi:10.1038/nmXXXXX)". Once the print version (identical to the AOP) is published, it should be cited as follows: "Author(s) Nature Medicine volume, page (year); advance online publication, (doi:10.1038/nmXXXXX)".
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