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Experience EMBO'S transparent peer-review |  | | |  | TABLE OF CONTENTS
| May 2012 Volume 18, Issue 5 |  | | |  |  Focus
Podcast
Editorial
News
Book Review
Correspondence
News and Views
Community Corner
Between Bedside and Bench
Research Highlights
Reviews
Articles
Letters
Technical Reports | | | Advertisement | | | | 
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Focus on Asthma
This special issue of Nature Medicine features a collection of review articles that highlight recent advances in our understanding of asthma and point to the future directions in this dynamic area of research.
www.nature.com/nm/focus/asthma
Produced with support from:
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Almirall, S.A. | | | | | Nature Medicine Podcast |  Top | |  | | With bated breath
Asthma unraveled, why hospital staph infections are so deadly and the latest on future treatments for sudden-onset hearing loss.
Listen Now | | | Editorial | Top | | | | A fresh perspective on asthma p631
doi:10.1038/nm.2777
Abstract | Full Text | PDF | | News | Top | | | | Hopes soar as cholesterol plummets with new drug class p633
David Holmes
doi:10.1038/nm0512-633
Full Text | PDF | | | | Malaria subsidy pilot soars, but some see turbulence ahead pp634 - 635
Amy Maxmen
doi:10.1038/nm0512-634
Full Text | PDF | | | | Biologic drugs set to top 2012 sales p636
doi:10.1038/nm0512-636a
Full Text | PDF | | | | Targeting hypoxia brings breath of fresh air to cancer therapy pp636 - 637
Melinda Wenner Moyer
doi:10.1038/nm0512-636b
Full Text | PDF | | | | Billions of dollars for research at stake in health-reform case p637
John Otrompke
doi:10.1038/nm0512-637
Full Text | PDF | | | | New biologic drugs get under the skin of psoriasis p638
Sarah C P Williams
doi:10.1038/nm0512-638
Full Text | PDF | | | | | Q&A | | | | Straight talk with...Chen Zhu p639
doi:10.1038/nm0512-639
In April, China's Minister of Health Chen Zhu and his mentor, Wang Zhen-yi of the Shanghai Jiao Tong University School of Medicine, received the Albert Szent-Györgi Prize from the Washington, DC-based National Foundation for Cancer Research, in recognition for their work on acute promyelocytic leukemia. On that occasion, Victoria Aranda and Roxanne Khamsi asked Chen about his plans for cancer research and for improving stem cell regulation in China.
Abstract | Full Text | PDF | | | | | News in Brief | | | | Biomedical briefing pp640 - 641
doi:10.1038/nm0512-640
Full Text | PDF | | | | | News Features | | | | Sound medicine pp642 - 645
Elie Dolgin
doi:10.1038/nm0512-642
Everyone from rock stars to nonagenarians experiences hearing loss, but no drugs have ever been approved specifically to prevent or treat this problem. Recently, a handful of drug companies have started to make some noise, with a number of experimental compounds now in human trials. Elie Dolgin sounds off on what could be a multibillion dollar market.
Full Text | PDF | | | | Innermost desires p644
doi:10.1038/nm0512-644
Full Text | PDF | | | | | Opinion | | | | The WHO must reform for its own health p646
Tikki Pang and Laurie Garrett
doi:10.1038/nm0512-646
The World Health Organization (WHO) is facing an unprecedented crisis that threatens its position as the premier international health agency. To ensure its leading role, it must rethink its internal governance and revamp its financing mechanisms.
Full Text | PDF | | Book Review | Top | | | | Founding a new field p647
David Nathan reviews Dreams & Due Diligence: Till and McCulloch's Stem Cell Discovery and Legacy by Joe Sornberger
doi:10.1038/nm.2751
Full Text | PDF | | Correspondence | Top | | | | Activation of BK channels may not be required for bitter tastant-induced bronchodilation pp648 - 650
Cheng-Hai Zhang, Chen Chen, Lawrence M Lifshitz, Kevin E Fogarty, Min-Sheng Zhu and Ronghua ZhuGe
doi:10.1038/nm.2733
Full Text | PDF | | | | Reply to: TAS2R-activation of BKca is essential for maximal physiological response in human airway smooth muscle pp650 - 651
Steven S An, Kathryn S Robinett, Deepak A Deshpande, Wayne C H Wang and Stephen B Liggett
doi:10.1038/nm.2734
Full Text | PDF | | News and Views | Top | | | | | | Community Corner | Top | | | | A step closer to effective transplant tolerance? pp664 - 665
doi:10.1038/nm.2770
Full Text | PDF | | Between Bedside and Bench | Top | | | | Topic: Guts over glory[mdash]why diets fail pp666 - 667
Rachel Larder and Stephen O'Rahilly
doi:10.1038/nm.2747
Losing weight can pose a challenge, but how to avoid putting those pounds back on can be a real struggle. A major health problem for obese people is that diseases linked to obesity, such as type 2 diabetes and cardiovascular disease, put their lives at risk, even in young individuals. Although bariatric surgery[mdash]a surgical method to reduce or modify the gastrointestinal tract[mdash]was originally envisioned for the most severe cases of obesity, evidence suggests that the benefit of this procedure may not be limited to the staggering weight loss it causes. Endogenous factors released from the gut, and modified after surgery, may explain why bariatric surgery can be beneficial for obesity-related diseases and why operated individuals successfully maintain the weight loss. In 'Bedside to Bench,' Rachel Larder and Stephen O'Rahilly peruse a human study with dieters who regained weight despite a successful diet. Appetite-regulating hormones in the gut may be responsible for this relapse in the long term. In 'Bench to Bedside,' Keval Chandarana and Rachel Batterham examine how two different methods of bariatric surgery highlight the relevance of gut-derived hormones not only in inducing sustained weight loss but also in improving glucose homeostasis. These insights may open new avenues to bypass the surgery and obtain the same results with targeted drugs.
Full Text | PDF | | | | Topic: Metabolic insights from cutting the gut pp668 - 669
Keval Chandarana and Rachel L Batterham
doi:10.1038/nm.2748
Losing weight can pose a challenge, but how to avoid putting those pounds back on can be a real struggle. A major health problem for obese people is that diseases linked to obesity, such as type 2 diabetes and cardiovascular disease, put their lives at risk, even in young individuals. Although bariatric surgery[mdash]a surgical method to reduce or modify the gastrointestinal tract[mdash]was originally envisioned for the most severe cases of obesity, evidence suggests that the benefit of this procedure may not be limited to the staggering weight loss it causes. Endogenous factors released from the gut, and modified after surgery, may explain why bariatric surgery can be beneficial for obesity-related diseases and why operated individuals successfully maintain the weight loss. In 'Bedside to Bench,' Rachel Larder and Stephen O'Rahilly peruse a human study with dieters who regained weight despite a successful diet. Appetite-regulating hormones in the gut may be responsible for this relapse in the long term. In 'Bench to Bedside,' Keval Chandarana and Rachel Batterham examine how two different methods of bariatric surgery highlight the relevance of gut-derived hormones not only in inducing sustained weight loss but also in improving glucose homeostasis. These insights may open new avenues to bypass the surgery and obtain the same results with targeted drugs.
Full Text | PDF | | Research Highlights | Top | | | | Bone: Repairing joints | Metabolism: Calcium-mediated control | Brain: Bouncing back after brain injury | Cardiovascular disease: Lipoprotein traffic control | Immunology: Targeting IL-17 in psoriasis | New from NPG | | | Reviews | Top | | | | Innate and adaptive immune responses in asthma pp673 - 683
Stephen T Holgate
doi:10.1038/nm.2731
Allergen sensitization is triggered by activating receptors of the innate arm of the immune system. This leads to the recruitment and activation of dendritic cells, which have a sentinel role in orchestrating the attendant adaptive response. Stephen Holgate highlights recent findings on how innate receptors are triggered, cellular sources of cytokines driving immune cell activation and the identification of new helper T cell subsets driving chronic allergic airway inflammation.
Abstract | Full Text | PDF | | | | The airway epithelium in asthma pp684 - 692
Bart N Lambrecht and Hamida Hammad
doi:10.1038/nm.2737
The airway epithelium has a sentinel role in initiating allergic responses and asthma. Bart Lambrecht and Hamida Hammad review recent findings on how allergens activate epithelial cells and induce the production of cytokines and chemokines that recruit and activate dendritic cells and other cells of the innate immune system. Activation of these cell types promotes adaptive immune responses, which are, the authors argue, further maintained and perpetuated by their interaction with airway epithelial cells.
Abstract | Full Text | PDF | | | | IgE and mast cells in allergic disease pp693 - 704
Stephen J Galli and Mindy Tsai
doi:10.1038/nm.2755
Both mast cells and IgE play crucial parts during the initiation and amplification of the allergic response during asthma, as well as during the tissue remodeling that occurs at the chronic stage. This review discusses how these two players can affect the development of asthma through independent and interdependent functions and the therapeutic implications for treating the clinical symptoms derived from allergic disease.
Abstract | Full Text | PDF | | | | T cell homing to epithelial barriers in allergic disease pp705 - 715
Sabina A Islam and Andrew D Luster
doi:10.1038/nm.2760
Efficient trafficking of lymphocytes between the blood, lymphoid organs and peripheral tissues is essential for an effective immune response. Sabina Islam and Andrew Luster summarize recent findings on the regulation of leukocyte homing to the lungs, gut and skin in allergic inflammation and how leukocyte trafficking can be targeted clinically.
Abstract | Full Text | PDF | | | | Asthma phenotypes: the evolution from clinical to molecular approaches pp716 - 725
Sally E Wenzel
doi:10.1038/nm.2678
The growing appreciation of asthma as a heterogeneous disease has led to the concept that asthma consists of multiple, different phenotypes, but now the challenge is to link underlying biology to phenotypes to allow a more robust classification and understanding of asthma. This review discusses the progress in defining asthma phenotypes and provides insights into how to apply this knowledge to provide more personalized approaches to treating asthma.
Abstract | Full Text | PDF | | | | Viral infections and atopy in asthma pathogenesis: new rationales for asthma prevention and treatment pp726 - 735
Patrick G Holt and Peter D Sly
doi:10.1038/nm.2768
Viral infections can worsen episodes of allergic sensitization to allergens, putting the affected individuals, often children, at risk for developing persistent asthma during adult life. Understanding how the mechanisms mediating the antiviral response and driving allergic inflammation caused by allergens interact is crucial. This will provide insights into when and what player or molecule to target for treatment and prevention of asthma in children at the early stages of the disease.
Abstract | Full Text | PDF | | | | Therapies for allergic inflammation: refining strategies to induce tolerance pp736 - 749
Cezmi A Akdis
doi:10.1038/nm.2754
This review outlines recent advances in the development of therapeutics that induce immune tolerance to treat asthma and allergic disease. It focuses on the distinct approaches of allergen-specific immunotherapy and biological immune modifiers and also highlights the possibility of combining these two strategies to harness the advantages of both types of therapy and address current unmet clinical needs associated with these conditions.
Abstract | Full Text | PDF | | | Articles | Top | | | | Interleukin-25 induces type 2 cytokine production in a steroid-resistant interleukin-17RB+ myeloid population that exacerbates asthmatic pathology pp751 - 758
Bryan C Petersen, Alison L Budelsky, Alan P Baptist, Matthew A Schaller and Nicholas W Lukacs
doi:10.1038/nm.2735
Interleukin-25 (IL-25) is released from lung epithelial cells in response to allergen challenge and promotes type 2 immune responses and allergic airway inflammation. Nicholas Lukacs and his colleagues now report that IL-25 acts on a myeloid population in the lung. These cells represent a major source of IL-4 and IL-13, promote allergic lung inflammation and are steroid resistant. The frequency of IL-4- and IL-13-producing myeloid cells is increased in individuals with asthma, suggesting these cells may have a crucial role in the development of asthma.
Abstract | Full Text | PDF | | | | Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury pp759 - 765
Mohammad Naimul Islam, Shonit R Das, Memet T Emin, Michelle Wei, Li Sun, Kristin Westphalen, David J Rowlands, Sadiqa K Quadri, Sunita Bhattacharya and Jahar Bhattacharya
doi:10.1038/nm.2736
Bone-marrow-derived stromal cells are known to protect against acute lung injury. Jahar Bhattacharya and colleagues now show that one way these cells offer such protection is to transfer their mitochondria to the injured lung epithelia to improve the bioenergetics of the recipient cells, thus probably allowing them to recover from injury more efficiently.
Abstract | Full Text | PDF | | | | RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing pp766 - 773
Wei Guo, Sebastian Schafer, Marion L Greaser, Michael H Radke, Martin Liss, Thirupugal Govindarajan, Henrike Maatz, Herbert Schulz, Shijun Li, Amanda M Parrish, Vita Dauksaite, Padmanabhan Vakeel, Sabine Klaassen, Brenda Gerull, Ludwig Thierfelder, Vera Regitz-Zagrosek, Timothy A Hacker, Kurt W Saupe, G William Dec, Patrick T Ellinor, Calum A MacRae, Bastian Spallek, Robert Fischer, Andreas Perrot, Cemil Ozcelik, Kathrin Saar, Norbert Hubner and Michael Gotthardt
doi:10.1038/nm.2693
Alternative splicing affects the function of many cardiac proteins, including that of the sarcomeric protein titin. Wei Guo et al. now show that the gene RBM20, previously identified as mutated in some individuals with dilated cardiomyopathy, is a splicing factor that regulates the alternative splicing of the gene encoding titin and many other key cardiac genes.
Abstract | Full Text | PDF | | | | Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia pp774 - 782
Tobias Eckle, Katherine Hartmann, Stephanie Bonney, Susan Reithel, Michel Mittelbronn, Lori A Walker, Brian D Lowes, Jun Han, Christoph H Borchers, Peter M Buttrick, Douglas J Kominsky, Sean P Colgan and Holger K Eltzschig
doi:10.1038/nm.2728
Tobias Eckle et al. describe a new regulatory circuit in the heart by which adenosine receptor signaling controls expression of the circadian protein Per2, which stabilizes the transcription factor Hif-1[alpha], promotes glycolytic metabolism and has cardioprotective effects. Exposing mice to intense light was able to stabilize Per2 in the heart and reduce cardiac injury after myocardial ischemia.
Abstract | Full Text | PDF | | | | Nuclear accumulation of HDAC4 in ATM deficiency promotes neurodegeneration in ataxia telangiectasia pp783 - 790
Jiali Li, Jianmin Chen, Christopher L Ricupero, Ronald P Hart, Melanie S Schwartz, Alexander Kusnecov and Karl Herrup
doi:10.1038/nm.2709
Ataxia-telangiectasia is a multifaceted disease that includes motor dysfunction caused by neuron death in the cerebellum. Now, Karl Herrup and colleagues report that ATM, the gene that is lost in the disease, keeps HDAC4 out of the nucleus and in the cytoplasm to maintain cerebellar neuron health.
Abstract | Full Text | PDF | | | | NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components pp791 - 798
Sarah L Doyle, Matthew Campbell, Ema Ozaki, Robert G Salomon, Andres Mori, Paul F Kenna, Gwyneth Jane Farrar, Anna-Sophia Kiang, Marian M Humphries, Ed C Lavelle, Luke A J O'Neill, Joe G Hollyfield and Peter Humphries
doi:10.1038/nm.2717
Age-related macular degeneration is a blinding disease associated with accumulation of aggregates called drusen in the retina. Now, Matthew Campbell and colleagues show that drusen can activate the inflammasome and that this activation protects against disease progression.
Abstract | Full Text | PDF | | | | Lethal inflammasome activation by a multidrug-resistant pathobiont upon antibiotic disruption of the microbiota pp799 - 806
Janelle S Ayres, Norver J Trinidad and Russell E Vance
doi:10.1038/nm.2729
The maintenance of a normal intestinal microbiota is associated with gut integrity and healthy immune responses. In this issue, Janelle Ayres and her colleagues report that disruption of the gut microbiome with antibiotics, coupled with gut injury, leads to the outgrowth of a pathogenic commensal bacterium and a sepsis-like disease. Their results show that the Naip5-Nlrc4 inflammasome is crucial for sensing the pathobiont and is a key factor in triggering the disease phenotype.
Abstract | Full Text | PDF | | | | Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer pp807 - 815
Elena Provasi, Pietro Genovese, Angelo Lombardo, Zulma Magnani, Pei-Qi Liu, Andreas Reik, Victoria Chu, David E Paschon, Lei Zhang, Jurgen Kuball, Barbara Camisa, Attilio Bondanza, Giulia Casorati, Maurilio Ponzoni, Fabio Ciceri, Claudio Bordignon, Philip D Greenberg, Michael C Holmes, Philip D Gregory, Luigi Naldini and Chiara Bonini
doi:10.1038/nm.2700
Engineered T cells expressing a tumor antigen specific T cell receptor (TCR) have shown promise for cancer immunotherapy. However, the introduced TCR chains can pair with the endogenous TCR chains in T cells, and in mice, these mismatched TCRs can cause a lethal autoimmune reaction. Provasi et al. now show that they can eliminate expression of the endogenous TCR chains using zinc finger nucleases and express only the desired exogenous TCR by lentiviral transduction. The resultant TCR-edited lymphocytes showed tumor specificity without the risk of off-target toxicity.
Abstract | Full Text | PDF | | Letters | Top | | | | MRSA epidemic linked to a quickly spreading colonization and virulence determinant pp816 - 819
Min Li, Xin Du, Amer E Villaruz, Binh An Diep, Decheng Wang, Yan Song, Yueru Tian, Jinhui Hu, Fangyou Yu, Yuan Lu and Michael Otto
doi:10.1038/nm.2692
A mobile genetic element[mdash]sasX[mdash]has a key role in the pathogenesis of methicillin-resistant Staphylococcus aureus (MRSA) infection. This rapidly spreading determinant of MRSA pathogenic success markedly enhances nasal colonization, lung disease and immune evasion.
First paragraph | Full Text | PDF | | | | Leptin action through hypothalamic nitric oxide synthase-1-expressing neurons controls energy balance pp820 - 823
Rebecca L Leshan, Megan Greenwald-Yarnell, Christa M Patterson, Ian E Gonzalez and Martin G Myers Jr
doi:10.1038/nm.2724
The adipocyte-derived hormone leptin acts on the brain to signal the long-term status of energy balance in the body. Martin Myers and his colleagues narrow down the population of neurons in the brain that actuate leptin's effects on food intake, and thus systemic energy balance, to a relatively small percentage of Nos1+ cells in the hypothalamus.
First paragraph | Full Text | PDF | | Technical Reports | Top | | | | Unbiased identification of target antigens of CD8+ T cells with combinatorial libraries coding for short peptides pp824 - 828
Katherina Siewert, Joachim Malotka, Naoto Kawakami, Hartmut Wekerle, Reinhard Hohlfeld and Klaus Dornmair
doi:10.1038/nm.2720
Finding new methods to define the target antigens recognized by MHC class I-restricted T cells is an unmet need. Katherina Siewert and her colleagues have developed a sensitive technique based on recombinatorial plasmid screening of T cell receptors (TCRs) isolated from individual T cells that overcomes many of the current limitations and enables the characterization of T cell antigens from most T cells, including those isolated from frozen biopsy samples by laser microdissection. The approach was validated using a well-characterized influenza virus-specific TCR, MHC and peptide combination.
Abstract | Full Text | PDF | | | | A brain tumor molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle pp829 - 834
Moritz F Kircher, Adam de la Zerda, Jesse V Jokerst, Cristina L Zavaleta, Paul J Kempen, Erik Mittra, Ken Pitter, Ruimin Huang, Carl Campos, Frezghi Habte, Robert Sinclair, Cameron W Brennan, Ingo K Mellinghoff, Eric C Holland and Sanjiv S Gambhir
doi:10.1038/nm.2721
The ability to effectively assess tumor margins for brain tumor resection is a crucial factor in determining outcome in patients with brain tumors. Moritz Kircher and colleagues have developed a gold-silica nanoparticle that provides a triple-mode imaging capability of magnetic resonance, photoacoustic and Raman imaging, capitalizing on the complementary strengths of each modality for noninvasively delineating brain tumor margins both preoperatively and intraoperatively. The approach was tested in several mouse models, including one that recapitulates the infiltrating growth pattern of human gliomas.
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