Current issue


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Editorial

The curse of uncertainty p527

doi:10.1038/nm.4342

Proposed US budget cuts and the impending exit of the UK from the European Union have the potential to destabilize the global biomedical-research enterprise. In the meantime, the uncertainty of not knowing just how bad the effects will be will inflict its own damage.


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News

Host with the most: Targeting host cells instead of pathogens to fight infectious disease pp528 - 531

Amanda B. Keener

doi:10.1038/nm0517-528


Bringing RNA into the fold: Small molecules find new targets in RNA to combat disease pp532 - 534

Shraddha Chakradhar

doi:10.1038/nm0517-532


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Correction

Correction p534

doi:10.1038/nm0517-534


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News and Views

A role for oncostatin M in inflammatory bowel disease pp535 - 536

Walter M Kim, Arthur Kaser & Richard S Blumberg

doi:10.1038/nm.4338

A new study identifies oncostatin M (OSM) as a potential biomarker and therapeutic target for anti-tumor necrosis factor (TNF)-refractory inflammatory bowel disease (IBD), and pinpoints mucosal stromal cells as key players in OSM-mediated inflammation.

See also: Article by West et al.


Thymosin α1: a single drug with multiple targets in cystic fibrosis pp536 - 538

André M Cantin & John W Hanrahan

doi:10.1038/nm.4339

A new study in mice suggests that a single drug, thymosin α1, may simultaneously rectify the impaired trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) in cystic fibrosis (CF) and reduce inflammation, offering new hope for CF treatment.

See also: Article by Romani et al.


HIV persistence in macrophages pp538 - 539

Mario Stevenson

doi:10.1038/nm.4337

A recent study using a humanized mouse model shows that HIV-1 can persist in macrophages during antiretroviral therapy (ART), and suggests that macrophages may represent an obstacle to efforts to cure HIV-1 infection.

See also: Letter by Honeycutt et al.


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Perspective

Is autoimmunity the Achilles' heel of cancer immunotherapy? pp540 - 547

Carl H June, Jeremy T Warshauer & Jeffrey A Bluestone

doi:10.1038/nm.4321

In this Perspective, June, Bluestone and Warshauer discuss potential cellular and molecular explanations for the autoimmunity often associated with immunotherapy, and propose additional research and changes to reporting practices to aid efforts to understand and minimize these toxic side effects.


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Brief Communications

Diagnosis of Zika virus infection on a nanotechnology platform pp548 - 550

Bo Zhang, Benjamin A Pinsky, Jeyarama S Ananta, Su Zhao, Shylaja Arulkumar, Hao Wan, Malaya K Sahoo, Janaki Abeynayake, Jesse J Waggoner, Clay Hopes, Meijie Tang & Hongjie Dai

doi:10.1038/nm.4302

Antibody-based diagnosis of Zika virus (ZIKV) infection is complicated by cross-reactivity with antibodies against dengue virus. Hongjie Dai and colleagues report their development of a new IgA- and IgG-based diagnostic test that detects ZIKV with high specificity.


VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer pp551 - 555

Jianjun Gao, John F Ward, Curtis A Pettaway, Lewis Z Shi, Sumit K Subudhi, Luis M Vence, Hao Zhao, Jianfeng Chen, Hong Chen, Eleni Efstathiou, Patricia Troncoso, James P Allison, Christopher J Logothetis, Ignacio I Wistuba, Manuel A Sepulveda, Jingjing Sun, Jennifer Wargo, Jorge Blando & Padmanee Sharma

doi:10.1038/nm.4308

Prostate cancer is refractory to anti-CTLA-4 therapy, but the reason why is unclear. Padmanee Sharma and colleagues report that the inhibitory molecule VISTA, which negatively regulates T cells, is upregulated on macrophages in prostate tumors that have been treated with anti-CTLA-4 and may play a role in resistance to this immunotherapy.


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Articles

Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance pp556 - 567

Donnele Daley, Vishnu R Mani, Navyatha Mohan, Neha Akkad, Atsuo Ochi, Daniel W Heindel, Ki Buom Lee, Constantinos P Zambirinis, Gautam SD Balasubramania Pandian, Shivraj Savadkar, Alejandro Torres-Hernandez, Shruti Nayak, Ding Wang, Mautin Hundeyin, Brian Diskin, Berk Aykut, Gregor Werba, Rocky M Barilla, Robert Rodriguez, Steven Chang, Lawrence Gardner, Lara K Mahal, Beatrix Ueberheide & George Miller

doi:10.1038/nm.4314

Activation of dectin-1-dependent signaling in macrophages through ligation by galectin 9 promotes an immunosuppressive, protumorigenic microenvironment in pancreatic adenocarcinoma (PDA). Blocking dectin 1 ligation restores anti-tumor immunity and delays tumor growth, thus offering a novel strategy for improving the effectiveness of immunotherapy in patients with PDA.


A stemness-related ZEB1–MSRB3 axis governs cellular pliancy and breast cancer genome stability pp568 - 578

Anne-Pierre Morel, Christophe Ginestier, Roxane M Pommier, Olivier Cabaud, Emmanuelle Ruiz, Julien Wicinski, Mojgan Devouassoux-Shisheboran, Valérie Combaret, Pascal Finetti, Christelle Chassot, Christiane Pinatel, Frédérique Fauvet, Pierre Saintigny, Emilie Thomas, Caroline Moyret-Lalle, Joël Lachuer, Emmanuelle Despras, Jean-Luc Jauffret, François Bertucci, Jérôme Guitton, Anne Wierinckx, Qing Wang, Nina Radosevic-Robin, Frédérique Penault-Llorca, David G Cox, Frédéric Hollande, Stéphane Ansieau, Julie Caramel, Daniel Birnbaum, Arnaud M Vigneron, Agnès Tissier, Emmanuelle Charafe-Jauffret & Alain Puisieux

doi:10.1038/nm.4323

During malignant transformation, the ability of mammary epithelial cells to cope with oncogene-induced DNA damage and avoid chromosomal instability is determined by stemness-related expression of the canonical epithelial-to-mesenchymal transition transcription factor ZEB1 and its target MSRB3, a methionine sulfoxide reductase involved in antioxidant defense.


Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor–neutralizing therapy in patients with inflammatory bowel disease pp579 - 589

Nathaniel R West, Ahmed N Hegazy, Benjamin M J Owens, Samuel J Bullers, Bryan Linggi, Sofia Buonocore, Margherita Coccia, Dieter Görtz, Sébastien This, Krista Stockenhuber, Johanna Pott, Matthias Friedrich, Grigory Ryzhakov, Frédéric Baribaud, Carrie Brodmerkel, Constanze Cieluch, Nahid Rahman, Gerhard Müller-Newen, Raymond J Owens, Anja A Kühl, Kevin J Maloy, Scott E Plevy, Carolina Arancibia, Adam Bailey, Ellie Barnes, Beth Bird-Lieberman, Oliver Brain, Barbara Braden, Jane Collier, James East, Lucy Howarth, Satish Keshav, Paul Klenerman, Simon Leedham, Rebecca Palmer, Fiona Powrie, Astor Rodrigues, Alison Simmons, Peter Sullivan, Simon P L Travis, Holm Uhlig, Oxford IBD Cohort Investigators, Satish Keshav, Simon P L Travis & Fiona Powrie

doi:10.1038/nm.4307

The cytokine oncostatin M drives intestinal inflammation in mice, and its abundance in the intestine of patients with inflammatory bowel disease predicts response to tumor necrosis factor–neutralizing therapy.

See also: News and Views by Kim et al.


Thymosin α1 represents a potential potent single-molecule-based therapy for cystic fibrosis pp590 - 600

Luigina Romani, Vasilis Oikonomou, Silvia Moretti, Rossana G Iannitti, Maria Cristina D'Adamo, Valeria R Villella, Marilena Pariano, Luigi Sforna, Monica Borghi, Marina M Bellet, Francesca Fallarino, Maria Teresa Pallotta, Giuseppe Servillo, Eleonora Ferrari, Paolo Puccetti, Guido Kroemer, Mauro Pessia, Luigi Maiuri, Allan L Goldstein & Enrico Garaci

doi:10.1038/nm.4305

Thymosin α1 is used in the clinic as a treatment in viral disease and acts as an anti-inflammatory. Here it was found to also correct the misfolding of mutant CTFR and potentiate its activity, thus improving outcome in a mouse model of cystic fibrosis.

See also: News and Views by Cantin & Hanrahan


Marginal zone B cells control the response of follicular helper T cells to a high-cholesterol diet pp601 - 610

Meritxell Nus, Andrew P Sage, Yuning Lu, Leanne Masters, Brian Y H Lam, Stephen Newland, Sandra Weller, Dimitrios Tsiantoulas, Juliette Raffort, Damiënne Marcus, Alison Finigan, Lauren Kitt, Nichola Figg, Reinhold Schirmbeck, Manfred Kneilling, Giles S H Yeo, Christoph J Binder, José Luis de la Pompa & Ziad Mallat

doi:10.1038/nm.4315

Splenic marginal zone B cells suppress atherosclerosis in mice by dampening the proatherogenic T follicular helper response via a PDL1-dependent interaction with T follicular helper cells.


A heart–brain–kidney network controls adaptation to cardiac stress through tissue macrophage activation pp611 - 622

Katsuhito Fujiu, Munehiko Shibata, Yukiteru Nakayama, Fusa Ogata, Sahohime Matsumoto, Koji Noshita, Shingo Iwami, Susumu Nakae, Issei Komuro, Ryozo Nagai & Ichiro Manabe

doi:10.1038/nm.4326

The ability of the heart to withstand pressure overload, as occurs in heart failure, depends on a multi-organ circuit, in which sympathetic activation of the kidney leads to release of the cytokine CSF2 into the circulation, stimulating cardiac-resident macrophages that protect the heart.


Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis pp623 - 630

Katrin Fischer, Henry H Ruiz, Kevin Jhun, Brian Finan, Douglas J Oberlin, Verena van der Heide, Anastasia V Kalinovich, Natasa Petrovic, Yochai Wolf, Christoffer Clemmensen, Andrew C Shin, Senad Divanovic, Frank Brombacher, Elke Glasmacher, Susanne Keipert, Martin Jastroch, Joachim Nagler, Karl-Werner Schramm, Dasa Medrikova, Gustav Collden, Stephen C Woods, Stephan Herzig, Dirk Homann, Steffen Jung, Jan Nedergaard, Barbara Cannon, Matthias H Tschöp, Timo D Müller & Christoph Buettner

doi:10.1038/nm.4316

In contrast to previously reported findings, M2-like polarized macrophages are not a source of catecholamines and do not contribute to browning of the fat.


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Letters

The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue pp631 - 637

Matthew D Lynes, Luiz O Leiria, Morten Lundh, Alexander Bartelt, Farnaz Shamsi, Tian Lian Huang, Hirokazu Takahashi, Michael F Hirshman, Christian Schlein, Alexandra Lee, Lisa A Baer, Francis J May, Fei Gao, Niven R Narain, Emily Y Chen, Michael A Kiebish, Aaron M Cypess, Matthias Blüher, Laurie J Goodyear, Gökhan S Hotamisligil, Kristin I Stanford & Yu-Hua Tseng

doi:10.1038/nm.4297

Cold stimulation induces the synthesis and release of the lipid species 12,13-diHOME from brown adipose tissue. This ‘lipokine’ then acts on brown adipocytes to promote the uptake of fatty acids to fuel this cell type's heat production.


HIV persistence in tissue macrophages of humanized myeloid-only mice during antiretroviral therapy pp638 - 643

Jenna B Honeycutt, William O Thayer, Caroline E Baker, Ruy M Ribeiro, Steven M Lada, Youfang Cao, Rachel A Cleary, Michael G Hudgens, Douglas D Richman & J Victor Garcia

doi:10.1038/nm.4319

Persistence of HIV is attributed primarily to latent infection of CD4+ T cells. Honeycutt et al. report that in humanized mice lacking T cells HIV can rebound from myeloid cells after antiretroviral treatment interruption, suggesting that persistence of HIV could involve other cell types.

See also: News and Views by Stevenson


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