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News

Source code: Putting metagenomics to the test in the clinic pp645 - 648

Carrie Arnold

doi:10.1038/nm0617-645


Biased for benefit: Stimulating the world's most popular drug targets with more nuance pp649 - 651

Dyani Lewis

doi:10.1038/nm0617-649


Viral vanguard: Designing cancer-killing viruses to chase metastatic tumors pp652 - 655

Shraddha Chakradhar

doi:10.1038/nm0617-652


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News and Views

Understanding cancer from the stem cells up pp656 - 657

Christopher A Eide & Brian J Druker

doi:10.1038/nm.4353

A new study that uses an integrated single-cell transcriptomics approach to characterize cancer stem cell populations during treatment with molecularly targeted therapies offers insights into disease evolution and points to new therapeutic targets.

See also: Article by Giustacchini et al.


A role for neutrophils in asthma exacerbations pp658 - 659

William W Busse

doi:10.1038/nm.4351

A recent study has found that rhinovirus-induced exacerbation of asthma is in part mediated by the release of neutrophil extracellular traps and double-stranded DNA by neutrophils in the airway.

See also: Article by Toussaint et al.


Patrolling monocytes sense peripheral infection and induce cytokine-mediated neuronal dysfunction pp659 - 661

Josef Priller & Chotima Böttcher

doi:10.1038/nm.4349

A new study reveals that virus-associated activation of a subset of circulating monocytes results in the release of the proinflammatory cytokine tumor necrosis factor (TNF)-α, which induces increased turnover of synapses in the brain and learning deficits in mice.

See also: Article by Garré et al.


The cannabis paradox: when age matters pp661 - 662

Andrés Ozaita & Ester Aso

doi:10.1038/nm.4348

New evidence in mouse models reveals that exposure to Δ9-tetrahydrocannabinol (THC), the main psychoactive component in Cannabis sativa, might improve cognitive performance in aging animals.

See also: Letter by Bilkei-Gorzo et al.


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Perspective

Biology and evolution of poorly differentiated neuroendocrine tumors pp664 - 673

David S Rickman, Himisha Beltran, Francesca Demichelis & Mark A Rubin

doi:10.1038/nm.4341

Rubin and colleagues discuss the origin and evolution of poorly differentiated neuroendocrine tumors, and highlight potential new therapeutic strategies.


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Brief Communications

Metformin ameliorates core deficits in a mouse model of fragile X syndrome pp674 - 677

Ilse Gantois, Arkady Khoutorsky, Jelena Popic, Argel Aguilar-Valles, Erika Freemantle, Ruifeng Cao, Vijendra Sharma, Tine Pooters, Anmol Nagpal, Agnieszka Skalecka, Vinh T Truong, Shane Wiebe, Isabelle A Groves, Seyed Mehdi Jafarnejad, Clément Chapat, Elizabeth A McCullagh, Karine Gamache, Karim Nader, Jean-Claude Lacaille, Christos G Gkogkas & Nahum Sonenberg

doi:10.1038/nm.4335

Metformin treatment for 10 d rescues several behavioral deficits related to fragile X syndrome in adult Fmr1/y mice.


Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer's disease pp678 - 680

Alice D Lam, Gina Deck, Alica Goldman, Emad N Eskandar, Jeffrey Noebels & Andrew J Cole

doi:10.1038/nm.4330

Using intracranial electrode recordings in two individuals with Alzheimer's disease, Lam et al. discover hippocampal seizure activity that could not be detected by traditional EEG monitoring.


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Articles

Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation pp681 - 691

Marie Toussaint, David J Jackson, Dawid Swieboda, Anabel Guedán, Theodora-Dorita Tsourouktsoglou, Yee Man Ching, Coraline Radermecker, Heidi Makrinioti, Julia Aniscenko, Michael R Edwards, Roberto Solari, Frédéric Farnir, Venizelos Papayannopoulos, Fabrice Bureau, Thomas Marichal & Sebastian L Johnston

doi:10.1038/nm.4332

Targeting NETosis alleviates type-2 immunopathology induced by rhinovirus infection in a mouse model of airway hypersensitivity, and correlative data suggest that a similar mechanism may operate in human rhinovirus-exacerbated asthma.

See also: News and Views by Busse


Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia pp692 - 702

Alice Giustacchini, Supat Thongjuea, Nikolaos Barkas, Petter S Woll, Benjamin J Povinelli, Christopher A G Booth, Paul Sopp, Ruggiero Norfo, Alba Rodriguez-Meira, Neil Ashley, Lauren Jamieson, Paresh Vyas, Kristina Anderson, Åsa Segerstolpe, Hong Qian, Ulla Olsson-Strömberg, Satu Mustjoki, Rickard Sandberg, Sten Eirik W Jacobsen & Adam J Mead

doi:10.1038/nm.4336

Applying a new, more sensitive single-cell transcriptomics method to diagnosis, remission and progression samples from patients with chronic myeloid leukemia reveals insight into the heterogeneity of cells that resist treatment with targeted therapy, as well as into the dynamics of disease progression and its effects on nontransformed hematopoietic stem cells.

See also: News and Views by Eide & Druker


Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients pp703 - 713

Ahmet Zehir, Ryma Benayed, Ronak H Shah, Aijazuddin Syed, Sumit Middha, Hyunjae R Kim, Preethi Srinivasan, Jianjiong Gao, Debyani Chakravarty, Sean M Devlin, Matthew D Hellmann, David A Barron, Alison M Schram, Meera Hameed, Snjezana Dogan, Dara S Ross, Jaclyn F Hechtman, Deborah F DeLair, JinJuan Yao, Diana L Mandelker, Donavan T Cheng, Raghu Chandramohan, Abhinita S Mohanty, Ryan N Ptashkin, Gowtham Jayakumaran, Meera Prasad, Mustafa H Syed, Anoop Balakrishnan Rema, Zhen Y Liu, Khedoudja Nafa, Laetitia Borsu, Justyna Sadowska, Jacklyn Casanova, Ruben Bacares, Iwona J Kiecka, Anna Razumova, Julie B Son, Lisa Stewart, Tessara Baldi, Kerry A Mullaney, Hikmat Al-Ahmadie, Efsevia Vakiani, Adam A Abeshouse, Alexander V Penson, Philip Jonsson, Niedzica Camacho, Matthew T Chang, Helen H Won, Benjamin E Gross, Ritika Kundra, Zachary J Heins, Hsiao-Wei Chen, Sarah Phillips, Hongxin Zhang, Jiaojiao Wang, Angelica Ochoa, Jonathan Wills, Michael Eubank, Stacy B Thomas, Stuart M Gardos, Dalicia N Reales, Jesse Galle, Robert Durany, Roy Cambria, Wassim Abida, Andrea Cercek, Darren R Feldman, Mrinal M Gounder, A Ari Hakimi, James J Harding, Gopa Iyer, Yelena Y Janjigian, Emmet J Jordan, Ciara M Kelly, Maeve A Lowery, Luc G T Morris, Antonio M Omuro, Nitya Raj, Pedram Razavi, Alexander N Shoushtari, Neerav Shukla, Tara E Soumerai, Anna M Varghese, Rona Yaeger, Jonathan Coleman, Bernard Bochner, Gregory J Riely, Leonard B Saltz, Howard I Scher, Paul J Sabbatini, Mark E Robson, David S Klimstra, Barry S Taylor, Jose Baselga, Nikolaus Schultz, David M Hyman, Maria E Arcila, David B Solit, Marc Ladanyi & Michael F Berger

doi:10.1038/nm.4333

MSK-IMPACT is a clinical sequencing platform able to detect genomic mutations, copy number alterations and structural variants in a panel of cancer-related genes. This assay is implemented prospectively to inform patient enrollment in genomically matched clinical trials at Memorial Sloan Kettering Cancer Center (MSKCC). Sequencing results of tumor and matched normal tissue from a cohort of >10,000 patients with detailed clinical annotation provide an overview of the genomic landscape of advanced solid cancers and bring new insights into molecularly guided cancer therapy.


CX3CR1+ monocytes modulate learning and learning-dependent dendritic spine remodeling via TNF-α pp714 - 722

Juan Mauricio Garré, Hernandez Moura Silva, Juan J Lafaille & Guang Yang

doi:10.1038/nm.4340

In a rodent model of viral infection, immune activation causes impairments in motor-learning-dependent cortical synaptic remodeling that are mediated by peripheral monocytes rather than by CNS-resident microglia.

See also: News and Views by Priller & Böttcher


MAFB prevents excess inflammation after ischemic stroke by accelerating clearance of damage signals through MSR1 pp723 - 732

Takashi Shichita, Minako Ito, Rimpei Morita, Kyoko Komai, Yoshiko Noguchi, Hiroaki Ooboshi, Ryusuke Koshida, Satoru Takahashi, Tatsuhiko Kodama & Akihiko Yoshimura

doi:10.1038/nm.4312

The scavenger receptor MSR1 contributes to the clearance of damage-associated molecular patterns (DAMPs) by infiltrating myeloid cells in the post-stroke rodent brain. Myeloid cell MSR1 deficiency impairs clearance and exacerbates stroke-induced impairments, whereas a pharmacological intervention to boost MSR1 expression improves pathological and functional outcomes.


Pericytes impair capillary blood flow and motor function after chronic spinal cord injury pp733 - 741

Yaqing Li, Ana M Lucas-Osma, Sophie Black, Mischa V Bandet, Marilee J Stephens, Romana Vavrek, Leo Sanelli, Keith K Fenrich, Antonio F Di Narzo, Stella Dracheva, Ian R Winship, Karim Fouad & David J Bennett

doi:10.1038/nm.4331

In rat models of spinal cord injury, the region of the spinal cord below the site of injury becomes hypoxic owing to inadequate blood flow. This effect on blood flow is due to increased production of neurotransmitters known as ‘trace amines,’ which act on pericytes to constrict blood vessels. Alleviation of hypoxia by hyperoxic breathing or inhibition of trace amine synthesis or action improves locomotor function in the injured rats.


Tmbim1 is a multivesicular body regulator that protects against non-alcoholic fatty liver disease in mice and monkeys by targeting the lysosomal degradation of Tlr4 pp742 - 752

Guang-Nian Zhao, Peng Zhang, Jun Gong, Xiao-Jing Zhang, Pi-Xiao Wang, Miao Yin, Zhou Jiang, Li-Jun Shen, Yan-Xiao Ji, Jingjing Tong, Yutao Wang, Qiao-Fang Wei, Yong Wang, Xue-Yong Zhu, Xin Zhang, Jing Fang, Qingguo Xie, Zhi-Gang She, Zhihua Wang, Zan Huang & Hongliang Li

doi:10.1038/nm.4334

Toll-like receptor (TLR) 4 is a key mediator of non-alcoholic fatty liver disease progression. Targeting TLR4 degradation via the lysosome pathway improves outcome in mouse and monkey models of this condition.


Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction pp753 - 762

Weier Qi, Hillary A Keenan, Qian Li, Atsushi Ishikado, Aimo Kannt, Thorsten Sadowski, Mark A Yorek, I-Hsien Wu, Samuel Lockhart, Lawrence J Coppey, Anja Pfenninger, Chong Wee Liew, Guifen Qiang, Alison M Burkart, Stephanie Hastings, David Pober, Christopher Cahill, Monika A Niewczas, William J Israelsen, Liane Tinsley, Isaac E Stillman, Peter S Amenta, Edward P Feener, Matthew G Vander Heiden, Robert C Stanton & George L King

doi:10.1038/nm.4328

Studying patients with long-term diabetes who lack diabetic nephropathy reveals that targeting pyruvate kinase M2 protects against renal disease.


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Letters

A live-attenuated Zika virus vaccine candidate induces sterilizing immunity in mouse models pp763 - 767

Chao Shan, Antonio E Muruato, Bruno T D Nunes, Huanle Luo, Xuping Xie, Daniele B A Medeiros, Maki Wakamiya, Robert B Tesh, Alan D Barrett, Tian Wang, Scott C Weaver, Pedro F C Vasconcelos, Shannan L Rossi & Pei-Yong Shi

doi:10.1038/nm.4322

Pei-Yong Shi and colleagues report that a deletion mutant of Zika virus is safe and effective as a live-attenuated vaccine in mice and induces sterilizing immunity. Their results encourage further testing of the candidate vaccine for possible future use in humans.


Decreased alertness due to sleep loss increases pain sensitivity in mice pp768 - 774

Chloe Alexandre, Alban Latremoliere, Ashley Ferreira, Giulia Miracca, Mihoko Yamamoto, Thomas E Scammell & Clifford J Woolf

doi:10.1038/nm.4329

In mice, sleep loss increases sensitivity to painful stimuli. Restoration of normal sleep or acute treatment with wake-promoting agents can normalize pain sensitivities.


Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment pp775 - 781

Ok Hee Jeon, Chaekyu Kim, Remi-Martin Laberge, Marco Demaria, Sona Rathod, Alain P Vasserot, Jae Wook Chung, Do Hun Kim, Yan Poon, Nathaniel David, Darren J Baker, Jan M van Deursen, Judith Campisi & Jennifer H Elisseeff

doi:10.1038/nm.4324

Pharmacological or genetic depletion of senescent cells in the joint ameliorates osteoarthritis in mice.


A chronic low dose of Δ9-tetrahydrocannabinol (THC) restores cognitive function in old mice pp782 - 787

Andras Bilkei-Gorzo, Onder Albayram, Astrid Draffehn, Kerstin Michel, Anastasia Piyanova, Hannah Oppenheimer, Mona Dvir-Ginzberg, Ildiko Rácz, Thomas Ulas, Sophie Imbeault, Itai Bab, Joachim L Schultze & Andreas Zimmer

doi:10.1038/nm.4311

In mice aged 12–18 months, chronic administration of low-dose Δ9-tetrahydrocannabinol (THC) improves performance in behavioral learning and memory tasks, whereas a similar administration in younger mice (aged 2 months) impairs performance.

See also: News and Views by Ozaita & Aso


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Corrigendum

Corrigendum: SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia p788

Constanze Schneider, Thomas Oellerich, Hanna-Mari Baldauf, Sarah-Marie Schwarz, Dominique Thomas, Robert Flick, Hanibal Bohnenberger, Lars Kaderali, Lena Stegmann, Anjali Cremer, Margarethe Martin, Julian Lohmeyer, Martin Michaelis, Veit Hornung, Christoph Schliemann, Wolfgang E Berdel, Wolfgang Hartmann, Eva Wardelmann, Federico Comoglio, Martin-Leo Hansmann, Alexander F Yakunin, Gerd Geisslinger, Philipp Ströbel, Nerea Ferreirós, Hubert Serve, Oliver T Keppler & Jindrich Cinatl Jr

doi:10.1038/nm0617-788a


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Errata

Erratum: PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer p788

Fara Brasó-Maristany, Simone Filosto, Steven Catchpole, Rebecca Marlow, Jelmar Quist, Erika Francesch-Domenech, Darren A Plumb, Leila Zakka, Patrycja Gazinska, Gianmaria Liccardi, Pascal Meier, Albert Gris-Oliver, Maggie Chon U Cheang, Anna Perdrix-Rosell, Manar Shafat, Elodie Noël, Nirmesh Patel, Kristen McEachern, Maurizio Scaltriti, Pau Castel, Farzana Noor, Richard Buus, Sumi Mathew, Johnathan Watkins, Violeta Serra, Pierfrancesco Marra, Anita Grigoriadis & Andrew N Tutt

doi:10.1038/nm0617-788b


Erratum: Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents p788

Nicole E Burma, Robert P Bonin, Heather Leduc-Pessah, Corey Baimel, Zoe F Cairncross, Michael Mousseau, Jhenkruthi Vijaya Shankara, Patrick L Stemkowski, Dinara Baimoukhametova, Jaideep S Bains, Michael C Antle, Gerald W Zamponi, Catherine M Cahill, Stephanie L Borgland, Yves DeKoninck & Tuan Trang

doi:10.1038/nm0617-788c


Erratum: Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor–neutralizing therapy in patients with inflammatory bowel disease p788

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, Oxford IBD Cohort Investigators, Satish Keshav, Simon P L Travis & Fiona Powrie

doi:10.1038/nm0617-788d


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